TW202313618A - Wee1 inhibitors and methods for treating cancer - Google Patents

Abstract

Compounds of general Formula (I) are provided herein. Such compounds, as well as pharmaceutically acceptable salts and compositions thereof, are useful for treating diseases or conditions, including conditions characterized by excessive cellular proliferation, such as breast cancer.

Description

WEE1 inhibitors and methods for treating cancer

The present application relates generally to compounds that are WEE1 inhibitors and/or degraders thereof, and methods of using the same for the treatment of conditions characterized by excessive cellular proliferation, such as cancer.

illustrate

DNA is constantly damaged by the environment. Light, chemicals, pressure, and cell replication cause single- or double-strand breaks along the DNA backbone. In general, organisms resist DNA damage by re-attaching or re-attaching or re-synthesizing repair proteins for damaged DNA. The correct functioning of these proteins is essential for life. Misplacement of nucleotides into DNA can cause mutations (and other genetic alterations, including but not limited to insertions, deletions, and frameshifts), genetic diseases, and loss of protein function. Complete loss of DNA repair can lead to cell death, tumor progression, and cancer.

Cell cycle checkpoints are important for proper DNA repair lines, ensuring that cells do not undergo cellular replication until the integrity of their gene bodies is restored. WEE1 is a nuclear kinase that is involved in arrest at the G2-M cell cycle checkpoint for DNA repair prior to entry into mitosis. Normal cells repair damaged DNA during G1 arrest. Cancer cells often have defective G1-S checkpoints and rely on functional G2-M checkpoints for DNA repair. WEE1 is overexpressed in various cancer types.

Various inhibitors and/or degraders of WEE1 are known to those of ordinary skill in the art. See eg WO 2019/173082 and WO 2020/069105. However, there remains an urgent need for inhibitors and/or degraders of WEE1 for the treatment of conditions characterized by excessive cellular proliferation, such as cancer.

(I) Various embodiments provide a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has the following structure:

(I)

Wherein ring A, ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as described below.

One embodiment provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C ₁ -C ₆ alkyl;

Ring A is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted 5 to 6 membered monocyclic heteroaryl;

Ring B is selected from the group consisting of substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, and substituted or unsubstituted 5-7 membered monocyclic heterocyclyl;

； R ² series

;

Y is CH or N;

m is 0, 1, 2, or 3;

R ³ is selected from the group consisting of halogen and substituted or unsubstituted C ₁ -C ₆ alkyl;

、–NH–、–N(未經取代C _1-6烷基)–、–N(未經取代C ₃- ₆環烷基)–、–NH(CH ₂) _1-6–、–N(未經取代C _1-6烷基)(CH ₂) _1-6–及–N(未經取代C ₃- ₆環烷基)(CH ₂) _1-6–； 其中： X ¹及X ²係獨立地選自由碳或氮組成之群組； X ³係不存在、–CH ₂–、–NH–、–N(未經取代C _1-6烷基)–、–N(未經取代C ₃- ₆環烷基)–、–C(=O)-NH–、–C(=O)N-(未經取代C _1-6烷基)–或–C(=O)-N(未經取代C ₃- ₆環烷基)–；且 Het係經取代或未經取代4至10員雜環基； ^R is absent or selected from the group consisting of:

, –NH–, –N(unsubstituted C _1-6 alkyl)–, –N(unsubstituted C ₃ - ₆ cycloalkyl)–, –NH(CH ₂ ) _1-6 –, –N( Unsubstituted C _1-6 alkyl) (CH ₂ ) _1-6 – and –N (unsubstituted C ₃ - ₆ cycloalkyl) (CH ₂ ) _1-6 –; wherein: X ¹ and X ² are independently selected from the group consisting of carbon or nitrogen; X ³ is absent, -CH ₂ -, -NH-, -N (unsubstituted C _1-6 alkyl) -, -N (unsubstituted C _{3 -6} cycloalkyl)–, –C(=O)-NH–, –C(=O)N-(unsubstituted C _1-6 alkyl)– or –C(=O)-N (unsubstituted Substituted C ₃ - ₆ cycloalkyl) -; and Het is a substituted or unsubstituted 4 to 10 membered heterocyclic group;

R ⁵ is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, –(C=O)–, –(C=S)–, –(C=O)-NH–, –(C =O)-(C ₁ -C ₆ alkyl)-O–, –(C=O)-N(C ₁ -C ₆ alkyl)–, –(C=O)-N(C ₃ -C ₆ Cycloalkyl)–, –(C=O)-O–, –(C=S)-NH–, substituted or unsubstituted (C ₁ -C ₆ alkylene)-O–, or substituted or unsubstituted Substituted (C ₁ -C ₆ alkylene)-NH–, provided that when X ³ is –C(=O)-NH–, –C(=O)N-(unsubstituted C _1-6 alkyl )– or –C(=O)-N(unsubstituted C ₃ - ₆ cycloalkyl)–, R ⁵ does not exist;

R ⁶ is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₆ -C ₁₂ aryl)–, Substituted or unsubstituted - (C ₁ -C ₆ alkylene) - (C ₃ -C ₁₀ cycloalkyl) -, substituted or unsubstituted - (C ₁ -C ₆ alkylene) - (C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, or –C ₁ -C ₆ alkylene- O–;

R ⁷ is -(CH ₂ CH ₂ -O) _n -, wherein n is 0, 1, 2, 3, 4 or 5;

R ⁸ is absent, substituted or unsubstituted C ₁ -C ₁₀ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-O-, substituted or unsubstituted - (C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-O-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted Substituted – (C ₁ -C ₆ alkylene) -NH- (C ₁ -C ₆ alkylene), substituted or unsubstituted – (C ₁ -C ₆ alkylene) - (C=O) NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ Alkylene)-NH-(C ₁ -C ₆ Alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ Alkylene)-NH(C=O)-(C ₁ - C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O–, Substituted or unsubstituted - (C ₁ -C ₆ alkylene) -NH (C = O) - (C ₁ -C ₆ alkylene) -, substituted or unsubstituted - (C ₁ -C ₆ alkylene Alkyl)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene) –NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O) NH-(C ₁ -C ₆ alkylene) –NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene )–O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-(C=O)NH–, via Substituted or unsubstituted – (C ₁ -C ₆ alkylene) -NH-(C ₁ -C ₆ alkylene) -(C=O) NH–, substituted or unsubstituted – (C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–; substituted or unsubstituted –(C ₁ -C ₆ alkylene) -C≡C–, substituted or unsubstituted – (C ₁ -C ₆ alkylene) - (C ₆ -C ₁₂ aryl) –, substituted or unsubstituted – (C ₁ -C ₆ alkylene)-(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₄ -C ₁₀ heterocyclyl)–, Substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, –(C ₆ -C ₁₂ aryl)–, –(C ₃ -C ₁₀ cycloalkane base)—,—(5 to 10 membered heteroaryl), or—(C ₄ -C ₁₀ heterocyclyl);

The premise is that at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ exists;

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、及

。 ^R9 is selected from the group consisting of:

,

,

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,

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,

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,and

.

Another embodiment provides a pharmaceutical composition comprising an effective amount of the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or its combination.

Another embodiment provides an effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound as described above for improving or treating cancer wherein the cancer is selected from brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder/cholangiocarcinoma, liver cancer, pancreatic cancer, Colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body cancer, cervical cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms' cancer (Wilms' cancer), skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera , malignant lymphoma, multiple myeloma, Hodgkin's lymphoma (Hodgkin's lymphoma), and non-Hodgkin's lymphoma.

Another embodiment provides an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound as described above for use in inhibiting malignant growth or tumor replication, wherein the malignant growth or the tumor is caused by a cancer selected from the group consisting of brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, Lung cancer, gastric cancer, gallbladder/cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, corpus uterus, cervix, renal pelvis/ureter, bladder, prostate, penis, testis Carcinoma, fetal cancer, Wilms' carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, true Polycythemia, malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

Another embodiment provides an effective amount of a compound of formula (I) as described herein, or a pharmaceutical composition of such a compound as described above, in the manufacture of a drug for improving or treating malignant growth or tumor, Wherein the malignant growth or the tumor is caused by a cancer selected from the group consisting of brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder/cholangiocarcinoma, liver cancer , pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body cancer, cervical cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms' cancer , skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple Myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

These and other embodiments are described in more detail below.

Incorporated by reference into the priority application

This application claims priority to U.S. Provisional Patent Application Serial No. 63/202,176, filed May 28, 2021, and U.S. Provisional Application Serial No. 63/282,403, filed November 23, 2021, which are incorporated herein by reference in their entirety

WEE1 is a tyrosine kinase that is a key component of the ATR-mediated control of the G2 cell cycle checkpoint that prevents entry into mitosis in response to cellular DNA damage. ATR phosphorylates and activates CHK1, which in turn activates WEE1, leading to selective phosphorylation of cyclin-dependent kinase 1 (CDK1) at Tyr15, thereby stabilizing the CDK1-cyclin B complex and arresting cell cycle progression. This process confers a survival advantage by allowing tumor cells time to repair damaged DNA before entering mitosis. Inhibition of WEE1 abolishes the G2 checkpoint, promoting cancer cells with DNA damage to enter unscheduled mitosis and undergo cell death via mitotic catastrophe. Therefore, WEE1 inhibition and/or degradation has the potential to sensitize tumors to DNA damaging agents such as cisplatin and induce tumor cell death. definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications, and other publications cited herein are hereby incorporated by reference in their entirety unless otherwise indicated. If a term in this article has multiple definitions, unless otherwise stated, the definition in this section prevails.

Whenever a group is described as "optionally substituted," that group can be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted", if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituent is indicated, it means that the indicated "optionally substituted" or "substituted" groups may be selected from one or more of the following individually and independently Substitution of groups: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl), cycloalkyl (alkyl), heteroaryl Alkyl (alkyl), heterocyclyl (alkyl), hydroxyl, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-aminoformyl, N-aminoformyl, O-thiamineformyl Acyl, N-thiaminyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, nitro, sulfenyl Acyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, amino, monosubstituted amino, disubstituted amino, and amine (C ₁ -C ₆ alkyl ).

As used herein, "a" and "b" in "C _a to C _b " are integers which refer to the number of carbon atoms in the group. Indicated groups may be inclusive containing "a" to "b" carbon atoms. Thus, "C ₁ to C ₄ alkyl" refers to all alkyl groups having 1 to 4 carbons, ie CH ₃ -, CH ₃ CH ₂ -, CH ₃ CH ₂ CH ₂ -, (CH ₃ ) ₂ CH -, CH ₃ CH ₂ CH ₂ CH ₂ -, CH ₃ CH ₂ CH(CH ₃ )-, and (CH ₃ ) ₃ C-. If "a" and "b" are not specified, the broadest range described in these definitions is assumed.

If two "R" groups are described as being "taken together," the R groups and the atoms to which they are attached can form cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocycles. For example, without limitation, if R ^a and R ^b of an NR ^a R ^b group are described as "together", it means that they are covalently bonded to each other to form a ring:

As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety can be branched or straight chain. Examples of branched chain alkyl groups include, but are not limited to, isopropyl, secondary butyl, tertiary butyl, and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as "1 to 30" refers to each integer within the given range; e.g., "1 to 30 carbon atoms" means that an alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although this definition also covers the term "alkyl" when no numerical range is specified) . The alkyl group can also be a medium size alkyl group having 1 to 12 carbon atoms. The alkyl group can also be a lower alkyl group having 1 to 6 carbon atoms. Alkyl groups can be substituted or unsubstituted.

The term "alkenyl" as used herein refers to a monovalent linear or branched chain group of 2 to 20 carbon atoms containing a carbon double bond(s), including but not limited to 1-propenyl, 2 -propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyl groups can be unsubstituted or substituted.

The term "alkynyl" as used herein refers to a monovalent linear or branched chain group of 2 to 20 carbon atoms containing a carbon triple bond(s), including but not limited to 1-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be unsubstituted or substituted.

As used herein, "cycloalkyl" refers to a fully saturated (no double or triple bond) monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged cycloalkyl" refers to a compound in which the cycloalkyl contains a linkage to one or more atoms that are not adjacent atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. Cycloalkyl can contain 3 to 30 atoms in one (or more) ring(s), 3 to 20 atoms in one (or more) ring(s), 3 to 10 atoms in one (or more) ring(s) Atoms, containing 3 to 8 atoms in one (or more) rings, or 3 to 6 atoms in one (or more) rings. Cycloalkyl groups can be unsubstituted or substituted. Examples of monocycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups are decahydronaphthyl, dodecahydro-1H-propenyl naphthyl, and tetrahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[1.1.1]pentyl, adamantyl , and norbornyl (norbornanyl); and examples of spirocycloalkyl include spiro[3.3]heptane and spiro[4.5]decane.

As used herein, "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one is present, the double bonds cannot A fully delocalized π-electron system is formed in all rings (otherwise the group would be an "aryl" as defined herein). For example, a cycloalkenyl group can contain 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). When two or more rings are included, the rings can be joined together by fused, bridged or spiro-connected. Cycloalkenyl groups can be unsubstituted or substituted.

As used herein, "carbocyclyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged, or helical fashion as described herein. Carbocyclyl can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), ) containing 3 to 8 atoms in the ring, or 3 to 6 atoms in the ring(s). A carbocyclyl can be unsubstituted or substituted. Examples of carbocyclyl include, but are in no way limited to, cycloalkyl and cycloalkenyl as defined herein, and 1,2,3,4-tetrahydronaphthalene, 2,3-dihydro-1H-indene, 5,6 , 7,8-tetrahydroquinoline, and the non-aromatic moiety of 6,7-dihydro-5H-cyclopenta[b]pyridine.

As used herein, "aryl" means a carbocyclic (full carbon) monocyclic or polycyclic aromatic ring system (including fused ring systems in which two carbocyclic rings share a bond) having Fully delocalized π-electron systems. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C ₆ -C ₁₄ aryl group, a C ₆ -C ₁₀ aryl group, or a C ₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted.

、吡咯、

唑、苯并

唑、1,2,3-

二唑、1,2,4-

二唑、噻唑、1,2,3-噻二唑、1,2,4-噻二唑、苯并噻唑、咪唑、苯并咪唑、吲哚、吲唑、吡唑、苯并吡唑、異

唑、苯并異

唑、異噻唑、三唑、苯并三唑、噻二唑、四唑、吡啶、嗒

、嘧啶、吡

、嘌呤、喋啶、喹啉、異喹啉、喹唑啉、喹

啉、

啉、及三

。雜芳基可係經取代或未經取代的。 As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system with a fully delocalized π-electron system) containing one or more heteroatoms (e.g., 1, 2, or 3 heteroatoms), that is, elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur. The number of atoms in the ring(s) of a heteroaryl can vary. For example, a heteroaryl group may contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s), or 5 to 6 atoms in the ring(s), such as Nine carbon atoms and one heteroatom; eight carbon atoms and two heteroatoms; seven carbon atoms and three heteroatoms; eight carbon atoms and one heteroatom; seven carbon atoms and two heteroatoms; six carbon atom and three heteroatoms; five carbon atoms and four heteroatoms; five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms atom and one heteroatom; three carbon atoms and two heteroatoms; or two carbon atoms and three heteroatoms. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (such as at least one aryl ring and at least one heteroaryl ring or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furan, thiophene, benzothiophene, thiophene,

, pyrrole,

Azole, benzo

Azole, 1,2,3-

Oxadiazole, 1,2,4-

Oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, iso

azoles, benziso

Azole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridine

, pyrimidine, pyrimidine

, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoline

phylloline,

phylloline, and three

. Heteroaryl groups can be substituted or unsubstituted.

烷、1,4-二

烷、1,2-二氧雜環戊烷、1,3-二氧雜環戊烷、1,4-二氧雜環戊烷、1,3-氧硫雜環己烷(1,3-oxathiane)、1,4-氧硫雜環己二烯(1,4-oxathiin)、1,3-氧硫雜環戊烷(1,3-oxathiolane)、1,3-二硫雜環戊烯(1,3-dithiole)、1,3-二硫雜環戊烷(1,3-dithiolane)、1,4-氧硫雜環己烷、四氫-1,4-噻

、2H-1,2-

、馬來醯亞胺、琥珀醯亞胺、巴比妥酸、硫巴比妥酸、二氧哌

、乙內醯脲、二氫尿嘧啶、三

烷、六氫-1,3,5-三

、咪唑啉、咪唑啶、異

唑啉、異

唑啶、

唑啉、

唑啶、

唑啶酮、噻唑啉、噻唑啶、嗎啉、環氧乙烷、哌啶N-氧化物、哌啶、哌

、吡咯啶、氮

、吡咯啶酮、吡咯啶二酮、4-哌啶酮、吡唑啉、吡唑啶、2-氧吡咯啶、四氫吡喃、4H-吡喃、四氫噻喃、硫嗎啉、硫嗎啉亞碸、硫嗎啉碸、及其苯并稠合類似物（例如，苯并咪唑啶酮、四氫喹啉、及/或3,4-亞甲基二氧基苯基）。螺雜環基之實例包括2-氮雜螺[3.3]庚烷、2-氧雜螺[3.3]庚烷、2-氧雜-6-氮雜螺[3.3]庚烷、2,6-二氮雜螺[3.3]庚烷、2-氧雜螺[3.4]辛烷、及2-氮雜螺[3.4]辛烷。 As used herein, "heterocyclyl" or "heteroalicyclyl" refers to three, four, five, six, seven, eight, nine, ten to up to 18 membered monocyclic, bicyclic, and tricyclic ring systems, wherein the carbon atoms form the ring system together with 1 to 5 heteroatoms. Heterocycles may optionally contain one or more unsaturated bonds positioned in this manner, however, fully delocalized π-electron systems do not occur in all rings. Heteroatom(s) are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. The heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities such that the definition includes pendant oxygen systems as well as thio systems such as lactamides, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be fused, bridged, or joined together in a helical fashion. As used herein, the term "fused" refers to two rings that share two atoms and a bond. As used herein, the term "bridged heterocyclyl" or "bridged heteroalicyclyl" refers to a heterocyclyl or heteroalicyclyl group in which one or more of the non-adjacent atoms are linked. A bonded compound of atoms. As used herein, the term "spiro" refers to two rings that share an atom and are not joined by a bridge. Heterocyclic and heteroalicyclic groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s) , 3 to 8 atoms in the ring(s), 3 to 6 atoms in the ring(s). For example, five carbon atoms and one heteroatom; four carbon atoms and two heteroatoms; three carbon atoms and three heteroatoms; four carbon atoms and one heteroatom; three carbon atoms and two heteroatoms; two carbon atoms and three heteroatoms; one carbon atom and four heteroatoms; three carbon atoms and one heteroatom; or two carbon atoms and one heteroatom. In addition, any nitrogen in the heteroalicyclic ring may be quaternary ammonized. A heterocyclyl or heteroalicyclic group can be unsubstituted or substituted. Examples of such "heterocyclyl" or "heteroalicyclyl" include, but are not limited to, 1,3-dioxin, 1,3-di

Alkane, 1,4-bis

alkane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiolane (1,3- oxathiane), 1,4-oxathiin (1,4-oxathiin), 1,3-oxathiolane (1,3-oxathiolane), 1,3-dithiolane (1,3-dithiole), 1,3-dithiolane (1,3-dithiolane), 1,4-oxathiolane, tetrahydro-1,4-thiolane

, 2H-1,2-

, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopane

, hydantoin, dihydrouracil, three

Alkane, hexahydro-1,3,5-tri

, imidazoline, imidazolidine, iso

oxazoline, iso

Azolidine,

oxazoline,

Azolidine,

Pazolidone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperidine

, pyrrolidine, nitrogen

, pyrrolidone, pyrrolidinone, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine, sulfur Morpholinoxine, thiomorpholino, and benzo-fused analogs thereof (eg, benzimidazolidinone, tetrahydroquinoline, and/or 3,4-methylenedioxyphenyl). Examples of spiroheterocyclyl include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6-di Azaspiro[3.3]heptane, 2-oxaspiro[3.4]octane, and 2-azaspiro[3.4]octane.

As used herein, "aralkyl" and "aryl(alkyl)" refer to an aryl group as a substituent attached via a lower alkylene group. The lower alkylene and aryl groups of the aralkyl group may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

唑基烷基、及咪唑基烷基、及其苯并稠合類似物。 As used herein, "heteroaralkyl" and "heteroaryl (alkyl)" refer to a heteroaryl group as a substituent linked via a lower alkylene group. The lower alkylene and heteroaryl groups of heteroaralkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, iso

Azolylalkyl, and imidazolylalkyl, and benzofused analogs thereof.

"Heteroalicyclyl (alkyl)" and "heterocyclyl (alkyl)" refer to a heterocyclic group or a heteroaliphatic group linked via a lower alkylene group as a substituent Ring base. The lower alkylene and heterocyclyl of (heteroalicyclic)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, tetrahydro-2H-pyran-4-yl (methyl), piperidin-4-yl (ethyl), piperidin-4-yl (propyl), tetrahydro-2H-thiopyran -4-yl (methyl) and 1,3-thiazinan-4-yl (methyl) (1,3-thiazinan-4-yl (methyl)).

）來取代。 As used herein, a "lower alkylene group" is a straight-chain _-CH2 -tethering group that forms a bond to connect molecular fragments via its terminal carbon atoms. Examples _{include ,} but _are not limited to, methylene ( _-CH2- ), ethylenyl ( _-CH2CH2- ), propylenyl ( _-CH2CH2CH2- ), and butylene ( _{-CH2CH 2CH2CH2- ) .} A lower alkylene group can be obtained by replacing one or more hydrogens of the lower alkylene group and/or by replacing two hydrogens on the same carbon with a cycloalkyl group (for example,

) to replace.

As used herein, the term "hydroxy" refers to an -OH group.

As used herein, "alkoxy" refers to the formula -OR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl as defined herein radical, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A non-limiting list of alkoxy groups are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, secondary butoxy group, tertiary butoxy, phenoxy, and benzyloxy. Alkoxy groups can be substituted or unsubstituted.

As used herein, "acyl" refers to hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl) attached as a substituent through a carbonyl group , heteroaryl (alkyl), and heterocyclyl (alkyl). Examples include formyl, acetyl, propionyl, benzyl, and acryl. Acyl groups can be substituted or unsubstituted.

"cyano" refers to a "-CN" group.

The term "halogen atom" or "halogen" as used herein means any radioactive stable atom in column 7 of the periodic table of elements, such as fluorine, chlorine, bromine, and iodine.

"thiocarbonyl" refers to a "-C(=S)R" group, where R may be the same as defined for O-carboxy. Thiocarbonyl groups can be substituted or unsubstituted.

"O-carbamyl" refers to the "-OC(=O)N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl (alkyl). An O-aminoformyl group can be substituted or unsubstituted.

"N-carbamyl" refers to the "ROC(=O)N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The N-aminoformyl group can be substituted or unsubstituted.

"O-thiocarbamyl (O-thiocarbamyl)" refers to the group "-OC(=S)-N( _RA R _B )", wherein R _A and R _B can be independently hydrogen, alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heteroaryl Cyclic (alkyl). The O-thiacarbamoyl group can be substituted or unsubstituted.

"N-thiocarbamyl" refers to the group "ROC(=S)N( _RA )-", wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkyne radical, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl base). The N-thiacarbamoyl group can be substituted or unsubstituted.

"C-amido" refers to a "-C(=O)N( _RA R _B )" group, wherein R _A and R _B can be independently hydrogen, alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl( alkyl). A C-amido group can be substituted or unsubstituted.

"N-amido" refers to the "RC(=O)N( _RA )-" group, wherein R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, Cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl) . N-amido groups can be substituted or unsubstituted.

"S-sulfonamido (S-sulfonamido)" refers to the "-SO ₂ N( _RA R _B )" group, where R _A and R _B can be independently hydrogen, alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl ). The S-sulfonylamino group can be substituted or unsubstituted.

"N-sulfonamido (N-sulfonamido)" refers to the "RSO ₂ N( _RA )-" group, where R and _RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkane radical, cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). The N-sulfonylamino group can be substituted or unsubstituted.

The "O-carboxy" group refers to the "RC(=O)O-" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic radical, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. O-carboxy can be substituted or unsubstituted.

The terms "ester" and "C-carboxy" refer to a "-C(=O)OR" group, where R may be the same as defined for O-carboxy. Esters and C-carboxy groups can be substituted or unsubstituted.

"Nitro" refers to a -NO ₂ "group.

A "sulfenyl" group refers to a "-SR" group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, Heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl). A sulfenyl group can be substituted or unsubstituted.

A "sulfinyl" group refers to a "-S(=O)-R" group, where R may be the same as defined for sulfenyl. A sulfinyl group can be substituted or unsubstituted.

"Sulfonyl" refers to a "SO ₂ R" group, wherein R may be the same as defined for sulfenyl. A sulfonyl group can be substituted or unsubstituted.

As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkyl, dihaloalkyl, trihaloalkyl, and polyhaloalkyl). haloalkyl). Such groups include, but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl, 2-fluoroisobutyl, and pentafluoroethyl. Haloalkyl groups can be substituted or unsubstituted.

As used herein, "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) alkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Haloalkoxy can be substituted or unsubstituted.

As used herein, the term "amino" refers to a -NH ₂ group.

A "mono-substituted amine" group refers to a " _-NHRA " group, where _RA can be alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, hetero Aryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as defined herein. _RA can be substituted or unsubstituted. Examples of monosubstituted amine groups include, but are not limited to, -NH(methyl), -NH(phenyl), and the like.

A "di-substituted amine" group refers to a "-NR _A R _B " group, wherein R _A and R _B can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl, Alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl), or heterocyclyl(alkyl), as described herein definition. _RA and _RB can independently be substituted or unsubstituted. Examples of disubstituted amine groups include, but are not limited to, −N(methyl) ₂ , −N(phenyl)(methyl), −N(ethyl)(methyl), and the like.

As used herein, an "amine(alkyl)" group refers to a "(alkylene)-NR'R"" group, where R' and R" are independently hydrogen or alkyl , as defined herein. Amine (alkyl) groups may be substituted or unsubstituted. Examples of amine (alkyl) groups include, but are not limited to, −CH ₂ NH (methyl), −CH ₂ NH (benzene -CH ₂ CH ₂ NH (methyl), -CH ₂ CH ₂ NH (phenyl), -CH ₂ N (methyl) ₂ , -CH ₂ N (phenyl) (methyl), -NCH ₂ (ethyl)(methyl), −CH ₂ CH ₂ N(methyl) ₂ , −CH ₂ CH ₂ N(phenyl)(methyl), −NCH ₂ CH ₂ (ethyl)(methyl) , and the like.

When the number of substituents is not specified (eg, haloalkyl), then one or more substituents may be present. For example, "haloalkyl" may include one or more of the same or different halogens. As another example, "C ₁ -C ₃ alkoxyphenyl (C ₁ -C ₃ alkoxyphenyl)" may include one or more same or different alkoxy groups containing one, two, or three atoms.

As used herein, a group means a species with a single unpaired electron such that the species containing the group can covalently bond to another species. Therefore, radicals are not necessarily free radicals in this context. In contrast, a group denotes a specific portion of a larger molecule. The term "radical" is used interchangeably with the term "group".

The term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to the organism to which it is administered and does not invalidate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of a compound. Pharmaceutical salts can be obtained by reacting compounds with inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acids), sulfuric acid, nitric acid, and phosphoric acids (such as 2,3-dihydroxypropyl phosphate di hydrogen salt). Pharmaceutical salts can also be obtained by reacting compounds with organic acids, such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic acid, Alkaline acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, salicylic acid, 2-oxoglutaric acid or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, such as ammonium salt, alkali metal salt (such as sodium, potassium, or lithium salt), alkaline earth metal salt (such as calcium or magnesium salt), Carbonates, bicarbonates, organic bases such as dicyclohexylamine, N-methyl-D-glucosamine, ginseng(hydroxymethyl)methylamine, C ₁ -C ₇ alkylamines, cyclohexylamine , triethanolamine, ethylenediamine), and salts with amino acids (such as arginine and lysine). With respect to compounds of formula (I), those of ordinary skill in the art understand that when salts are formed by protonation of nitrogen-based groups (e.g., NH ₂ ), the nitrogen-based groups can be associated with a positive charge association (for example, NH ₂ can become NH ₃ ⁺ ), and this positive charge can be balanced by a negatively charged counterion such as Cl ⁻ .

As used herein, the terms "WEE1 inhibition", "WEE1 inhibitor", and similar terms refer to the inhibition of the activity or function of WEE1 tyrosine kinase, e.g., by targeting the phosphorylation of CDK1 To degrade WEE1 tyrosine kinase and/or reduce the activity of WEE1 tyrosine kinase. WEE1 inhibitors that act by degrading WEE1 tyrosine kinase are referred to herein as WEE1 degraders.

It is understood that in any compound described herein having one or more chiral centers, unless absolute stereochemistry is explicitly indicated, each center may independently have the R-configuration, or the S-configuration, or mixtures thereof . Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixture. Furthermore, it should be understood that in any of the compounds described herein having one or more double bonds yielding geometric isomers (which may be defined as E or Z), each double bond may independently be E or Z or a mixture thereof. Likewise, it is to be understood that in any such compound, all tautomeric forms are also intended to be included.

It is understood that where compounds disclosed herein have unfilled valencies, then the valences should be filled with hydrogen or isotopes thereof, such as hydrogen-1 (protium) and hydrogen-2 (deuterium).

It is understood that the compounds described herein may be isotopically labeled. Substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. Wherever a hydrogen atom may be present in a compound, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references herein to compounds encompass all potential isotopic forms, unless the context clearly dictates otherwise.

It should be understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include different crystal-packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated form with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and may be formed with pharmaceutically acceptable solvents such as water, ethanol, or the like during the crystallization process. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

Where a range of values is provided, it is understood that the upper and lower limits of the range, as well as each intervening value therebetween, are encompassed in the examples.

Unless expressly stated otherwise, the terms and phrases used in this application, and variations thereof (particularly in the appended claims), should be interpreted as open-ended and not limiting. As an example of the foregoing, the term "including" should be read to mean "including, without limitation/including but not limited to" or the like; as used herein, the term "comprising )" is synonymous with "including", "containing", or "characterized by", and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; The term "having" should be read as "having at least"; the term "include" should be read as "including but not limited to"; the term "example" is used to provide discussion items illustrative examples rather than an exhaustive or limiting list thereof; and the use of terms such as "preferably", "preferred", or "desired/desirable" and words of similar meaning , should not be interpreted as implying that certain features are critical, necessary, or even important to the structure or function, but merely intended to emphasize alternative or additional features that may or may not be utilized in a specific embodiment. Furthermore, the term "comprising" should be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound, composition, or device, the word "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

With respect to the use of substantially any plural and/or singular terms herein, one of ordinary skill in the art may switch from the plural to the singular and/or from the singular to the plural as appropriate to the context and/or application. Various singular/plural permutations may be explicitly set forth herein for clarity. The indefinite article "one (a or an)" does not exclude the plural. The mere fact that certain measures are listed in mutually different subparagraphs does not indicate that a combination of these measures cannot be used to advantage. Any element symbols in claims should not be construed as limiting the scope. compound

(I) Some embodiments disclosed herein relate to a compound of formula (I), or a pharmaceutically acceptable salt thereof, which has the following structure:

(I)

Wherein ring A, ring B, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as described below.

唑、經取代或未經取代噻唑、經取代或未經取代吡啶、經取代或未經取代吡

、經取代或未經取代嘧啶、及經取代或未經取代嗒

。 In various embodiments, ring A of formula (I) is selected from the group consisting of substituted or unsubstituted phenyl, and substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In one embodiment, Ring A is unsubstituted. In some embodiments, Ring A is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. In one embodiment, ring A is selected from the group consisting of substituted or unsubstituted pyrrole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted imidazole, Substituted or unsubstituted pyrazole, substituted or unsubstituted

azole, substituted or unsubstituted thiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyridine

, substituted or unsubstituted pyrimidines, and substituted or unsubstituted pyrimidines

.

係選自由下列組成之群組：

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

、及

；其中前述基團之各者係經取代的或未經取代的。在一實施例中，

係經取代或未經取代

。 In some embodiments, the formula (I)

is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,and

; wherein each of the aforementioned groups is substituted or unsubstituted. In one embodiment,

substituted or unsubstituted

.

In various embodiments, ring B of formula (I) is selected from the group consisting of substituted or unsubstituted monocyclic 5-7 membered carbocyclyl, and substituted or unsubstituted 5-7 membered Monocyclic heterocyclyl. In some embodiments, Ring B is a substituted or unsubstituted monocyclic 5-7 membered carbocyclyl. For example, in one embodiment, Ring B is a substituted or unsubstituted monocyclic 5-membered carbocyclyl. In some embodiments, Ring B is unsubstituted. In other embodiments, Ring B is substituted with 1, 2, or 3 substituents independently selected from the group consisting of: halogen, hydroxyl, amine, unsubstituted N-bond Biamido, unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₁ -C ₆ alkyl.

係選自由下列組成之群組：

、

、及

；其中前述基團之各者係經取代或未經取代。 In various embodiments, the formula (I)

is selected from the group consisting of:

,

,and

; wherein each of the aforementioned groups is substituted or unsubstituted.

In various embodiments, R ¹ of formula (I) is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C ₁ -C ₆ alkyl. In some embodiments, R ¹ is unsubstituted. For example, in one embodiment, R ¹ is unsubstituted C _1-6 alkyl. In some embodiments, R ¹ is substituted. For example, in one embodiment, R ¹ is substituted C ₁ -C ₆ alkyl. In some embodiments, ^R is hydrogen. In other embodiments, R ¹ is halogen.

；Y係CH或N；m係0、1、2或3；並且R ³係選自由下列所組成之群組：鹵素及經取代或未經取代C ₁-C ₆烷基。在一些實施例中，Y係CH。在一些實施例中，m係0。 In various embodiments, ^R of formula (I) is

; Y is CH or N; m is 0, 1, 2, or 3; and R ³ is selected from the group consisting of halogen and substituted or unsubstituted C ₁ -C ₆ alkyl. In some embodiments, Y is CH. In some embodiments, m is 0.

、–NH–、–N(未經取代C _1-6烷基)–、–N(未經取代C ₃- ₆環烷基)–、–NH(CH ₂) _1-6–、–N(未經取代C _1-6烷基)(CH ₂) _1-6–及–N(未經取代C ₃- ₆環烷基)(CH ₂) _1-6–； In various embodiments, ^R of formula (I) is absent or selected from the group consisting of:

, –NH–, –N(unsubstituted C _1-6 alkyl)–, –N(unsubstituted C ₃ - ₆ cycloalkyl)–, –NH(CH ₂ ) _1-6 –, –N( Unsubstituted C _1-6 alkyl) (CH ₂ ) _1-6 - and -N (unsubstituted C ₃ - ₆ cycloalkyl) (CH ₂ ) _1-6 -;

Wherein: X ¹ and X ² are independently selected from the group consisting of carbon or nitrogen; X ³ is absent, -CH ₂ -, -NH-, -N(unsubstituted C _1-6 alkyl)-, –N(unsubstituted C ₃ - ₆ cycloalkyl)–, –C(=O)-NH–, –C(=O)N-(unsubstituted C _1-6 alkyl)– or –C( =O)—N(unsubstituted C _{3 -6} cycloalkyl)—; and Het is a substituted or unsubstituted 4 to 10 membered heterocyclic group.

In various embodiments, R ⁴ of formula (I) is absent, -NH-, -N ₍ unsubstituted C _1-6 alkyl)- or -N(unsubstituted C _3-6 cycloalkyl )–. In other embodiments, R ⁴ is -NH(CH ₂ ) _1-6 -, -N(unsubstituted C _1-6 alkyl)(CH ₂ ) _1-6 - or -N(unsubstituted C ₃ - ₆ cycloalkyl) (CH ₂ ) _1-6 -.

。在一些實施例中，X ¹係碳。在一些實施例中，X ¹係氮。在一些實施例中，X ²係碳。在一些實施例中，X ²係氮。在一些實施例中，X ¹係碳且X ²係氮。在一些實施例中，X ¹係氮且X ²係氮。 In various embodiments, ^R of formula (I) is

. In some embodiments, ^X is carbon. In some embodiments, ^X is nitrogen. In some embodiments, ^X is carbon. In some embodiments, X is ^nitrogen . In some embodiments, X ¹ is carbon and X ² is nitrogen. In some embodiments, X ¹ is nitrogen and X ² is nitrogen.

之一些實施例中，X ³係不存在的。在其他實施例中，X ³係–CH ₂–、–NH–、–N(未經取代C _1-6烷基)–或–N(未經取代C ₃- ₆環烷基)–。在其他實施例中，X ³係–C(=O)-NH–、–C(=O)N-(未經取代C _1-6烷基)–或–C(=O)-N(未經取代C ₃- ₆環烷基)–。 In the R ⁴ series of formula (I)

In some embodiments, ^X is absent. In other embodiments, X ³ is -CH ₂ -, -NH-, -N(unsubstituted C _1-6 alkyl)- or -N(unsubstituted C _{3 -6} cycloalkyl)-. In other embodiments, X ^is -C(=O)-NH-, -C(=O)N-(unsubstituted C _1-6 alkyl)- or -C(=O)-N (unsubstituted Substituted C ₃ - ₆ cycloalkyl)-.

之一些實施例中，Het係經取代或未經取代單環4至8員雜環基。舉例而言，在一些實施例中，單環4至8員雜環基係選自由下列組成之群組：經取代或未經取代吡咯啶、經取代或未經取代哌

、經取代或未經取代哌啶、或經取代或未經取代1,4-二氮雜環庚烷。舉例而言，在一些實施例中，單環4至8員雜環基係選自由下列組成之群組：未經取代吡咯啶、未經取代哌

、未經取代哌啶及未經取代1,4-二氮雜環庚烷。 In the R ⁴ series of formula (I)

In some embodiments, Het is a substituted or unsubstituted monocyclic 4-8 membered heterocyclyl. For example, in some embodiments, the monocyclic 4-8 membered heterocyclyl is selected from the group consisting of substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperidine

, substituted or unsubstituted piperidine, or substituted or unsubstituted 1,4-diazepane. For example, in some embodiments, the monocyclic 4-8 membered heterocyclyl is selected from the group consisting of unsubstituted pyrrolidine, unsubstituted piperidine

, unsubstituted piperidine and unsubstituted 1,4-diazepane.

In various embodiments, ^R of formula (I) is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, -(C=O)-, -(C=S)-, -( C=O)-NH–, –(C=O)-(C ₁ -C ₆ alkyl)-O–, –(C=O)-N(C ₁ -C ₆ alkyl)–, –(C =O)-N(C ₃ -C _6cycloalkyl )–, –(C=O)-O–, –(C=S)-NH–, substituted or unsubstituted (C ₁ -C ₆ Alkyl)-O– or substituted or unsubstituted (C ₁ -C ₆ alkylene)-NH–, provided that when X ³ is –C(=O)-NH–, –C(=O)N When -(unsubstituted C _1-6 alkyl)- or -C(=O)-N(unsubstituted C _3-6 cycloalkyl) _- , R ⁵ does not exist. In some embodiments, ^R is absent. In some embodiments, R ⁵ is a substituted or unsubstituted C ₁ -C ₆ alkylene. In some embodiments, R ⁵ is -(C=O)-, -(C=S)-, -(C=O)-NH-, -(C=O)-(C ₁ -C ₆ alkyl )-O–, –(C=O)-N(C ₁ -C ₆ alkyl)–, –(C=O)-N(C ₃ -C ₆ cycloalkyl)–, –(C=O) -O– or –(C=S)-NH–. For example, in some embodiments, R ^is -(C=O)-. In other embodiments, R is substituted or unsubstituted -(C ₁ -C ₆ alkylene) -O-, or ^substituted or unsubstituted -(C ₁ -C ₆ alkylene) -NH –.

In various embodiments, R ⁶ of formula (I) is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene)- (C ₆ -C ₁₂ aryl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)–(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)-(C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, or -C ₁ -C ₆ alkylene-O-. For example, in one embodiment, R ⁶ is absent. In some embodiments, R ⁶ is a substituted or unsubstituted C ₁ -C ₆ alkylene. For example, in one embodiment, R ⁶ is an unsubstituted C ₁ -C ₆ alkylene group. In some embodiments, R ⁶ is substituted or unsubstituted -(C ₁ -C ₆ alkylene) -(C ₆ -C ₁₂ aryl) -, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₃ -C ₁₀ heterocyclyl)–, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)-, or -C ₁ -C ₆ alkylene-O-.

In various embodiments, R ⁷ of formula (I) is —(CH ₂ CH ₂ —O) _n —, wherein n is 0, 1, 2, 3, 4 or 5. For example, in some embodiments n is 0, in which case ^R7 is absent. In other embodiments, n is 1, 2, 3, 4 or 5. For example, in one embodiment, n is 1. In another embodiment, n is 2.

In various embodiments, ^R of formula (I) is absent, substituted or unsubstituted C ₁ -C ₁₀ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene) -O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted – (C ₁ -C ₆ alkylene) -O-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene), substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)- NH(C=O)-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ - C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)–, substituted or Unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene) –NH–, via Substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O– , substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)– , substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O) NH-(C ₁ -C ₆ alkylene) –O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene )-(C=O)NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-(C=O)NH–, via Substituted or unsubstituted – (C ₁ -C ₆ alkylene) -NH- (C ₁ -C ₆ alkylene) - (C = O) NH - (C ₁ -C ₆ alkylene) -; Substituted or unsubstituted –(C ₁ -C ₆ alkylene)-C≡C–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₆ -C ₁₂ aryl)– , substituted or unsubstituted – (C ₁ -C ₆ alkylene) - (C ₃ -C ₁₀ cycloalkyl) –, substituted or unsubstituted – (C ₁ -C ₆ alkylene) - ( C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, –(C ₆ -C ₁₂ aryl) , -(C3-C10 cycloalkyl)-, -(5 to 10 membered heteroaryl), or -(C ₄ -C ₁₀ heterocyclyl).

In various embodiments, R ⁸ of formula (I) is substituted or unsubstituted C ₁ -C ₁₀ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-O-, Substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-O-(C ₁ -C ₆ alkylene) )–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)–, or substituted or unsubstituted – (C ₁ -C ₆ alkylene Alkyl)-(C=O)NH–. In various embodiments, R ⁸ is unsubstituted.

In various embodiments, R ⁸ of formula (I) is a substituted or unsubstituted C ₁ -C ₁₀ alkylene. For example, in one embodiment, R ⁸ is unsubstituted C ₁ -C ₁₀ alkylene. In various embodiments, R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-O—. For example, in one embodiment, R ⁸ is unsubstituted -(C ₁ -C ₆ alkylene)-O-). In various embodiments, R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-NH—. For example, in one embodiment, R ⁸ is unsubstituted -(C ₁ -C ₆ alkylene)-NH—.

In various embodiments, R ⁸ of formula (I) is substituted or unsubstituted -(C ₁ -C ₆ alkylene) -NH-(C ₁ -C ₆ alkylene) -NH—, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)- NH(C=O)-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ - C ₆ alkylene)—O—, or substituted or unsubstituted—(C ₁ -C ₆ alkylene)—NH(C═O)—(C ₁ -C ₆ alkylene)—.

In various embodiments, formula (I) R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene) -NH-(C ₁ -C ₆ alkylene) -NH(C=O) -(C ₁ -C ₆ alkylene) -NH-, substituted or unsubstituted -(C ₁ -C ₆ alkylene) -NH-(C ₁ -C ₆ alkylene) -NH(C= O)-(C ₁ -C ₆ alkylene)-O-, substituted or unsubstituted-(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH( C=O)-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene group)-, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)-NH-, substituted or unsubstituted- (C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)-O-, substituted or unsubstituted-(C ₁ -C ₆ alkylene)- NH(C=O)-(C ₁ -C ₆ alkylene)-(C=O)NH-, substituted or unsubstituted-(C ₁ -C ₆ alkylene)-NH-(C ₁ - C ₆ alkylene)-(C=O)NH, or substituted or unsubstituted-(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-(C= O) NH-(C ₁ -C ₆ alkylene)-.

In various embodiments, R ⁸ of formula (I) is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-C≡C-, substituted or unsubstituted -(C ₁ -C ₆ Alkylene)-(C ₆ -C ₁₂ aryl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted Substituted - (C ₁ -C ₆ alkylene) - (C ₄ -C ₁₀ heterocyclyl) -, substituted or unsubstituted - (C ₁ -C ₆ alkylene) - (5 to 10 membered heterocyclyl) aryl)–, –(C ₆ -C ₁₂ aryl)–, –(C ₃ -C ₁₀ cycloalkyl)–, – (5 to 10 membered heteroaryl) or –(C ₄ -C ₁₀ heterocycle base)-.

In various embodiments, at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is present in formula (I);

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。 In various embodiments, ^R of formula (I) is selected from the group consisting of:

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。 In various embodiments, ^R of formula (I) is selected from the group consisting of:

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。 In various embodiments, ^R of formula (I) is selected from the group consisting of:

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。 In one embodiment, R ⁹ of formula (I) is

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。 合成 In various embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds, or a pharmaceutically acceptable salt thereof:

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. synthesis

Compounds of formula (I), or pharmaceutically acceptable salts thereof, can be manufactured in various ways by those of ordinary skill in the art using known techniques and guided by the detailed teachings provided herein, including the examples provided below. For example, in one example, compounds of formula (I) are prepared according to the general scheme depicted in FIG. 1 . Examples of compounds of formula (I) can be prepared as depicted in Figures 1 and 2 . Any preliminary reaction steps required to form starting compounds or other precursors can be performed by those of ordinary skill in the art, for example by appropriate adaptation of the reagents and conditions described in the Examples. In Figures 1 and 2, variables including A, B, R ¹ , R ² , R ^4a , R ⁴ , R ^5a , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ can be described elsewhere herein. described, and taking into account the synthetic transformations involved (as understood by those of ordinary skill in the art). As further illustrated in the examples below, R ^4a and R ^5a are synthetic precursors understood by those of ordinary skill in the art to be R ⁴ and R ⁵ , respectively. The descriptions of the various chemical groups that may be represented by ^R4a and ^R5a are substantially the same as for ^R4 and ^R5 , respectively (as described elsewhere herein). Pharmaceutical composition

Some embodiments described herein relate to a pharmaceutical composition, which may include an effective amount of one or more compounds described herein (such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutical The above acceptable carrier, diluent, excipient, or a combination thereof.

The term "pharmaceutical composition" refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components such as diluents or carriers. Pharmaceutical compositions facilitate the administration of compounds to organisms. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid . Pharmaceutical compositions will generally be designed for a particular intended route of administration.

The term "physiologically acceptable" defines a carrier, diluent, or excipient that does not abolish the biological activity and properties of the compound, nor does it cause significant injury or damage to the animal to which the composition is intended to be delivered .

As used herein, "carrier" refers to a compound that facilitates the incorporation of the compound into cells or tissues. For example, but not limited to, dimethylsulfoxide (DMSO) is a frequently utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

As used herein, "diluent" refers to an ingredient in a pharmaceutical composition that lacks significant pharmacological activity but may be medically necessary or desirable. For example, diluents can be used to increase the volume of an effective drug whose mass is too small to manufacture and/or administer. It can also be a liquid used to dissolve a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, but not limited to, phosphate buffered saline that mimics the pH and isotonicity of human blood.

As used herein, "excipient" means a substantially inert substance added to a pharmaceutical composition to provide, but not limited to, volume, consistency, stability, binding capacity to the composition , lubrication, disintegration ability, etc. For example, stabilizers such as antioxidants and metal chelating agents are excipients. In one embodiment, the pharmaceutical composition includes antioxidants and/or metal chelating agents. A "diluent" is a type of excipient.

The pharmaceutical compositions described herein may be administered to human patients by themselves, or may be pharmaceutical compositions in which they are admixed with other active ingredients (as in combination therapy), or carriers, diluents, excipients, or combinations thereof administered to human patients. Proper formulation depends upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those of ordinary skill in the art.

The pharmaceutical compositions disclosed herein may be manufactured in a manner known per se, for example by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating, or tableting processes. Furthermore, the active ingredient is contained in an amount effective for its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts with pharmaceutically compatible counterions.

Various techniques for administering compounds, salts, and/or compositions exist in the art, including but not limited to oral, rectal, pulmonary, topical, aerosol, injection, infusion, and parenteral delivery, including intramuscular, subcutaneous, Intravenous, intramedullary, intrathecal, direct intraventricular, intraperitoneal, intranasal, and intraocular injections. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be administered orally.

Compounds, salts, and/or compositions can also be administered locally rather than systemically, for example, by direct injection or implantation of the compound, usually in a depot or sustained release formulation, into the affected area. Additionally, the compounds can be administered in a targeted drug delivery system such as liposomes coated with tissue-specific antibodies. The liposomes will be targeted to and selectively taken up by the organ. For example, intranasal or pulmonary delivery may be desired to target respiratory diseases or conditions.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms (containing the active ingredient). The pack may eg comprise metal or plastic foil, eg a blister pack. The pack or dispenser unit may be accompanied by administration instructions. The package or dispenser may also be accompanied by a notice associated with the container regulating the manufacture, use, or sale of the drug in a form prescribed by a government agency reflecting the agency's approval of the drug form for human or veterinary administration. give. For example, the notification could be a label or a product leaflet approved by the Food and Drug Administration for a prescription drug. Compositions, which may include compounds described herein and/or salts formulated in a compatible pharmaceutical carrier, may also be prepared, placed in an appropriate container and labeled for treatment of the indicated condition. Therapeutic uses and methods

Some embodiments described herein relate to a method for ameliorating and/or treating a cancer described herein, which may comprise administering to a subject suffering from a cancer described herein an effective amount of a compound described herein (e.g. , a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to or comprise an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) (e.g., a compound of formula Use of a pharmaceutical composition of the compound of (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for improving and/or treating the cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for improving and/or treating the cancer described herein Or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof).

Some embodiments described herein relate to a method for inhibiting the replication of a malignant growth or tumor, which may comprise combining the growth or the tumor with an effective amount of a compound described herein (e.g., a compound of formula (I) or its pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is Caused by cancers described herein. Other embodiments described herein pertain to or comprise an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) (e.g., a compound of formula Use of a pharmaceutical composition of a compound of (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the replication of malignant growth or tumor caused by the cancer described herein . Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for inhibiting malignant growth or tumor replication or comprising effective A pharmaceutical composition of an amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the malignant growth or the tumor is caused by a cancer described herein.

Some embodiments described herein relate to a method for ameliorating or treating cancer described herein, which may include treating malignant growths or tumors with an effective amount of a compound described herein (for example, a compound of formula (I) or pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to or comprise an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) (e.g., a compound of formula The use of the pharmaceutical composition of the compound of (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a drug for improving or treating cancer, which may include contacting malignant growths or tumors, wherein the malignant growths or the tumors are caused by Caused by the cancers described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for improving or treating cancer or comprising an effective amount of the compound described herein A pharmaceutical composition of said compound (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), which may include contacting a malignant growth or tumor, wherein the malignant growth or the tumor is caused by a cancer described herein cause.

Some embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and/or A method of reducing overexpression of WEE1 in a cell), which may comprise providing to cancer cells from a cancer described herein an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof ) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein pertain to or comprise an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) (e.g., a compound of formula The pharmaceutical composition of the compound of (I) or its pharmaceutically acceptable salt) is used to inhibit the activity of WEE1 (for example, inhibit the activity of WEE1 in TP53 mutant cells, inhibit the activity of WEE1 in TP53 wild-type cells, inhibit the activity of WEE1 activity in p53-deficient cells, and/or to reduce overexpression of WEE1 in cells). Still other embodiments described herein relate to a method for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and/or or reducing the overexpression of WEE1 in cells) an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein (for example, a compound of formula A pharmaceutical composition of the compound of (I) or a pharmaceutically acceptable salt thereof). Some embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and/or A method of reducing overexpression of WEE1 in a cell), which may comprise providing to cancer cells from a cancer described herein an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof ) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to a method for inhibiting the activity of WEE1 (e.g., inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, and/or A method of reducing overexpression of WEE1 in a cell, which may comprise administering a cancer cell from a cancer described herein with an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof ) or a pharmaceutical composition comprising an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof), thereby inhibiting the activity of WEE1.

Some embodiments described herein relate to a method for improving or treating cancer described herein, which may include using an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof) to inhibit the activity of WEE1 (for example, inhibit the activity of WEE1 in TP53 mutant cells activity, inhibit the activity of WEE1 in TP53 wild-type cells, inhibit the activity of WEE1 in p53-deficient cells, and/or reduce the overexpression of WEE1 in cells). Other embodiments described herein pertain to or comprise an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) (e.g., a compound of formula The pharmaceutical composition of the compound of (I) or a pharmaceutically acceptable salt thereof) is used in the manufacture to inhibit the activity of WEE1 (for example, inhibit the activity of WEE1 in TP53 mutant cells, inhibit the activity of WEE1 in TP53 wild-type cells, Inhibiting the activity of WEE1 in p53-deficient cells, and/or reducing the overexpression of WEE1 in cells) to improve or treat the cancer described herein. Still other embodiments described herein relate to a method for inhibiting the activity of WEE1 (for example, inhibiting the activity of WEE1 in TP53 mutant cells, inhibiting the activity of WEE1 in TP53 wild-type cells, inhibiting the activity of WEE1 in p53-deficient cells, inhibiting the activity of WEE1 in p53-deficient cells, and/or reducing the overexpression of WEE1 in cells) to improve or treat the effective amount of the compounds described herein (for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising effective A pharmaceutical composition of an amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof). Some embodiments described herein relate to a method for improving or treating the cancer described herein, which includes giving cancer cells an effective amount of a compound described herein (for example, a compound of formula (I) or its pharmaceutically acceptable salt) or a pharmaceutical composition comprising an effective amount of a compound described herein (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of WEE1 (for example, inhibits WEE1 activity in TP53 mutant cells, inhibit WEE1 activity in TP53 wild-type cells, inhibit WEE1 activity in p53-deficient cells, and/or reduce WEE1 overexpression in cells).

Some embodiments disclosed herein relate to a method for inhibiting the activity of WEE1, which may comprise providing an effective amount of a compound described herein to a subject suffering from a cancer described herein or to a cancer cell from a cancer described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition comprising an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) . Other embodiments disclosed herein relate to or comprise an effective amount of a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) (eg, a compound of formula (I) Use of a pharmaceutical composition of the compound of I) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of WEE1. Yet other embodiments disclosed herein relate to a compound described herein (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprising an effective amount of a compound described herein for use in inhibiting the activity of WEE1 (for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof).

Examples of suitable cancers include, but are not limited to: brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), gastric cancer, Gallbladder/cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body cancer, cervical cancer, renal pelvis/ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetus Carcinoma, Wilms' carcinoma, Skin cancer, Malignant melanoma, Neuroblastoma, Osteosarcoma, Ivan's tumor, Soft tissue sarcoma, Acute leukemia, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Polycythemia vera, Malignant Lymphoma, multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

As described herein, a cancer can become resistant to one or more anticancer agents. In some embodiments, a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or comprises an effective amount of a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) pharmaceutically acceptable salts) can be used to treat and/or ameliorate cancers that have become resistant to one or more anticancer agents, such as one or more WEE1 inhibitors. Examples of anticancer agents to which a subject may have developed resistance include, but are not limited to, WEE1 inhibitors such as AZD1775. In some embodiments, a cancer that has become resistant to one or more anticancer agents can be a cancer described herein.

-1-基)苯基胺基)-1,2-二氫吡唑并[3,4-d]嘧啶-3-酮)）之對象所經歷之相同副作用之嚴重性相比小25%。在一些實施例中，式(I)之化合物或其醫藥上可接受之鹽導致副作用之數目與接受已知WEE1抑制劑（例如，AZD1775）之對象所經歷之副作用之數目相比小25%。在一些實施例中，式(I)之化合物或其醫藥上可接受之鹽導致副作用（諸如本文中所述者之一）之嚴重性相較於接受已知WEE1抑制劑（諸如AZD1775）之對象所經歷的相同副作用之嚴重性減少約10%至約30%之範圍。在一些實施例中，式(I)之化合物或其醫藥上可接受之鹽導致副作用之數目相較於接受已知WEE1抑制劑（例如AZD1775）之對象所經歷的副作用之數目減少約10%至約30%之範圍。 Several known WEE1 inhibitors may cause one or more undesired side effects in the treated subject. Examples of unwanted side effects include, but are not limited to, thrombocytopenia, neutropenia, anemia, diarrhea, vomiting, nausea, abdominal pain, and constipation. In some embodiments, a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) reduces the number and/or severity of one or more side effects associated with known WEE1 inhibitors . In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, can cause side effects (such as one of those described herein) of a severity comparable to that of receiving known WEE1 inhibitors (such as AZD1775, formally The name is MK1775 (CAS No.: 955365-80-7, 2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(4-(4- Methylpiperene

-1-yl)phenylamino)-1,2-dihydropyrazolo[3,4-d]pyrimidin-3-one)) experienced 25% less severity of the same side effects. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a number of side effects that are 25% less than the number of side effects experienced by subjects receiving a known WEE1 inhibitor (eg, AZD1775). In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a side effect such as one described herein that is more severe than in subjects receiving a known WEE1 inhibitor such as AZD1775 The reduction in severity of the same side effects experienced ranged from about 10% to about 30%. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, results in a reduction in the number of side effects compared to the number of side effects experienced by subjects receiving a known WEE1 inhibitor, such as AZD1775, from about 10% to About 30% range.

In any one of the embodiments described above under the heading "Compound (Compound)" there is provided one or more compounds of formula (I) or a pharmaceutically acceptable salt thereof, which are useful for treating, improving cancer, and and/or inhibit the growth of cancers in which inhibiting the activity of WEE1 is beneficial.

As used herein, "subject" refers to an animal that is the object of treatment, observation, or experimentation. "Animal" includes cold-blooded and warm-blooded vertebrates and invertebrates such as fish, crustaceans, reptiles and especially mammals. "Mammal" includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and especially humans . In some embodiments, the subject may be a person. In some embodiments, the subject may be a child and/or an infant, such as a child or infant with a fever. In other embodiments, the subject can be an adult.

As used herein, the terms "treat, treating, treatment, therapeutic" and "therapy" do not necessarily mean complete cure or elimination of a disease or condition. Any alleviation to any degree of any undesirable sign or symptom of a disease or condition may be considered treatment and/or therapy. Additionally, treatment can include actions that can worsen a subject's overall sense of well-being or appearance.

The terms "therapeutically effective amount" and "effective amount" are used to indicate the amount of an active compound or pharmaceutical agent that elicits an indicated biological or pharmaceutical response. For example, a therapeutically effective amount of a compound, salt, or composition may be that amount required to prevent, alleviate, or ameliorate the symptoms of a disease or condition, or prolong the survival of a subject being treated. The response can occur in a tissue, system, animal, or human, and includes alleviation of signs or symptoms of the disease or condition being treated. In view of the disclosure provided herein, determination of an effective amount is well within the ability of one of ordinary skill in the art. The therapeutically effective amount of a compound disclosed herein required as a dosage will depend on the route of administration, the type of animal (including humans) being treated, and the physical characteristics of the particular animal under consideration. Dosage can be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concomitant drugs, and other factors as will be recognized by those of ordinary skill in the medical art.

For example, an effective amount of a compound or radiation is an amount that results in: (a) reduction, alleviation, or disappearance of one or more symptoms caused by cancer, (b) reduction in tumor size, (c) elimination of tumors, and/or (d) Long-term stable disease (growth arrest) of the tumor. In the treatment of lung cancer, such as non-small cell lung cancer, a therapeutically effective amount is an amount that reduces or eliminates cough, shortness of breath, and/or pain. As another example, an effective or therapeutically effective amount of a WEE1 inhibitor and/or degrader is an amount that results in a decrease in WEE1 activity and/or phosphorylation, such as phosphorylation of CDC2. Reduction of WEE1 activity is known to those of ordinary skill in the art and can be determined by analyzing WEE1 intrinsic kinase activity and downstream substrate phosphorylation.

The amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, required for treatment will vary not only with the particular compound or salt selected, but also with the route of administration, the disease or condition being treated. nature and/or symptoms, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician. In the case of administration of a pharmaceutically acceptable salt, the dosage may be calculated as the free base. Those of ordinary skill in the art will appreciate that, in certain instances, it may be desirable to administer the compounds disclosed herein in amounts exceeding, or even far exceeding, the dosage ranges described herein to effectively and aggressively treat, particularly invasive disease or condition.

In general, however, a suitable dosage will often be in the range of about 0.05 mg/kg to about 10 mg/kg. For example, a suitable dosage may be in the range of about 0.10 mg/kg to about 7.5 mg/kg body weight/day, such as about 0.15 mg/kg to about 5.0 mg/kg/recipient body weight/day, about 0.2 mg/kg to about 4.0 mg /kg/recipient body weight/day, or any amount in between. The compounds may be administered in unit dosage form; for example, each unit dosage form contains 1 to 500 mg, 10 to 100 mg, 5 to 50 mg, or any amount therebetween of the active ingredient.

The desired dose may conveniently be presented in a single dose, or in divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-doses themselves may be further divided, for example, into discrete, loosely spaced administrations.

As will be readily apparent to those of ordinary skill in the art, useful in vivo doses to be administered and the particular mode of administration will vary depending on the age, body weight, severity of affliction, and the species of mammal being treated, the particular compound employed, and The particular use for which these compounds are employed will vary. Determination of effective dosage levels (ie, dosage levels required to achieve the desired effect) can be achieved by those of ordinary skill in the art using routine methods, for example, human clinical trials, in vivo studies, and in vitro studies. For example, a useful dosage of a compound of formula (I) or a pharmaceutically acceptable salt thereof can be determined by comparing its in vitro activity with its in vivo activity in animal models. This comparison can be done by comparison with established drugs such as cisplatin and/or gemcitabine

Dosage and intervals may be adjusted individually to provide plasma levels or minimum effective concentration (MEC) of the active moiety sufficient to maintain a modulating effect. The MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC values. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10 to 90% of the time, preferably between 30 to 90% of the time, and optimally between 50 to 90% of the time . In cases of local administration or selective uptake, the local effective concentration of the drug may not be related to plasma concentration.

It should be noted that the attending physician will know how and when to terminate, interrupt or adjust administration due to toxicity or abnormal organ function. Conversely, the attending physician will also know to adjust treatment to higher levels if the clinical response is insufficient (excluding toxicity). The magnitude of the dosage administered in the management of the condition of interest will vary depending on the severity of the disease or condition being treated and the route of administration. The severity of a disease or condition can be assessed, for example, based in part on standard prognostic assessment methods. In addition, the dosage and possibly the frequency of administration will also vary according to the age, weight and response of the individual patient. Programs similar to those discussed above are available in veterinary medicine.

Efficacy and toxicity of the compounds, salts, and compositions disclosed herein can be assessed using known methods. For example, the toxicology of a particular compound or a subgroup of compounds sharing certain chemical moieties can be established by determining in vitro toxicity on cell lines, such as mammalian and preferably human cell lines. The results of such studies are generally predictive of toxicity in animals (eg, mammals) or, more specifically, humans. Alternatively, known methods can be used to determine the toxicity of a particular compound in animal models such as mice, rats, rabbits, dogs, or monkeys. The therapeutic effect of a particular compound can be established using several recognized methods such as in vitro methods, animal models or human clinical trials. When selecting a model to determine efficacy, one skilled in the art can be guided by the best current techniques to select the appropriate model, dose, route of administration and/or regimen. example

-1-基)苯基)胺基)-1,2-二氫-3H-吡唑并[3,4-d]嘧啶-3-酮

Additional embodiments are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way. Intermediate 1 (R)-2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(( 4-(piperene

-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

-1-羧酸三級丁酯（832 mg, 3.00 mmol）及DIEA(2.183 ml, 12.50 mmol)，在室溫下繼續反應16小時。然後向反應混合物中添加水（30 mL）並用EtOAc（2×50 mL）萃取兩次。用飽和aq.NaHCO ₃溶液及鹽水洗滌合併有機層，經硫酸鈉乾燥並蒸發，得到黑色殘留物，接著將該殘留物藉由使用以DCM-MeOH（0-10%）洗提之Combi-Flash的矽膠管柱層析法純化。合併純產物流份且蒸發，得到所欲的產物4-(4-((2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5H-環戊[b]吡啶-2-基)-3-側氧基-2,3-二氫-1H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)哌

-1-羧酸(R)-三級丁酯（ 中間物 1-1）（1150 mg，1.877 mmol，75%產率）。LC/MS (ESI) m/z613.4 [M+H] ⁺。 Step 1: In a 125 mL round bottom flask, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[b]pyridine -2-yl)-6-(methylthio) -1H -pyrazolo[3,4-d]pyrimidin-3( 2H )-one (such as Huang, Peter Qinhua et al., WO 2019/173082 Prepared as reported in A1) (959 mg, 2.5 mmol) was suspended in toluene (30 ml) and cooled to 0 °C. Next, m-CPBA (616 mg, 2.75 mmol) was slowly added to the flask. The reaction was continued for one hour at room temperature, then cooled back to 0 °C and 4-(4-aminophenyl)piperidine was added to the reaction mixture

-Tertiary-butyl 1-carboxylate (832 mg, 3.00 mmol) and DIEA (2.183 ml, 12.50 mmol), continued to react at room temperature for 16 hours. Then water (30 mL) was added to the reaction mixture and extracted twice with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aq.NaHCO ₃ solution and brine, dried over sodium sulfate and evaporated to give a black residue, which was then flashed using Combi-Flash eluting with DCM-MeOH (0-10%) Purified by silica gel column chromatography. The pure product fractions were combined and evaporated to give the desired product 4-(4-((2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[ b] pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piper

-1-Carboxylic acid (R)-tert-butyl ester ( intermediate 1-1 ) (1150 mg, 1.877 mmol, 75% yield). LC/MS (ESI) m/z 613.4 [M+H] ⁺ .

-1-基)苯基)胺基-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮（ 中間物 1）（150 mg，0.293 mmol，80%產率）。LC/MS (ESI) m/z513.41 [M+H] ⁺。

Step 2: Intermediate 1-1 (225 mg, 0.367 mmol) in a 25 mL round bottom flask. 2N HCl in ether (1 mL) was then added to the reaction mixture and maintained at this temperature for 3 hours. The reaction was then carefully quenched with cold saturated aqueous NaHCO ₃ and extracted with dichloromethane (3×15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The resulting residue was then purified by silica gel column chromatography using dichloromethane-MeOH (0-100%). The pure product fractions were combined and evaporated to give the desired product ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine- 2-yl)-6-((4-piper

-1-yl)phenyl)amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( Intermediate 1 ) (150 mg, 0.293 mmol, 80% yield). LC/MS (ESI) m/z 513.41 [M+H] ⁺ .

-1-基)-2,2,2-三氟乙酮(428 mg，1.565 mmol)及DIEA (1.139 ml，6.52 mmol)，在室溫下繼續反應16小時。然後向反應混合物中添加水（30 mL）並用EtOAc（2×50 mL）萃取兩次。將合併的有機層用飽和aq.NaHCO ₃溶液及鹽水洗滌，經硫酸鈉乾燥並蒸發。接著，藉由使用以DCM-MeOH（0-10%）洗提之Combi-Flash的矽膠管柱層析法純化。合併純產物流份並蒸發，得到所欲產物(R)-2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-6-((4-(4-(2,2,2-三氟乙醯)哌

-1-基)苯基)胺基-1 H-吡唑并[3,4- d]嘧啶-3(2 H)-酮（ 中間物 1-2）（550 mg，0.904 mmol，69.3%產率）。LC/MS (ESI) m/z609.4 [M+H] ⁺。 Step 1: In a 125 mL round bottom flask, ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[b]pyridine -2-yl)-6-(methylthio) -1H -pyrazolo[3,4-d]pyrimidin-3( 2H )-one (such as Huang, Peter Qinhua et al., WO 2019/173082 Prepared as reported in A1) (500 mg, 1.304 mmol) was suspended in toluene (30 ml) and cooled to 0 °C. Next, m-CPBA (321 mg, 1.434 mmol) was slowly added to the flask. The reaction was continued for one hour at room temperature, then cooled back to 0 °C and 1-(4-(4-aminophenyl)piperidine was added

-1-yl)-2,2,2-trifluoroethanone (428 mg, 1.565 mmol) and DIEA (1.139 ml, 6.52 mmol), and the reaction was continued at room temperature for 16 hours. Then water (30 mL) was added to the reaction mixture and extracted twice with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aq. NaHCO ₃ solution and brine, dried over sodium sulfate and evaporated. Then, it was purified by silica gel column chromatography using Combi-Flash eluting with DCM-MeOH (0-10%). The pure product fractions were combined and evaporated to give the desired product (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridine -2-yl)-6-((4-(4-(2,2,2-trifluoroacetyl)piper

-1-yl)phenyl)amino- 1H -pyrazolo[3,4- d ]pyrimidin-3( 2H )-one ( Intermediate 1-2 ) (550 mg, 0.904 mmol, 69.3% yield Rate). LC/MS (ESI) m/z 609.4 [M+H] ⁺ .

-1-基)苯基)胺基-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮（ 中間物 1）（109 mg，0.213 mmol，86%產率）。LC/MS (ESI) m/z513.4 [M+H] ⁺。 中間物2 甲磺酸3-((2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)胺基)丙酯

Step 2: In a 25 ml round bottom flask, Intermediate 1-2 (150 mg, 0.246 mmol) was dissolved in MeOH (5 ml) at room temperature and K ₂ CO ₃ (68.1 mg, 0.493 mmol) was added . The reaction was continued for 4 hours at room temperature. Ice water was then added to quench the reaction and extracted with dichloromethane (3 x 15 mL). The combined organic layers were washed with brine and evaporated to give a residue which was then dissolved in a small amount of dichloromethane and precipitated with ether and hexanes. The resulting precipitate was collected by filtration and dried to give the desired product ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b] Pyridin-2-yl)-6-((4-piper

-1-yl)phenyl)amino-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( Intermediate 1 ) (109 mg, 0.213 mmol, 86% yield). LC/MS (ESI) m/z 513.4 [M+H] ⁺ . Intermediate 2 Methanesulfonic acid 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propane ester

In a 50 mL round bottom flask, 2-(2,6-dioxopiperidin-3-yl)-4-((3-hydroxypropyl)amino)isoindoline-1,3- Diketone (prepared as reported in Mainolfi et al., WO 2020113233 A1) (200 mg, 0.604 mmol) was dissolved in dichloromethane (5 ml) and cooled to 0 °C. Then DIEA (0.264 ml, 1.509 mmol) and methanesulfonyl chloride (0.052 ml, 0.664 mmol) were added sequentially. The reaction was continued for 12 hours at room temperature. It was then evaporated, washed with saturated NaHCO ₃ (aq) solution and extracted into dichloromethane (3×15 mL), and the combined organic layers were washed with brine and evaporated. The resulting residue was purified by silica gel chromatography with dichloromethane-MeOH (0-10%). The pure product fractions were combined and evaporated to give the desired product 3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline methanesulfonate -4-yl)amino)propyl ester ( Intermediate 2 ) (155 mg, 0.379 mmol, 63% yield). LC/MS (ESI) m/z 410.28 [M+H] ⁺ . Intermediate 3 Methanesulfonic acid 6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)hexyl ester

Intermediate 3 was followed the procedure described in Intermediate 2 using 2-(2,6-dioxopiperidin-3-yl)-4-((6-hydroxyhexyl)amino)isoindoline -1,3-diketone (preparation method is similar to that described in Mainolfi et al., WO 2020113233 A1) substituted 2-(2,6-dioxopiperidin-3-yl)-4-((3- Hydroxypropyl) amino) isoindoline-1,3-dione prepared. LC/MS (ESI) m/z 452.1 [M+H] ⁺ . Intermediate 4 8-(((S)-1-((2S,4R)-4-hydroxyl-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl ) ethyl) carbamoyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctanoic acid

Step 1: In a 30 ml seal cap vial, 8-(tertiary butoxy)-8-oxooctanoic acid (57.0 mg, 0.247 mmol) was dissolved in DMF (2 ml) and HATU (103 mg, 0.270 mmol), DIEA (0.079 ml, 0.450 mmol) were added to the reaction vial. After 5 minutes, (2 S ,4 R )-1-(( RS )-2-amino-3,3-dimethylbutyryl)-4-hydroxy-N-(( S )-1-(4- (4-Methylthiazol-5-yl)phenyl)ethyl)pyrrolidin-2-yl)-carboxamide hydrochloride (VHL Hcl) (100 mg, 0.225 mmol) was added to the vial and incubated at room temperature Stir at room temperature for 5 hours. Next, transfer to a separatory funnel with EtOAc (20 mL) and extract with EtOAc (2 x 20 mL) after addition of water (5 mL). _The combined organic layers were washed with brine, dried over _Na2SO4 , and evaporated. The resulting residue was purified using column chromatography on a Combi-Flash eluting with DCM-DCM:MeOH (9:1 ) (0-100%). The pure product fractions were combined and evaporated to give the desired product 8-(((S)-1-((2S,4R)-4-hydroxy-2-((( S )-1-(4-(4 -Methylthiazol-5-yl)phenyl)ethyl)aminoformyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino-8 -Oxanoic acid tert-butyl ester ( intermediate 4-1 ) (102 mg, 0.170 mmol, 75% yield). LC/MS (ESI) m/z 657.4 [M+H] ⁺ .

Step 2: In a 25 mL round bottom flask, Intermediate 4-1 (100 mg) was dissolved in dichloromethane (2.0 mL), followed by the addition of TFA (1.0 mL) and continued at room temperature for one hour. Volatiles were removed using rotary evaporation and lyophilized after suspension in water-acetonitrile (1:1) (5 mL) to afford the desired product Intermediate 4 . LC/MS (ESI) m/z 599.36 [MH] ^- . Intermediate 5 10-(((S)-1-((2S,4R)-4-hydroxyl-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl ) ethyl) aminoformyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -10-oxodecanoic acid

Step 1: Following the procedure described in Step 1 for Intermediate 4 and substituting 10-(tert-butoxy)-10-oxodecanoic acid for 8-(tertiary-butoxy)-8-oxoctanoic acid , to prepare 10-(((RS)-1-((2S,4R)-4-hydroxy-2-(((S)-1-(4-(4-methylthiazol-5-yl)phenyl ) ethyl) aminoformyl) pyrrolidin-1-yl) -3,3-dimethyl-1-oxobutan-2-yl) amino) -10-oxo-decanoic acid tertiary butyl ester ( Intermediate 5-1 ). LC/MS (ESI) m/z 685.43 [M+H] ⁺ .

Step 2: Intermediate 5 was prepared following the procedure described in Step 2 of Intermediate 4 and using Intermediate 5-1 in place of Intermediate 4-1 . LC/MS (ESI) m/z 627.36 [MH] ^- . Intermediate 6 5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)amino)pentanoic acid

Step 1: In a 60 ml sealed glass vial, mix 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.778 g, 3.0 mmol) and Tert-butyl 5-bromopentanoate (0.854 g, 3.60 mmol) was suspended in NMP (10 ml). Then DIPEA (1.572 ml, 9.00 mmol) was added to the vial and heated at 110 °C for 12 hours. Then water (5 mL) was added and extracted with EtOAc (2 x 20 mL), the combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The resulting residue was purified by column chromatography on Combi-Flash eluting with DCM-DCM:MeOH (9:1 ) (0-100%). The pure product fractions were combined and evaporated to give the desired product 5-((2-(2,6-dioxopiperidin-3-yl)-1-dioxoisoindolin-4-yl) Amino) tert-butyl valerate ( Intermediate 6-1 ) (760 mg, 61% yield). LC/MS (ESI) m/z 414.35 [MH] ^- .

Step 2: In a 30 mL glass vial with seal cap, Intermediate 6-1 (250 mg, 0.602 mmol) was dissolved in DCM (4 ml) and treated with trifluoroacetic acid (2.0 ml, 26.0 mmol). The lid was closed and the reaction was continued for 2 hours at room temperature. The reaction mixture was then completely evaporated and lyophilized after addition of water (4.0 mL) to afford intermediate 6 . LC/MS (ESI) m/z 360.12 [M+H] ⁺ . Intermediate 7 (R)-2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methyl Sulfonyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

At -5°C, to 2-allyl-1-[(7 R )-7-ethyl-7-hydroxy-5,6-dihydrocyclopenta[ b ]pyridin-2-yl]-6- To a solution of methylmercapto-pyrazolo[3,4- d ]pyrimidin-3-one (0.300 g, 0.782 mmol) in i -PrOH (3 mL) was added potassium monopersulfate (oxone) ( 721.44 mg, 1.17 mmol) in H ₂ O (1 mL). The reaction was stirred at 0 to 5°C for 2 hours. The reaction was then filtered, and the filtrate was dried over 4Å molecular sieves and filtered. The filtrate was used in the next step without further purification. Intermediate 8 (R)-2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(( 4-(2-Hydroxyethyl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

To a solution of 2-(4-aminophenyl)ethanol (148.58 mg, 1.08 mmol) in i- PrOH (5 mL) was added ( R )-2-allyl-1-[7 -Ethyl-7-hydroxy-5,6-dihydrocyclopenta[ b ]pyridin-2-yl]-6-methylsulfonyl-pyrazolo[3,4- d ]pyrimidin-3-one ( intermediate Compound 7 ) (0.300 g, 0.722 mmol). The mixture was stirred at 80°C for 12 hours. LCMS showed the reaction was complete and the desired compound was detected. The reaction was concentrated under reduced pressure to a residue, which was purified by preparative TLC to afford ( R )-2-allyl-1-[7-ethyl-7-hydroxy-5,6-di Hydrocyclopenta[ b ]pyridin-2-yl]-6-[4-(2-hydroxyethyl)anilino]pyrazolo[3,4- d ]pyrimidin-3-one (0.200 g, yield 56 %, 96.2% purity). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.79 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 5.78 -5.64 (m, 1H), 5.04 (dd, J = 10.2, 1.0 Hz, 1H), 4.92 (dd, J = 17.1, 1.0 Hz , 1H), 4.77 (d, J = 5.8 Hz, 1H), 4.68 (d, J = 6.6 Hz, 1H), 4.01 - 3.93 (m, 1H), 3.89 (t, J = 6.4 Hz, 2H), 3.12 - 3.02 (m, 1H), 2.89 - 2.84 (m, 2H), 2.45 - 2.36 (m, 1H), 2.34 - 2.22 (m, 1H), 2.11 - 1.98 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); LCMS (ESI): m/z = 473.3 (M+H) ⁺ , RT: 0.578 min. Intermediate 9 Methanesulfonic acid ( R )-4-((2-allyl-1- (7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazole and[3,4- d ]pyrimidin-6-yl)amino)phenethyl ester

To a solution of Intermediate 8 (0.200 g, 0.407 mmol, 96.1% purity) in DCM (5 mL) was added TEA (170 µL, 1.22 mmol) and MsCl (93.3 mg, 0.814 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h under _N2 . LCMS showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC to provide Intermediate 9 (0.160 g, 61% yield, 85.2% purity). ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.83 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 5.75 - 5.64 (m, 1H), 5.03 (d, J = 10.3 Hz, 1H), 4.92 (d, J = 17.0 Hz, 1H), 4.87 - 4.79 (m, 1H), 4.74 - 4.65 (m, 1H), 4.43 (t, J = 6.8 Hz, 2H), 4.00 - 3.92 (m, 1H), 3.08 - 3.02 (m, 2H), 2.89 ( s, 3H), 2.94 - 2.86 (m, 1H), 2.40 (ddd, J = 13.4, 8.6, 4.5 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.06 - 1.99 (m, 2H), 1.00 ( t, J = 7.4 Hz, 3H); LCMS (ESI): m/z = 551.2 (M+H) ⁺ , RT: 1.127 min. Intermediate 10 3-(5-(4-(hydroxymethyl)piperidine -1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

烷（0.5 mL）中之溶液添加Cs ₂CO ₃（605 mg，1.86 mmol）及Pd-PEPPSI-Ihept（90.3 mg，92.8 µmol）。將反應在100℃及N ₂下攪拌12小時。LCMS顯示偵測到所欲化合物。將反應經由矽膠過濾且以DMF（5 mL）洗提。將濾液濃縮以得到殘餘物，將殘餘物藉由製備型TLC（PE:EA=0:1，Rf=0.1)純化，得到 中間物 10（0.200 g，產率51%，84.6%純度）。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 10.95 (s, 1H), 7.50 (d, J =8.2 Hz, 1H), 7.12 - 6.99 (m, 2H), 5.04 (dd, J =13.3, 4.9 Hz, 1H), 4.51 (t, J =5.1 Hz, 1H), 4.37 - 4.15 (m, 2H), 3.89 (br d, J =12.9 Hz, 2H), 3.28 (br t, J =5.5 Hz, 2H), 2.81 (br t, J =11.6 Hz, 2H), 2.36 (br dd, J =13.5, 4.6 Hz, 1H), 2.03 - 1.92 (m, 1H), 1.78 - 1.71 (m, 2H), 1.66 - 1.54 (m, 1H), 1.27 - 1.14 (m, 3H), 0.91 - 0.79 (m, 1H)；LCMS (ESI)： m/z= 358.0 (M+H) ⁺，RT：0.127 min. 中間物11 甲磺酸(1-(2-(2,6-二側氧基哌啶-3h-基)-1-側氧異吲哚啉-5-基)哌啶-4-基)甲酯

3-(5-Bromo-1-oxo-isoindolin _- 2-yl)piperidine-2,6-dione (0.300 g, 0.928 mmol) and 4-piperidinemethanol (106.9 mg, 0.928 mmol) in di

To a solution in alkanes (0.5 mL) were added Cs ₂ CO ₃ (605 mg, 1.86 mmol) and Pd-PEPPSI-Ihept (90.3 mg, 92.8 µmol). The reaction was stirred at 100 °C under _N2 for 12 hours. LCMS showed detection of the desired compound. The reaction was filtered through silica gel and eluted with DMF (5 mL). The filtrate was concentrated to give a residue, which was purified by preparative TLC (PE:EA=0:1, Rf=0.1) to give Intermediate 10 (0.200 g, 51% yield, 84.6% purity). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.95 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.12 - 6.99 (m, 2H), 5.04 (dd, J = 13.3, 4.9 Hz, 1H), 4.51 (t, J = 5.1 Hz, 1H), 4.37 - 4.15 (m, 2H), 3.89 (br d, J = 12.9 Hz, 2H), 3.28 (br t, J = 5.5 Hz, 2H), 2.81 (br t, J = 11.6 Hz, 2H), 2.36 (br dd, J = 13.5, 4.6 Hz, 1H), 2.03 - 1.92 (m, 1H), 1.78 - 1.71 (m, 2H), 1.66 - 1.54 (m, 1H), 1.27 - 1.14 (m, 3H), 0.91 - 0.79 (m, 1H); LCMS (ESI): m/z = 358.0 (M+H) ⁺ , RT: 0.127 min. Intermediate 11 (1-(2-(2,6-dioxopiperidin-3h-yl)-1-oxoisoindoline-5-yl)piperidin-4-yl)methyl methanesulfonate

To a solution of Intermediate 10 in DCM (1 mL) was added TEA (0.458 mL, 3.36 mmol) and MsCl (256 mg, 2.24 mmol) at 0 °C. The reaction was stirred at 20 °C for 1 hour. LCMS showed the reaction was complete and the desired compound was detected. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over _Na2SO4 and filtered. The filtrate was concentrated to give a residue, which was purified by preparative TLC (PE:EA=0:1, Rf=0.3) to give intermediate 11 (0.10 g, 41% yield). LCMS (ESI) m/z 436.2 [M+H] ⁺ . 0.602 min. Intermediate 12 ( R )-4-((2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5 H -cyclopenta[ b ]pyridine-2 -yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)benzaldehyde

The preparation step 1 of intermediate 12 was similar to the preparation of intermediate 8 to obtain ( R )-2-allyl-1-(7-ethyl-7-hydroxyl-6,7 in 33% yield and 91% purity -Dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-6-((4-(hydroxymethyl)phenyl)amino)-1,2-dihydro- 3H -pyrazolo [3,4- d ]pyrimidin-3-one. LCMS (ESI ⁺ ): m/z = 459.2 (M+H) ⁺ , RT: 0.683 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.75 (s, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 1H), 5.76 - 5.62 (m, 1H), 5.03 (d, J = 10.0 Hz, 1H), 4.92 (d, J = 16.0 Hz, 1H), 4.73 - 4.53 (m, 1H), 4.66 (s, 2H), 4.67 - 4.57 (m, 1H), 3.15 - 3.02 (m, 1H), 2.95 - 2.80 (m, 1H), 2.45 - 2.32 (m, 1H ), 2.33 - 2.21 (m, 1H), 2.11 - 1.95 (m, 1H), 1.94 - 1.80 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H).

Preparation of Intermediate 12 Step 2: To a solution of the product from Step 1 above (0.14 g, 0.28 mmol, 91% purity) in EtOAc (1.4 mL) was added _MnO2 (483 mg, 5.56 mmol) at 20 °C, and The mixture was stirred at 20°C under nitrogen for 12 hours. LCMS showed complete consumption of starting material. The mixture was filtered, and the filtrate was concentrated to afford intermediate 12 (0.070 g, 53% yield, 96.1% purity). LCMS (ESI ⁺ ): m/z = 457.2 (M+H) ⁺ , RT: 0.789 min. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 9.94 (s, 1H), 8.92 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 5.78 - 5.62 (m, 1H), 5.05 (d, J = 10.1 Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 4.83 (br dd, J = 15.8, 5.7 Hz, 1H), 4.72 (br dd, J = 15.8, 5.7 Hz, 1H), 3.18 - 3.02 (m, 1H), 2.97 - 2.84 ( m, 1H), 2.46 - 2.34 (m, 1H), 2.28 - 2.20 (m, 1H), 2.10 - 1.96 (m, 1H), 1.92 - 1.82 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H). Intermediate 13 methanesulfonic acid ( R )-3-(-4-((2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)propyl

The preparation step 1 of intermediate 13 was similar to the preparation of intermediate 8 , and ( R )-2-allyl-1-(7-ethyl-7-hydroxyl-6,7 -Dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-6-((4-(3-hydroxypropyl)phenyl)amino)-1,2-dihydro- 3H -pyridine Azolo[3,4- d ]pyrimidin-3-one. LCMS (ESI ⁺ ): m/z = 487.2 (M+H) ⁺ , RT: 0.590 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.33 - 10.08 (br, 1H), 8.86 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.1 Hz , 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 5.75 - 5.60 (m, 1H), 5.05 (s, 1H), 5.00 (d, J = 10.0 Hz, 1H), 4.86 (br d, J = 17.1 Hz, 1H), 4.82 – 4.65 (m, 1H), 4.56 (br dd, J = 15.5, 6.1 Hz, 1H), 4.50 - 4.41 (m, 1H ), 3.45 - 3.38 (m, 2H), 3.40 - 3.22 (m, 1H), 3.00 - 2.93 (m, 1H), 2.85 - 2.71 (m, 1H), 2.60 - 2.54 (m, 2H), 2.25 - 2.17 (m, 1H), 2.02 (ddd, J = 13.3, 7.7, 5.8 Hz, 1H), 2.00 - 1.80 (m, 1H), 1.77 - 1.71 (m, 2H), 0.87 (br t, J = 7.3 Hz, 3H).

-1-羧酸三級丁酯

The preparation step 2 of intermediate 13 is similar to the preparation of intermediate 9 to intermediate 13 , yield 47%, 97.52% purity). LCMS (ESI ⁺ ): m/z = 565.3 (M+H) ⁺ , RT: 0.850 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.23 (br s, 1H), 8.87 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 5.75 - 5.61 (m, 1H), 5.05 (s, 1H), 5.00 (d, J = 10 Hz, 1H), 4.85 (d, J = 17.0 Hz, 1H), 4.74 (br d, J = 2.5 Hz, 1H), 4.57 (br dd, J = 16.3, 5.8 Hz, 1H), 4.20 (br t, J = 6.0 Hz, 2H), 3.18 (s, 3H), 3.02 - 2.90 (m, 1H), 2.81- 2.73 (m, 1H), 2.39 - 2.55 (m, 2H), 2.26 - 2.16 (m, 1H) , 2.06 – 1.98 (m, 3H), 1.93 – 1.80 (m, 1H), 1.70 (br dd, J = 13.8, 7.3, Hz, 1H), 0.87 (br t, J = 7.0 Hz, 3H). Intermediate 14 4-4(-((2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piper

-1-Carboxylic acid tertiary butyl ester

-1-基)苯基)胺基)-1,2-二氫-3H-吡唑并[3,4-d]嘧啶-3-酮

Intermediate 14 was obtained by following a similar procedure as described in Intermediate 1 using 2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6-(methyl (R)-2- allyl -1- one (35.2 mg, 0.078 mmol) substituted ( R )-2-allyl-1- (7-Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(methylthio)-1,2-dihydro-3 H - pyrazolo[3,4- d ]pyrimidin-3-one to afford the desired title product intermediate 14 . LCMS (ESI ⁺ ): m/z = 587.3 (M+H) ⁺ , RT: 0.959 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.79 (s, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.77 (br d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.71 (tdd, J = 16.8, 10.5, 6.0 Hz, 1H), 5.03 ( dd, J = 10.5, 0.9 Hz, 1H), 4.91 (d, J = 16.8 Hz, 1H), 4.81 (d, J = 6.0 Hz, 2H), 3.64 - 3.55 (m, 4H), 3.14 - 3.05 (m , 4H), 1.57 (s, 6H), 1.49 (s, 9H) Intermediate 15 2-allyl-1-(6-(2-hydroxyprop-2-yl)pyridin-2-yl)-6- ((4-piperene

-1-yl)phenyl)amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

-1-基)-3-氯苯甲酸

A mixture of intermediate 14 (0.327 g, 557 µmol) in HCl/EA (4 M, 10 mL) was stirred at 20 °C for 1 h. LCMS showed the reaction was complete and the desired compound was detected. The reaction was concentrated under reduced pressure to afford intermediate 15 (0.291 g, 99.5% yield, HCl salt, 90.969% purity). LCMS (ESI ⁺ ): m/z = 487.2 (M+H) ⁺ , RT: 0.598 min. Intermediate 16 (R)-4-(4-(4-(2-allyl-1-(7- Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolyl[3,4 -d]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chlorobenzoic acid

Preparation of Intermediate 16 Step 1: To a solution of Intermediate 1 (0.150 g, 225 µmol, 77% purity) in DMSO (5 mL) was added methyl 3-chloro-4-fluorobenzoate ( 63.7 mg, 338 µmol) and DIEA (80.3 µL, 451 µmol). The mixture was stirred at 60 °C for 12 h under _N2 . LCMS showed the reaction was complete and the desired compound was detected. The reaction mixture was poured into H ₂ O (10 mL), and extracted with EtOAc (3×10 mL). The organic phase was washed with brine (10 mL) and dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a residue which was analyzed by preparative TLC (PE:EA=0:1, Rf=0.4) Purification afforded the methyl ester of intermediate 16 (0.100 g, 57% yield, 88% purity). LCMS (ESI ⁺ ): m/z = 681.26 (M+H) ⁺ , RT: 0.816 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.10 (br s, 1H, NH), 8.83 (s, 1H), 7.93 (s, 1H), 8.02 - 7.82 (m, 2H), 7.71 (d , J = 8.8 Hz, 2H), 7.73 – 7.58 (m, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.67 (br dd, J = 16.8 , 10.4 Hz, 1H), 5.05 (s, 1H, OH), 5.00 (d, J = 10.5 Hz, 1H), 4.86 (br d, J = 17.3 Hz, 1H), 4.82 - 4.68 (m, 1H), 4.62 - 4.52 (m, 1H), 3.84 (s, 3H), 3.40 - 3.20 (m, 8H), 3.03 - 2.93 (m, 1H), 2.83 - 2.74 (m, 1H), 2.26 - 2.15 (m, 1H ), 2.08 - 1.97 (m, 1H), 1.90 (br dd, J = 13.8, 7.2 Hz, 1H), 1.77 - 1.66 (m, 1H), 0.86 (br t, J = 7.3 Hz, 3H).

-1-基)-3-氯苯甲酸

Preparation Step 2 of Intermediate 16 : To a solution of Intermediate 16 (0.100 g, 129 µmol, 88% purity) in MeOH (1 mL) and H ₂ O (0.1 mL) was added NaOH (10.3 mg , 258 µmol). The mixture was stirred at 20 °C for 12 h under _N2 . LCMS showed the reaction was complete and the desired compound was detected. The mixture was adjusted to pH=5 by adding saturated aqueous AcOH (2 M) solution. The mixture was extracted with ethyl acetate (3 x 15 mL). The organic phase was washed with brine (3 x 5 mL) and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated in vacuo to afford intermediate 16 (0.100 g, 84% yield, 72% purity). LCMS (ESI ⁺ ): m/z = 667.25 (M+H) ⁺ , RT: 0.743 min. Intermediate 17 (R)-4-((4-4-(2-allyl-1-(7- Ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolyl[3,4 -d]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chlorobenzoic acid

Preparation of Intermediate 17 Step 1: To a solution of Intermediate 1 (0.200 g, 390 µmol) in DMF (4 mL ₎ was added _K2CO3 (108 mg, 780 µmol) and 4-(bromomethyl)-3 -Methyl chloro-benzoate (123 mg, 468 µmol). The mixture was stirred at 100°C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction mixture was poured into H ₂ O (10 mL), and extracted with EtOAc (3×15 mL). The organic layer was washed with brine (5 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by preparative TLC (PE:EA=0:1, Rf=0.3) to obtain the methyl ester of intermediate 17 (55 mg, yield 19%, 95% purity). LCMS (ESI ⁺ ): m/z = 695.3 (M+H) ⁺ , RT: 1.018 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.10 (br s, 1H, NH), 8.82 (s, 1 H), 7.93 (d, J = 8.8 Hz, 1H), 7.98 - 7.88 (m, 2H), 7.72 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.65 – 7.55 (m, 2H), 6.93 (br d, J=9.01 Hz, 2H), 5.58 - 5.74 (m, 1H), 5.04 (s, 1H, OH), 4.99 (d, J = 10.4 Hz, 1H), 4.84 (d, J = 16.5 Hz, 1H), 4.70 – 4.80 (m, 1H ), 4.62 – 4.52 (m, 1H), 3.87 (s, 3H), 3.71 (s, 2H), 3.40 – 3.30 (m, 4H), 3.20 – 3.10 (m, 4H), 2.92 - 3.01 (m, 1H ), 2.71- 2.84 (m, 1H), 2.13 - 2.28 (m, 1H), 1.95 - 2.06 (m, 1H), 1.84 - 1.93 (m, 1H), 1.70 (dd, J=13.63, 7.38 Hz, 1H ), 0.87 (t, J=7.44 Hz, 3H).

Preparation Step 2 of Intermediate 17 : Intermediate 17 was prepared following a similar procedure as described in Step 2 of Intermediate 16 (60 mg, 91% yield, 89% purity). LCMS (ESI ⁺ ): m/z = 681.3 (M+H) ⁺ , RT: 0.709 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ = 8.78 (s, 1H), 8.03 (d, J = 1.47 Hz, 1H), 7.95 (dd, J = 8.0, 1.53 Hz, 1H), 7.85 (d , J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.54 (br d, J = 8.93 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 5.71 (ddt, J = 16.8, 10.5, 6.0 Hz, 1H), 5.03 (dd, J = 10.5, 1.1 Hz, 1H), 4.93 (br dd, J = 17.1, 1.2 Hz, 2H), 4.82 (br d, J=6.0 Hz, 1H), 4.75 (br d, J=6.2 Hz, 1H), 3.88 (s, 2H), 3.26 - 3.17 (m, 4H), 3.10 - 3.00 (m , 1H), 2.90 – 2.80 (m, 1H), 2.82 – 2.75 (m, 4H), 2.45 – 2.35 (m, 1H), 2.15 (ddd, J =13.8, 8.6, 5.6 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.90 – 1.78 (m, 1H), 0.95 (t, J = 7.46 Hz, 3H). Intermediate 18 2-(2,6-dioxopiperidin-3-yl)-4-(4-oxopiperidin-1-yl)isoindoline-1,3-dione

Preparation step 1 of intermediate 18 : 2-(2,6-Dioxo-3-piperidinyl)-4-fluoro-isoindoline-1,3-dione at 20°C (500 mg, 1.81 mmol) in DMSO (5 mL) was added piperidin-4-ol (274 mg, 2.71 mmol) and DIEA (468 mg, 3.62 mmol). The reaction was stirred at 60 °C for 12 h under _N2 . LCMS showed the reaction was complete and the desired product was detected. The reaction was extracted with DCM (3 x 30 mL). The organic layer was washed with brine and _dried over _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give 2-(2,6-dioxo-3-piperidinyl)-4-(4-hydroxy-1-piperidinyl)isoindoline-1 ,3-Diketone (500 mg, 1.40 mmol, 77% yield). LCMS (ESI ⁺ ): m/z = 358.0 (M+H) ⁺ , RT: 1.826 min.

Preparation step 2 of intermediate 18 : 2-(2,6-dioxo-3-piperidinyl)-4-(4-hydroxy-1-piperidinyl)isodihydro A mixture of indole-1,3-dione (500 mg, 1.40 mmol) in DCM (5 mL) was added DMP (1.78 g, 4.20 mmol). The reaction was stirred at 20 °C for 12 h under _N2 . LCMS showed one major peak, desired MS detected. The reaction was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The organic layer was dried _{over Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure to give 2-(2,6-dioxo-3-piperidinyl)-4-(4-oxo-1-piperidinyl)isoindoline -1,3-Dione ( Intermediate 18 ) (450 g, 1.27 mmol, 90% yield), which was used in the next step without further purification. LCMS (ESI ⁺ ): m/z = 356.1 (M+H) ⁺ , RT: 0.689 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.05 (s, 1H, NH), 7.68 (dd, J = 8.3, 7.3 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.35 (d8, J = 7.3 Hz, 1H), 5.08 (dd, J = 12.9, 5.4 Hz, 1H), 3.60 (br t, J = 6.0 Hz, 4H), 2.93 - 2.78 (m, 1H), 2.65 - 2.65 (m, 1H), 2.53 (br t, J = 6.0 Hz, 4H), 2.55 - 2.45 (m, 1H), 2.05 - 1.96 (m, 1H). Intermediate 19 Tertiary butyl (4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl)carbamate

Preparation Step 1 of Intermediate 19 : Addition of 2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane (Ref: WO 2021/255212) (430 mg , 1.29 mmol) and TEA (352 µL, 2.58 mmol) in DCM (4.5 mL) was added TEAA (448 µL, 3.23 mmol). The reaction was then stirred at 30°C for 2 hours. LCMS showed completion of reaction and desired product. The reaction was cooled to 25 °C and quenched with _H2O (50 mL) at 0 °C and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with brine (30 mL) and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (PE: EA = 0: 1, Rf = 0.5) to obtain 2,2,2-trifluoro-1 -[6-(4-Nitrophenyl)-2,6-diazaspiro[3.3]hept-2-yl]ethanone (0.320 g yield 65%, 82.68% purity). LCMS (ESI ⁺ ): m/z = 316.0 (M+H) ⁺ , RT: 0.750 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.05 (d, J = 9.2 Hz, 2H), 6.46 (d, J = 9.2 Hz, 2H), 4.64 (s, 2H), 4.31 (s, 2H ), 4.23 (s, 4H).

Preparation step 2 of intermediate 19 : N- [4-[2-(2,2,2-trifluoroacetyl)-2,6 with a yield of 63% and a purity of 84.49% was obtained by standard hydrogen reduction and in situ Boc protection - tertiary-butyl diazaspiro[3.3]hept-6-yl]phenyl]carbamate. LCMS (ESI ⁺ ): m/z = 386.0 (M+H) ⁺ , RT: 0.768 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (br s, 1H, NH), 7.23 (br d, J = 8.8 Hz, 2H), 6.35 (d, J = 8.8 Hz, 2H), 4.59 (s, 2H), 4.27 (s, 2H), 3.89 (s, 4H), 1.44 (s, 9H).

Preparation step 3 of intermediate 19 is the deprotection of trifluoroacetamide in step 2, which is prepared by the same method as step 2 of intermediate 1 . Tertiary-butyl N-[4-(2,6-diazaspiro[3.3]hept-2-yl)phenyl]carbamate ( intermediate 19 ) was obtained with a yield of 88% and a purity of 84.49%. LCMS (ESI ⁺ ): m/z = 290.1 (M+H) ⁺ , RT: 0.469 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.94 (br s, 1H, NH), 7.21 (br d, J = 8.7 Hz, 2H), 6.33 (br d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.59 (s, 3H), 1.44 (s, 9H). Intermediate 20 4-(4-(6-(4-aminophenyl)-2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Preparation of Intermediate 20 Step 1: To a solution of Intermediate 18 (276 mg, 622 µmol, 80% purity) and Intermediate 19 (176 mg, 518 µmol) in DCM (2 mL) was added NaBH at 0 °C (OAc) ₃ (220 mg, 1.04 mmol). The reaction was then stirred at 25°C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was directly purified without work-up. The reaction was purified by preparative TLC (DCM: MeOH =10: 1, Rf = 0.5) to obtain tertiary butyl- N- [4-[2-[1-[2-(2,6-dioxo Base-3-piperidinyl)-1,3-dioxo-isoindoline-4-yl]-4-piperidinyl]-2,6-diazaspiro[3.3]hept-6 tert-butyl-yl]phenyl]carbamate ( Boc- intermediate 20 ) (0.190 g, 52% yield, 63.14% purity). LCMS (ESI ⁺ ): m/z = 629.2 (M+H)+, RT: 0.656 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.92 (br s, 1H, NH), 7.67 (dd, J = 6.8, 6.8 Hz,1H), 7.33 (d, J = 6.8 Hz, 1H), 7.32 (d, J = 6.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.34 (d, J = 8.8 Hz, 2H), 5.09 (dd, J = 5.4, 12.8 Hz, 1H), 3.78 (s, 4H), 3.64 - 3.52 (m, 2H), 3.17 (s, 2H), 3.02 - 2.80 (m, 3H), 2.64 - 2.53 (m, 2H), 2.22 - 2.11 (m, 1H), 2.08 - 1.97 (m, 1H), 1.75 (s, 4H), 1.44 (s, 9H), 1.40 - 1.25 (m, 2H).

Preparation Step 2 of Intermediate 20 : Boc- Intermediate 20 was treated with TFA/DCM at 0°C followed by 1 hour at 25°C to give 4-[4-[6-(4-aminophenyl)-2, 6-diazaspiro[3.3]hept-2-yl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3 - diketones ( intermediate 20 ). LCMS (ESI ⁺ ): m/z = 529.2 (M+H) ⁺ , RT: 0.133 min. Intermediate 21 2-(2,6-dioxopiperidin-3-yl)-4-(6-oxo-2-azaspiro[3.3]hept-2-yl)isoindoline- 1,3-diketone

Intermediate 21 was prepared following a similar two-step procedure as described in Intermediate 18 , substituting 2-azaspiro[3.3]hept-6-ol hydrochloride for piperidin-4-ol. Intermediate 21 was obtained in 88% yield in two steps. LCMS (ESI ⁺ ): m/z = 370.1 (M+H) ⁺ , RT: 0.677 min. Intermediate 22 methanesulfonic acid ( R )-(1-(4-((2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azene-3 -yl) methyl ester

-1-基)-2,2,2-三氟乙酮以與中間物7（300 mg, 722 µmol)反應，得到所欲產物( R)-2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-6-((4-(3-(羥甲基)吖呾-1-基)苯基)胺基)-1,2-二氫-3 H-吡唑并[3,4- d]嘧啶-3-酮（0.200 g，產率38%，70.46%純度）。LCMS (ESI ⁺)：m/z = 512.8 (M+H) ⁺，RT：0.728 min. Intermediate 22 was prepared in Step 1 in a similar manner to the procedure described in Intermediate 1 , using (1-(4-aminophenyl)azan-3-yl)methanol (350 mg, 190 mmol, 96.85% purity) in place of 1-(4-(4-Aminophenyl)piperene

-1-yl)-2,2,2-trifluoroethanone to react with intermediate 7 (300 mg, 722 µmol) to give the desired product ( R )-2-allyl-1-(7-ethane Cyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-6-((4-(3-(hydroxymethyl)azan-1-yl)benzene yl)amino)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one (0.200 g, 38% yield, 70.46% purity). LCMS (ESI ⁺ ): m/z = 512.8 (M+H) ⁺ , RT: 0.728 min.

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 22 was prepared in Step 2 following the procedure described in Intermediate 2 as standard mesylation conditions. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layers were dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to give ( R methanesulfonic acid)-(1-(4-((2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azene- 3-yl) methyl ester ( intermediate 22 ). LCMS (ESI ⁺ ): m/z = 592.4 (M+H) ⁺ , RT: 0.610 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.06 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (br d, J = 7.9 Hz, 1H), 7.68 (br d, J = 7.9 Hz, 1H), 7.58 - 7.34 (m, 2H), 6.43 (d, J = 8.1 Hz, 2H), 5.73 - 5.58 (m, 1H), 5.04 (s, 1H, OH), 4.99 (d, J = 10.4 Hz, 1H), 4.85 (br d, J = 17.4 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.44 (br d, J = 6.4 Hz, 2H ), 3.92 - 3.84 (m, 2H), 3.60 - 3.50 (m, 2H), 3.22 (s, 3H), 3.10 - 3.00 (m, 1H), 3.00 - 2.88 (m, 1H), 2.82 - 2.73 (m , 1H), 2.20 – 2.10 (m, 1H), 2.00 - 1.92 (m, 1H), 1.92 – 1.80 (m, 1H), 1.72 – 1.60 (m, 1H), 0.87 (br t, J = 6.8 Hz, 3H). Intermediate 23 3-(5-(4-(1-(4-aminophenyl)piperidin-4-yl)piper

-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)異吲哚啉-1,3-二酮及1-(4-硝基苯基)哌啶-4-酮，得到產率54%及98%純度的3-(5-(4-(1-(4-硝基苯基)哌啶-4-基)哌

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。LCMS (ESI ⁺)： m/z= 533.2 (M+H) ⁺，RT：0.770 min. Step 1 of the preparation of intermediate 23 was analogous to the first step of the preparation of intermediate 20 using 2-(2,6-dioxopiperidine-3- base)-5-(piper

-1-yl)isoindoline-1,3-dione and 1-(4-nitrophenyl)piperidin-4-one, 3-(5-( 4-(1-(4-nitrophenyl)piperidin-4-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione. LCMS (ESI ⁺ ): m/z = 533.2 (M+H) ⁺ , RT: 0.770 min.

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮，且無需進一步純化即可用於下一步驟。LCMS (ESI ⁺)： m/z= 503.2 (M+H) ⁺，RT：0.644 min. 中間物24 (R)-2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5H-環戊[b]吡啶-2-基)-6-((4-(4-側氧哌啶-1-基)苯基)胺基)-1,2-二氫-3H-吡唑并[3,4-d]嘧啶-3-酮

Preparation step 2 of intermediate 23 : standard hydrogen reduction under hydrogen balloon to obtain intermediate 23 , i.e. 3-(5-(4-(1-(4-aminophenyl)piperidin-4-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione and was used in the next step without further purification. LCMS (ESI ⁺ ): m/z = 503.2 (M+H) ⁺ , RT: 0.644 min. Intermediate 24 (R)-2-allyl-1-(7-ethyl-7-hydroxyl-6, 7-Dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-((4-(4-oxopiperidin-1-yl)phenyl)amino)-1,2-dihydro -3H-pyrazolo[3,4-d]pyrimidin-3-one

-1-基)-2,2,2-三氟乙酮，與 中間物 7反應而製備，得到所欲標題產物 中間物 24，( R)-2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-6-((4-(4-側氧哌啶-1-基)苯基)胺基)-1,2-二氫-3 H-吡唑并[3,4- d]嘧啶-3-酮。LCMS (ESI ⁺)： m/z= 526.3 (M+H) ⁺，RT：0.777 min. 中間物25 2-(2,6-二側氧基哌啶-3-基)-4-(3-側氧基吖呾-1-基)異吲哚啉-1,3-二酮

Intermediate 24 was obtained by substituting 1-(4-(4- Aminophenyl)piperene

-1-yl)-2,2,2-trifluoroethanone, prepared by reaction with intermediate 7 to give the desired title product Intermediate 24 , ( R )-2-allyl-1-(7-ethane yl-7-hydroxy-6,7-dihydro- 5H -cyclopent[ b ]pyridin-2-yl)-6-((4-(4-oxopiperidin-1-yl)phenyl)amine base)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one. LCMS (ESI ⁺ ): m/z = 526.3 (M+H) ⁺ , RT: 0.777 min. Intermediate 25 2-(2,6-dioxopiperidin-3-yl)-4-(3- Pendant oxyazene-1-yl)isoindoline-1,3-dione

Intermediate 25 was prepared by following a similar two-step procedure as described in Intermediate 18 , substituting aziridine-3-ol hydrochloride for piperidin-4-ol. Intermediate 21 was obtained in 30% yield in two steps. LCMS (ESI ⁺ ): m/z = 346.1 (M+H) ⁺ , RT: 0.722 min. ¹ H NMR (400 MHz, DMSO- d6 ) δ = 7.67 (dd, J = 8.3, 7.2 Hz, 1H), 7.26 (d, J = 6.9 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H) , 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 5.01 (s, 4H), 2.93 - 2.83 (m, 1H), 2.62 - 2.54 (m, 2H), 2.06 - 1.99 (m, 1H). Intermediate 26 (4-(3-oxoazan-1-yl)phenyl)carbamate tertiary butyl ester

Preparation of Intermediate 26 Step 1: 1-(4-Nitrophenyl)azepine-3 (Ref: WO 2005/075461) (2.00 g, 10.3 mmol) was dissolved in EtOAc (40 mL) at 20 °C To the solution in Pd/C (80.0 mg, 667 µmol) and tertiary butyloxycarbonyl carbonate (2.700 g, 12.36 mmol) were added. The reaction was then stirred at 30 °C for 12 hours under _H2 (50 psi). LCMS showed the reaction was complete and the desired product was detected. The reaction mixture was filtered, and the filter cake was washed with EA (25 mL), and the collected filtrate was concentrated to obtain a crude product, which was purified by column chromatography on silica gel (with PE: EA = 100: 1 to 1:3) to obtain tertiary-butyl N- [4-(3-hydroxyazan-1-yl)phenyl]carbamate (2.500 g, 68% yield, 67.20% purity). LCMS (ESI, m/z): 265.0 [M+H] ⁺ , RT: 0.576 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.96 br s, 1H, NH), 7.20 (br d, J = 8.1 Hz, 2H), 6.34 (d, J = 8.8 Hz, 2H), 5.53 ( d, J = 6.8 Hz, 1H, OH), 4.58 - 4.44 (m, 1H), 4.00 (t, J = 7.0 Hz, 2H), 3.44 - 3.37 (m, 2H), 1.44 (s, 9H).

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Preparation of Intermediate 26 Step 2: To a solution of pyridine-sulfur trioxide (3.790 g, 23.83 mmol, 6.3 eq) in DMSO (30 mL) was added TEA (3.83 g, 37.8 mmol, 5.27 mL) at 25 °C and tert-butyl N- [4-(3-hydroxyazan-1-yl)phenyl]carbamate from Step 1 (1.00 g, 3.78 mmol). The reaction was then stirred at 25 °C for 12 h under _N2 . LCMS showed one major peak of desired MS. The reaction was quenched with cold water (50 mL) at 0 °C, then the mixture was filtered, and the filter cake was collected by suction filtration and dried in vacuo to afford intermediate 26 , N- [4-(3-oxo Azan-1-yl)phenyl]carbamate tert-butyl ester (0.45 g, 29.47% yield, 65% purity). LCMS (ESI ⁺ ): m/z = 263.1 (M+H) ⁺ , RT: 0.624 min. ¹ H NMR (400 MHz, DMSO- d6 ) δ = 9.03 (br s, 1H, NH), 7.31 (br d, J = 8.1 Hz, 2H), 6.53 (d, J = 8.9 Hz, 2H), 4.62 ( s, 4H), 1.46 (s, 9H). Intermediate 27 4-(4-(1-(4-aminophenyl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

-1-基)異吲哚啉-1,3-二酮反應而製備。兩步驟以30%產率獲得 中間物 27，4-(4-(1-(4-胺基苯基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮。LCMS (ESI ⁺)： m/z= 489.1 (M+H) ⁺，RT：0.486 min. 中間物28 甲磺酸(1-(2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)吖呾-3-基)甲酯

Intermediate 27 followed a similar two-step procedure as described in Intermediate 20 , using Intermediate 26 in place of Intermediate 19 and 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin

-1-yl) isoindoline-1,3-dione reaction and preparation. The intermediate 27 , 4-(4-(1-(4-aminophenyl)azan-3-yl)piperene, was obtained in 30% yield in two steps

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. LCMS (ESI ⁺ ): m/z = 489.1 (M+H) ⁺ , RT: 0.486 min. Intermediate 28 methanesulfonic acid (1-(2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindoline-4-yl)azan-3-yl)methyl ester

The preparation step 1 of intermediate 28 is the same as the step 1 of intermediate 18 , using aziridine-3-methanol instead of piperidin-4-ol to obtain 2-(2,6--dioxo-3-piperidinyl )-4-[3-(Hydroxymethyl)azan-1-yl]isoindoline-1,3-dione (0.20 g, 65% yield, 80.49% purity). LCMS (ESI ⁺ ): m/z = 344.1 (M+H) ⁺ , RT: 0.705 min.

The preparation step 2 of intermediate 28 is the same as the step 2 of intermediate 11 to obtain intermediate 28 , methanesulfonic acid (1-(2-(2,6-dioxo-piperidin-3-yl)-1,3 - Dioxoisoindolin-4-yl)azan-3-yl)methyl ester (0.08 g, 38.18% yield, 94.30% purity). LCMS (ESI ⁺ ): m/z = 422.1 (M+H) ⁺ , RT: 0.721 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (s, 1H), 7.58 (dd, J = 8.5, 7.2 Hz, 1H), 7.13 (d, J = 6.8 Hz, 1H), 6.81 (d , J = 8.6 Hz, 1H), 5.05 (dd, J = 12.8, 5.3 Hz, 1H), 4.44 (d, J = 6.7 Hz, 2H), 4.30 (br t, J = 8.0 Hz, 2H), 4.01 - 3.95 (m, 2H), 3.23 (s, 3H), 3.13 - 3.04 (m, 1H), 2.93 - 2.81 (m, 1H), 2.60 - 2.52 (m, 2H), 2.03 -1.93 (m, 1H). Intermediate 29 Methanesulfonic acid (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)azene-3 -yl) methyl ester

The preparation of intermediate 29 was carried out in the same manner as intermediate 28, using 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione Substituted 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione. The reaction was diluted with water (5 mL) and extracted with DCM (3 x 5 mL). After filtration, the filtrate was concentrated to obtain a crude product, which was purified by preparative TLC (PE:EA=1:1, Rf=0.4) to give intermediate 29, methanesulfonic acid (1-(2-(2 ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azan-3-yl)methyl ester (0.13 g, yield 65 %, 92.41% purity). LCMS (ESI ⁺ ): m/z = 422.0 (M+H) ⁺ , RT: 0.527 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (br s, 1H, NH), 7.65 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.68 ( dd, J = 8.3, 2.1 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.45 (d, J = 6.5 Hz, 2H), 4.14 (br t, J = 8.0 Hz, 2H) , 3.84 (dd, J = 8.6, 5.4 Hz, 2H), 3.23 (s, 3H), 3.20 - 3.12 (m, 1H), 2.62 - 2.50 (m, 2H), 2.35 - 2.28 (m, 1H), 2.05 - 1.95 (m, 1H). Intermediate 30 4-((1'-(4-aminophenyl)-[1,3'-diazepine]-3-yl)amino)-2-(2,6-dioxopiper Pyridine-3-yl)isoindoline-1,3-dione

-1-基)-1,2-二氫-3H-吡唑并[3,4-d]嘧啶-3-酮

Intermediate 30 was followed a similar two-step procedure as described in Intermediate 20 , using Intermediate 26 in place of Intermediate 19 and 4-(azene-3-amino)-2-(2,6-dioxopiperidine Pyridyl-3-yl) isoindoline-1,3-dione (reference: CN 113214227) reaction and preparation. Intermediate 30 , 4-((1'-(4-aminophenyl)-[1,3'-diazines]-3-yl)amino)-2 was obtained in 15% yield in two steps -(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione. LCMS (ESI ⁺ ): m/z = 475.1 (M+H) ⁺ , RT: 0.541 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.12 (br s, 1H, NH), 9.70 (br s, 2H, NH ₂ ), 7.65 (t, J = 7.8 Hz, 1H), 7.25 - 7.12 (m, 4H), 7.08 (br d, J = 8.5 Hz, 1H), 6.55 (d, J = 8.6 Hz, 2H), 5.09 (dd, J = 12.6, 5.4 Hz, 1H), 4.52 (br s, 2H), 4.47 - 4.38 (m, 1H), 4.27 (br s, 2H), 4.05 (br t, J = 8.0 Hz, 2H), 3.89 (br dd, J = 9.1, 3.2 Hz, 2H), 2.90 ( ddd, J = 17.0, 13.7, 5.3 Hz, 1H), 2.65 - 2.53 (m, 3H), 2.11 - 1.97 (m, 1H). Intermediate 31 (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-6-(piper

-1-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

-1-基)乙-1-酮（35.2 mg，0.078 mmol）取代1-(4-(4-胺基苯基)哌

-1-基)-2,2,2-三氟乙酮，與 中間物 7反應，接著去除三氟乙醯胺保護基團而製備，得到75%產率及81.79%純度之所欲標題產物 中間物 31，( R)-2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-6-(哌

-1-基)-1,2-二氫-3 H-吡唑并[3,4- d]嘧啶-3-酮。LCMS (ESI ⁺)： m/z= 422.2 (M+H) ⁺，RT：0.471分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 8.76 (s, 1H), 7.84 (d, J= 8.2 Hz, 1H), 7.63 (d, J= 8.1 Hz, 1H), 5.70 - 5.56 (m, 1H), 5.07 - 4.91 (m, 2H), 4.87 - 4.78 (m, 1H), 4.73 (br dd, J= 15.7, 5.4 Hz, 1H), 4.52 (br dd, J= 15.8, 6.1 Hz, 1H), 3.79 - 3.69 (m, 2H), 3.30 - 3.10 (m, 2H), 2.99 - 2.88 (m, 1H), 2.79 - 2.68 (m, 4H), 2.52 -2.45 (m, 1H), 2.33 – 2.20 (m, 1H), 2.06 - 1.97 (m, 1H), 1.92 - 1.83 (m, 1H), 1.76 - 1.62 (m, 1H), 0.86 (br t, J= 7.3 Hz, 3H)。 中間物32 4-(4-吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Intermediate 31 was prepared by following a similar procedure as described in Intermediate 1 using 2,2,2-trifluoro-1-(piper

-1-yl)ethan-1-one (35.2 mg, 0.078 mmol) substituted 1-(4-(4-aminophenyl)piperene

-1-yl)-2,2,2-trifluoroethanone, prepared by reaction with intermediate 7 , followed by removal of the trifluoroacetamide protecting group, afforded the desired title product in 75% yield and 81.79% purity Intermediate 31 , ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-6- (Piperin

-1-yl)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one. LCMS (ESI ⁺ ): m/z = 422.2 (M+H) ⁺ , RT: 0.471 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 8.76 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 5.70 - 5.56 (m , 1H), 5.07 - 4.91 (m, 2H), 4.87 - 4.78 (m, 1H), 4.73 (br dd, J = 15.7, 5.4 Hz, 1H), 4.52 (br dd, J = 15.8, 6.1 Hz, 1H ), 3.79 - 3.69 (m, 2H), 3.30 - 3.10 (m, 2H), 2.99 - 2.88 (m, 1H), 2.79 - 2.68 (m, 4H), 2.52 -2.45 (m, 1H), 2.33 – 2.20 (m, 1H), 2.06 - 1.97 (m, 1H), 1.92 - 1.83 (m, 1H), 1.76 - 1.62 (m, 1H), 0.86 (br t, J = 7.3 Hz, 3H). Intermediate 32 4-(4-Azines-3-yl)piperene

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

-1-基)異吲哚啉-1,3-二酮反應而製備。獲得 中間物 30 ，4-(4-(吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（60 mg，產率76%，96.77%純度）。LCMS (ESI ^-): m/z = 396.1 (M-H) ^-，RT：0.626分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.09 (s, 1H, NH), 8.81 (br s, 1H, NH), 7.74 (dd, J= 8.2, 7.4 Hz, 1H), 7.41 (d, J= 7.4 Hz, 1H), 7.38 (d, J= 8.2 Hz, 1H), 5.09 (dd, J= 12.7, 5.4 Hz, 1H), 4.12 - 4.02 (m, 4H), 3.81 - 3.62 (m, 1H), 3.41 (br s, 4H), 2.94 - 2.79 (m, 5H), 2.70 – 2.55 (m, 1H), 2.50 – 2.40 (m, 1H), 2.08 - 1.98 (m, 1H)。 中間物33 4-(4-(3-胺基吖呾-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Intermediate 32 was obtained by substituting intermediate 26 with 2- (2,6 - difercial Oxypiperidin-3-yl)-4-(piper

-1-yl) isoindoline-1,3-dione reaction and preparation. Obtain intermediate 30 , 4-(4-(azines-3-yl)piperene

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (60 mg, 76% yield, 96.77% purity). LCMS (ESI ⁻ ): m/z = 396.1 (MH) ⁻ , RT: 0.626 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.09 (s, 1H, NH), 8.81 (br s, 1H, NH), 7.74 (dd, J = 8.2, 7.4 Hz, 1H), 7.41 (d , J = 7.4 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 5.09 (dd, J = 12.7, 5.4 Hz, 1H), 4.12 - 4.02 (m, 4H), 3.81 - 3.62 (m, 1H), 3.41 (br s, 4H), 2.94 - 2.79 (m, 5H), 2.70 - 2.55 (m, 1H), 2.50 - 2.40 (m, 1H), 2.08 - 1.98 (m, 1H). Intermediate 33 4-(4-(3-Aminoazimin-1-yl)piperidin-1-yl)-2-(2,6-two-side oxypiperidin-3-yl)isoindoline -1,3-dione

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮(0.12 g，產率61%，72%純度）。LCMS (ESI ⁺)： m/z= 412.2 (M+H) ⁺，RT：0.664 min. 中間物34 4-(4-(6-胺基-2-氮雜螺[3.3]庚-2-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Intermediate 33 was prepared following a similar two-step procedure as described in Intermediate 27 by reacting Intermediate 18 with tertiary-butyl aziridine-3-ylcarbamate instead of Intermediate 26 . Obtain Intermediate 33 , 4-(4-(azene-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.12 g, 61% yield, 72% purity). LCMS (ESI ⁺ ): m/z = 412.2 (M+H) ⁺ , RT: 0.664 min. Intermediate 34 4-(4-(6-amino-2-azaspiro[3.3]hept-2-yl )piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Intermediate 34 was prepared following a similar two-step procedure as described in Intermediate 27 by reacting Intermediate 18 with tert-butyl (2-azaspiro[3.3]hept-6-yl)carbamate instead of Intermediate 26 . Intermediate 34 was obtained, 4-(4-(6-amino-2-azaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2,6-dioxopiper pyridin-3-yl) isoindoline-1,3-dione (0.18, 96% yield, 86.05% purity). LCMS (ESI ⁺ ): m/z = 452.2 (M+H) ⁺ , RT: 0.715 min. Intermediate 35 4-(6-(4-aminophenyl)-2,6-diazaspiro[3.3 ]hept-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Intermediate 35 was prepared by following a similar procedure as described in step 1 for intermediate 18 , substituting intermediate 19 for piperidin-4-ol, followed by standard TFA acidic Boc deprotection conditions. Intermediate 35 , 4-(6-(4-aminophenyl)-2,6-diazaspiro[3.3]hept-2-yl)-2-(2,6-dioxopiperidine) was obtained -3-yl) isoindoline-1,3-dione (0.03 g, 98% purity). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.03 (br s, 1H, NH), 7.58 (dd, J = 8.1, 7.0 Hz, 1H), 7.13 (d, J = 7.0 Hz, 1H), 6.81 (br d, J = 8.5 Hz, 1H), 6.48 (br d, J = 8.4 Hz, 2H), 6.24 (br d, J = 8.4 Hz, 2H), 5.06 (br dd, J = 12.9, 5.3 Hz , 1H), 4.53 - 4.31 (br s, 2H, NH ₂ ), 4.35 (s, 4H), 3.81 (s, 4H), 2.96 - 2.81 (m, 1H), 2.62 - 2.52 (m, 2H), 2.07 - 1.94 (m, 1H). Intermediate 36 4-(6-Amino-2-azaspiro[3.3]hept-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-diketone

烷酸性Boc去保護條件而製備。獲得 中間物 36，4-(6-胺基-2-氮雜螺[3.3]庚-2-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（100 mg，產率35%，81.28%純度）。LCMS (ESI ⁺)：m/z = 503.2 (M+H) ⁺，RT：0.831 min. 中間物37 1-(4-硝基苯基)-4-(哌啶-4-基甲基)哌

Intermediate 36 was obtained by substituting tertiary-butyl (2-azaspiro[3.3]hept-6-yl)carbamate for intermediate 19 following a similar procedure as described in step 1 for intermediate 35 , followed by standard 4N HCl/di

Prepared under alkanoic Boc deprotection conditions. Intermediate 36 , 4-(6-Amino-2-azaspiro[3.3]hept-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline was obtained -1,3-Dione (100 mg, 35% yield, 81.28% purity). LCMS (ESI ⁺ ): m/z = 503.2 (M+H) ⁺ , RT: 0.831 min. Intermediate 37 1-(4-nitrophenyl)-4-(piperidin-4-ylmethyl)piper

（3.768 g，18.21 mmol），並將反應物質在80℃下攪拌16小時。將反應混合物用水（100 mL）淬熄並用乙酸乙酯（2 × 100 mL）萃取。將有機層用飽和鹽水溶液(50 mL）洗滌，經無水硫酸鈉乾燥，過濾並濃縮，得到粗製物。將粗製物藉由使用0至25% EtOAc/石油醚作為洗提液之矽膠急驟層析法純化，得到 Boc- 中間物374-((4-(4-硝基苯基)哌

-1-基)甲基)哌啶-1-羧酸三級丁酯（6.30 g，68%）。MS (LCMS) m/z405.56 [M+H] ⁺; ¹H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J= 9.6 Hz, 2H), 6.82 (d, J= 9.6 Hz, 2H), 4.13-4.10 (m, 2H), 3.41(br t, J= 5.0 Hz, 4H), 2.76 (br t, J= 12.2 Hz, 2H), 2.54 (br t, J= 5.0 Hz, 4H), 2.24 (d, J= 7.2 Hz, 2H), 1.75 (br d, J= 13.6 Hz, 2H), 1.62 - 1.48 (m, 1H), 1.46 (s, 9H), 1.10 (td, J= 11.6, 4.0 Hz, 2H)。 Preparation of Intermediate 37 Step 1: To a stirred solution of tert-butyl 4-(iodomethyl)piperidine-1-carboxylate (7.400 g, 22.76 mmol) in DMF (74 mL) was added potassium carbonate (6.281 g, 45.512 mmol) and 1-(4-nitrophenyl)piperene

(3.768 g, 18.21 mmol), and the reaction mass was stirred at 80°C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layer was washed with saturated brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give crude. The crude was purified by flash chromatography on silica gel using 0 to 25% EtOAc/petroleum ether as eluent to afford Boc- intermediate 37 4-((4-(4-nitrophenyl)piper

-1-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (6.30 g, 68%). MS (LCMS) m/z 405.56 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 9.6 Hz, 2H), 6.82 (d, J = 9.6 Hz, 2H), 4.13-4.10 (m, 2H), 3.41(br t, J = 5.0 Hz, 4H), 2.76 (br t, J = 12.2 Hz, 2H), 2.54 (br t, J = 5.0 Hz, 4H), 2.24 ( d, J = 7.2 Hz, 2H), 1.75 (br d, J = 13.6 Hz, 2H), 1.62 - 1.48 (m, 1H), 1.46 (s, 9H), 1.10 (td, J = 11.6, 4.0 Hz, 2H).

之TFA鹽（4.10 g，65%）。MS (LCMS) m/z305.19 [M+H-TFA] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 8.76 (br s, 1H), 8.52 (br s, 1H), 8.13 (d, J= 9.6 Hz, 2H), 7.16 (d, J= 9.6 Hz, 2H), 4.18 (br s, 2H), 3.75 - 3.54 (m, 2H), 3.39 - 3.30 (m, 4H), 3.12 - 3.10 (m, 4H), 2.95 - 2.85 (m, 2H), 2.15 (br s, 1H), 1.92 (d, J= 13.2 Hz, 2H), 1.47 - 1.31 (m, 2H)。 中間物38 4-(4-((4-(4-胺基苯基)哌

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異二氫吲哚-1,3-二酮

Preparation of Intermediate 37 Step 2: To a stirred solution of Boc- Intermediate 37 (6.30 g, 15.6 mmol) in DCM (60 mL) at 0 °C was added trifluoroacetic acid (11.9 mL, 156 mmol) dropwise, The reaction mass was stirred at room temperature for 2 hours. Upon completion, the reaction mass was concentrated under reduced pressure. The residue was washed with ether (50 mL) to give 1-(4-nitrophenyl)-4-(piperidin-4-ylmethyl)piper

TFA salt (4.10 g, 65%). MS (LCMS) m/z 305.19 [M+H-TFA] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.76 (br s, 1H), 8.52 (br s, 1H), 8.13 (d, J = 9.6 Hz, 2H), 7.16 (d, J = 9.6 Hz, 2H), 4.18 (br s, 2H), 3.75 - 3.54 (m, 2H), 3.39 - 3.30 (m, 4H), 3.12 - 3.10 ( m, 4H), 2.95 - 2.85 (m, 2H), 2.15 (br s, 1H), 1.92 (d, J = 13.2 Hz, 2H), 1.47 - 1.31 (m, 2H). Intermediate 38 4-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-two-side oxypiperidin-3-yl)isoindoline-1,3-dione

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（350 mg，61%，兩步驟）。MS (LCMS) m/z531.65 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H, NH), 7.69 (dd , J= 8.4, 7.2 Hz, 1H), 7.33 (d, J= 8.4 Hz, 1H), 7.31 (d, J= 7.2 Hz, 1H), 6.68 (d, J= 9.6 Hz, 2H), 6.49 (d, J= 7.6 Hz, 2H), 5.08 (dd, J= 13.2, 5.2 Hz, 1H), 4.58 (br s, 2H), 3.71 - 3.68 (m, 2H), 3.54 – 3.37 (m, 1H), 3.16 (d, J= 5.2 Hz, 2H), 2.95 - 2.80 (m, 6H), 2.62 - 2.50 (m, 2H), 2.26 - 2.24 (m, 2H), 2.07 - 1.95 (m, 1H), 1.86 - 1.62 (m, 3H), 1.36 - 1.31 (m, 2H)。 中間物39 5-(4-((4-(4-胺基苯基)哌

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異二氫吲哚-1,3-二酮

Intermediate 38 was prepared by following a similar procedure as described in Step 1 for Intermediate 35 , substituting Intermediate 37 for Intermediate 35 , followed by standard Pd/carbon catalyzed nitrohydrogen reduction under hydrogen balloon conditions. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 38 , 4-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (350 mg, 61 %, two steps). MS (LCMS) m/z 531.65 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H, NH), 7.69 (dd , J = 8.4, 7.2 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.31 ( d, J = 7.2 Hz, 1H), 6.68 (d, J = 9.6 Hz, 2H), 6.49 (d, J = 7.6 Hz, 2H), 5.08 (dd, J = 13.2, 5.2 Hz, 1H), 4.58 ( br s, 2H), 3.71 - 3.68 (m, 2H), 3.54 – 3.37 (m, 1H), 3.16 (d, J = 5.2 Hz, 2H), 2.95 - 2.80 (m, 6H), 2.62 - 2.50 (m , 2H), 2.26 - 2.24 (m, 2H), 2.07 - 1.95 (m, 1H), 1.86 - 1.62 (m, 3H), 1.36 - 1.31 (m, 2H). Intermediate 39 5-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-two-side oxypiperidin-3-yl)isoindoline-1,3-dione

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（605 mg，57%，兩步驟）。MS (LCMS) m/z531.51 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.03 (s, 1H, NH), 7.64 (d, J= 8.4 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J= 8.8 Hz, 1H), 6.68 (d, J= 8.8 Hz, 2H), 6.49 (d, J= 8.4 Hz, 2H), 5.05 (dd, J= 8.8, 5.2 Hz, 1H),), 4.58 (br s, 2H), 4.05 (d, J= 12.8 Hz, 2H), 3.03 - 2.81 (m, 7H), 2.65 - 2.48 (m, 4H), 2.22 - 2.18 (m, 2H), 2.02 - 1.99 (m, 1H), 1.92 -1.75 (m, 3H), 1.30 - 1.05 (m, 2H)。 中間物40 3-(4-(4-((4-(4-胺基苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 39 was obtained by following a similar procedure as described for Intermediate 38 using 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline 1,3-dione Substitution of 2-(2,6-side oxypiperidin 3-yl)-4-fluoroisoindoline-1,3-dione and preparation. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 39 , 5-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (605 mg, 57 %, two steps). MS (LCMS) m/z 531.51 [M+H] ⁺ . ¹ H NMR (400 MHz , DMSO- d ₆ ) δ 11.03 (s, 1H, NH), 7.64 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.49 (d, J = 8.4 Hz, 2H), 5.05 (dd, J = 8.8, 5.2 Hz, 1H),), 4.58 (br s, 2H) , 4.05 (d, J = 12.8 Hz, 2H), 3.03 - 2.81 (m, 7H), 2.65 - 2.48 (m, 4H), 2.22 - 2.18 (m, 2H), 2.02 - 1.99 (m, 1H), 1.92 -1.75 (m, 3H), 1.30 - 1.05 (m, 2H). Intermediate 40 3-(4-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

烷（5 mL）中之攪拌溶液添加磷酸三鉀（1.045 g，4.928 mmol），且將反應物質與氮氣脫氣15分鐘。向此混合物添加Pd-PEPPSI-iHeptCl（0.160 g，0.164 mmol）且在120℃下將反應物質攪拌16小時。完成後，將反應物質用冰冷水（10 mL）稀釋且用10% MeOH/DCM（2 ×30 mL）萃取。將有機層經硫酸鈉乾燥，過濾，並在減壓下濃縮，得到粗製物。將粗製物藉由使用0至7%甲醇/DCM作為洗提液之矽膠急驟層析法純化，得到3-(4-(4-((4-(4-硝基苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（305 mg，34%）。MS (LCMS) m/z547.52 [M+H] ⁺; ¹H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J= 9.6 Hz, 2H), 8.00 (br s, 1H), 7.53 (d, J= 7.2 Hz, 1H), 7.43 (dd, J= 7.6, 7.2 Hz, 1H), 7.15 (d, J= 7.6 Hz, 1H), 6.83 (d, J= 9.6 Hz, 2H), 5.26 (dd, J= 8.0, 5.2 Hz, 1H), 4.46 (d, J= 16.0 Hz, 1H), 4.19 (d, J= 16.0 Hz, 1H), 3.44 - 3.30 (m, 6H), 2.98 - 2.70 (m, 4H), 2.59 - 2.56 (m, 4H), 2.46 - 2.34 (m, 1H), 2.30 (d, J= 7.2 Hz, 2H), 2.26 - 2.16 (m, 1H), 1.96 - 1.85 (m, 2H), 1.78 - 1.63 (m, 1H), 1.43 - 1.30 (m, 2H)。 Preparation of Intermediate 40 Step 1: Add Intermediate 37 (0.500 g, 1.64 mmol) and 3-(4-bromo-1-oxoisoindoline-2-yl)piperidine-2 at room temperature ,6-diketone (0.531 g, 1.64 mmol) in 1,4-dione

To a stirred solution in alkanes (5 mL) was added tripotassium phosphate (1.045 g, 4.928 mmol) and the reaction mass was degassed with nitrogen for 15 minutes. To this mixture was added Pd-PEPPSI-iHeptCl (0.160 g, 0.164 mmol) and the reaction mass was stirred at 120 °C for 16 hours. Upon completion, the reaction mass was diluted with ice cold water (10 mL) and extracted with 10% MeOH/DCM (2 x 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 7% methanol/DCM as eluent to afford 3-(4-(4-((4-(4-nitrophenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (305 mg, 34%). MS (LCMS) m/z 547.52 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (d, J = 9.6 Hz, 2H), 8.00 (br s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.43 (dd, J = 7.6, 7.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 9.6 Hz, 2H), 5.26 (dd, J = 8.0, 5.2 Hz, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.19 (d, J = 16.0 Hz, 1H), 3.44 - 3.30 (m, 6H), 2.98 - 2.70 (m, 4H ), 2.59 - 2.56 (m, 4H), 2.46 - 2.34 (m, 1H), 2.30 (d, J = 7.2 Hz, 2H), 2.26 - 2.16 (m, 1H), 1.96 - 1.85 (m, 2H), 1.78 - 1.63 (m, 1H), 1.43 - 1.30 (m, 2H).

-1-基)甲基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（270 mg，95%）。MS (LCMS) m/z517.67 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1H, NH), 7.42 (dd, J= 8.0, 7.6 Hz, 1H), 7.29 (d, J= 7.6 Hz, 1H), 7.16 (d, J= 8.0 Hz, 1H), 6.68 (d, J= 8.4 Hz, 2H), 6.59 (d, J= 8.4 Hz, 2H), 5.11 (dd, J= 13.2, 4.8 Hz, 1H), 4.64 (br s, 2H, NH), 4.43 (d, J= 17.2 Hz, 1H), 4.29 (d, J= 17.2 Hz, 1H), 3.39 - 3.32 (m, 2H), 2.92 - 2.89 (m, 6H), 2.80 - 2.68 (m, 3H), 2.65 - 2.45 (m, 4H), 2.32 - 2.15 (m, 2H), 2.05 -1.97 (m, 1H), 1.88 - 1.80 (m, 2H), 1.80 – 1.17 (m, 1H), 1.35 - 1.21 (m, 2H)。 中間物41 3-(5-(4-((4-(4-胺基苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)-1-甲基哌啶-2,6-二酮

Preparation step 2 of intermediate 40 is similar to preparation step 2 of intermediate 39 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 40 , 3-(4-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (270 mg, 95%). MS (LCMS) m/z 517.67 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1H, NH), 7.42 (dd, J = 8.0, 7.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.16 ( d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 8.4 Hz, 2H), 5.11 (dd, J = 13.2, 4.8 Hz, 1H), 4.64 ( br s, 2H, NH), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.39 - 3.32 (m, 2H), 2.92 - 2.89 (m, 6H), 2.80 - 2.68 (m, 3H), 2.65 - 2.45 (m, 4H), 2.32 - 2.15 (m, 2H), 2.05 -1.97 (m, 1H), 1.88 - 1.80 (m, 2H), 1.80 – 1.17 (m , 1H), 1.35 - 1.21 (m, 2H). Intermediate 41 3-(5-(4-((4-(4-aminophenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)-1-methylpiperidine-2,6-dione

-1-基)甲基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)-1-甲基哌啶-2,6-二酮（兩步驟0.230 g，27%產率）。MS (LCMS) m/z531.36 [M+H] ⁺。 ¹H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J= 8.4 Hz, 1H), 6.99 (d, J= 8.8 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J= 8.4 Hz, 2H), 6.66 (d, J= 8.4 Hz, 2H), 5.16 (dd, J= 13.2, 4.8 Hz, 1H), 4.37 (d, J= 15.6 Hz, 1H), 4.24 (d, J= 15.6 Hz, 1H), 3.84 (d, J= 12.8 Hz, 2H), 3.18 (s, 3H), 3.06(br s, 4H), 2.90 -2.76 (m, 3H), 2.59 (br s, 4H), 2.35 - 2.22 (m, 2H), 2.20 - 2.11 (m, 1H), 1.95 - 1.86 (m, 2H), 1.85 - 1.70 (m, 1H), 1.72 - 1.50 (m, 2H), 1.40 - 1.23 (m, 2H)。 中間物42 1-(吖呾-3-基)-4-(4-硝基苯基)哌

Intermediate 41 was obtained by following a similar procedure as described for Intermediate 40 using 3-(5-bromo-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6 Prepared by substituting -diketone for 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione. Intermediate 41 , 3-(5-(4-((4-(4-aminophenyl)piperene) was obtained

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)-1-methylpiperidine-2,6-dione (two steps 0.230 g, 27% yield). MS (LCMS) m/z 531.36 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 6.88 (s, 1H), 6.82 (d, J = 8.4 Hz , 2H), 6.66 (d, J = 8.4 Hz, 2H), 5.16 (dd, J = 13.2, 4.8 Hz, 1H), 4.37 (d, J = 15.6 Hz, 1H), 4.24 (d, J = 15.6 Hz , 1H), 3.84 (d, J = 12.8 Hz, 2H), 3.18 (s, 3H), 3.06(br s, 4H), 2.90 -2.76 (m, 3H), 2.59 (br s, 4H), 2.35 - 2.22 (m, 2H), 2.20 - 2.11 (m, 1H), 1.95 - 1.86 (m, 2H), 1.85 - 1.70 (m, 1H), 1.72 - 1.50 (m, 2H), 1.40 - 1.23 (m, 2H ). Intermediate 42 1-(Azines-3-yl)-4-(4-nitrophenyl)piper

（3.000 g，14.47 mmol）及3-側氧基吖呾-1-羧酸三級丁酯（2.478 g，14.47 mmol）於二氯甲烷（30 mL）中之攪拌溶液添加NaBH(OAc) ₃（9.200 g，43.43 mmol），並將所得混合物在室溫下攪拌3小時。接著將反應用水(30 mL）淬熄，並用二氯甲烷(3 x 50 mL）萃取。將有機層用水（20 mL）、鹽水（20 mL）洗滌，經無水硫酸鈉乾燥，並在減壓下濃縮。將殘餘物藉由使用0至60%乙酸乙酯/石油醚作為洗提液之矽膠急驟管柱層析法純化，得到 Boc- 中間物42（3.60 g，69%）。MS (LCMS) m/z363.47 [M+H] ⁺; ¹H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J= 9.6 Hz, 2H), 6.83 (d, J= 9.6 Hz, 2H), 4.00 - 3.93 (m, 2H), 3.88 - 3.82 (m, 2H), 3.45 (br t, J= 5.0 Hz, 4H), 3.13 (p, J= 5.0 Hz, 1H), 2.51 (m, J= 5.0 Hz, 4H), 1.44 (s, 9H)。 Preparation Step 1 of Intermediate 42 : To 1-(4-nitrophenyl)piperene

NaBH(OAc) ₃ ( 9.200 g, 43.43 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was then quenched with water (30 mL) and extracted with dichloromethane (3 x 50 mL). The organic layer was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 0 to 60% ethyl acetate/petroleum ether as eluent to afford Boc- intermediate 42 (3.60 g, 69%). MS (LCMS) m/z 363.47 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (d, J = 9.6 Hz, 2H), 6.83 (d, J = 9.6 Hz, 2H), 4.00 - 3.93 (m, 2H), 3.88 - 3.82 (m, 2H), 3.45 (br t, J = 5.0 Hz, 4H), 3.13 (p, J = 5.0 Hz, 1H), 2.51 (m, J = 5.0 Hz, 4H), 1.44 (s, 9H).

（2.31 g，89%）用於下一步反應而不經進一步純化。MS (LCMS) m/z263.25 [M+H] ⁺。 中間物43 5-(3-(4-(4-胺基苯基)哌

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Step 2 of the preparation of intermediate 42 is under standard TFA acidic Boc deprotection conditions to give intermediate 42 , 1-(azene-3-yl)-4-(4-nitrophenyl)piper

(2.31 g, 89%) was used in the next reaction without further purification. MS (LCMS) m/z 263.25 [M+H] ⁺ . Intermediate 43 5-(3-(4-(4-aminophenyl)piperene

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（0.350 g，70%及62%，兩步驟）。MS (LCMS) m/z489.59 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 7.65 (d, J= 8.0 Hz, 1H), 6.80 (d, J= 1.6 Hz, 1H), 6.69 (d, J= 8.8 Hz, 2H), 6.66 (dd, J= 8.0, 1.6 Hz, 2H), 6.49 (d, J= 8.8 Hz, 2H), 5.06 (dd, J= 12.8, 5.2 Hz, 1H), 4.61 (br s, 2H, NH ₂), 4.12 (t, J= 7.6 Hz, 2H), 3.93 - 4.84 (m, 2H), 3.42 - 3.32 (m, 1H), 2.94 (br s, 4H), 2.93 - 2.81 (m, 1H), 2.64 - 2.48 (m, 6H), 2.05 - 1.95 (m, 1H)。 中間物44 3-(4-(3-(4-(4-胺基苯基)哌

-1-基)吖呾-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 43 was prepared by substituting Intermediate 42 for Intermediate 37 following a similar procedure as described for Intermediate 39 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 43 , 5-(3-(4-(4-aminophenyl)piperene

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.350 g, 70% and 62 %, two steps). MS (LCMS) m/z 489.59 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 7.65 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 6.69 (d, J = 8.8 Hz, 2H), 6.66 (dd, J = 8.0, 1.6 Hz, 2H), 6.49 (d, J = 8.8 Hz, 2H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.61 ( br s, 2H, NH ₂ ), 4.12 (t, J = 7.6 Hz, 2H), 3.93 - 4.84 (m, 2H), 3.42 - 3.32 (m, 1H), 2.94 (br s, 4H), 2.93 - 2.81 (m, 1H), 2.64 - 2.48 (m, 6H), 2.05 - 1.95 (m, 1H). Intermediate 44 3-(4-(3-(4-(4-aminophenyl)piperene

-1-yl)azan-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)吖呾-1-基)-1-側氧基異吲哚啉-2-基)哌啶2,6-二酮（305 mg，36%及91%，兩步驟）。MS (LCMS) m/z475.58 [M+H] ⁺。 中間物45 3-(5-(3-(4-(4-胺基苯基)哌

-1-基)吖呾-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 44 was prepared by substituting Intermediate 42 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 44 , 3-(4-(3-(4-(4-aminophenyl)piperene

-1-yl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine 2,6-dione (305 mg, 36% and 91%, two steps). MS (LCMS) m/z 475.58 [M+H] ⁺ . Intermediate 45 3-(5-(3-(4-(4-aminophenyl)piperene

-1-yl)azan-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)吖呾-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（410 mg，46%及97%，兩步驟）。MS (LCMS) m/z475.61 [M+H] ⁺。 中間物46 1-(1-(4-硝基苯基)吖呾-3-基)哌

Intermediate 45 was prepared by substituting Intermediate 42 for Intermediate 37 following the procedure described for Intermediate 41 . Intermediate 45 , 3-(5-(3-(4-(4-aminophenyl)piperene) was obtained

-1-yl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (410 mg, 46% and 97%, two steps). MS (LCMS) m/z 475.61 [M+H] ⁺ . Intermediate 46 1-(1-(4-nitrophenyl)azan-3-yl)piper

-1-羧酸三級丁酯(1.8 g，7.46 mmol）及1-氟基-4-硝基苯（1.05 g，7.46 mmol）於DMF（18 mL）中之溶液添加K ₂CO ₃(1.55 g，11.2 mmol），並將反應混合物在50℃攪拌16小時。將反應混合物冷卻至室溫，並用冰冷水（25 mL）稀釋。將所得材料過濾並收集，與戊烷（5 mL）一起研磨並在真空下進一步乾燥30分鐘，獲得 Boc- 中間物46，4-(1-(4-硝基苯基)吖呾-3-基)哌

-1-羧酸三級丁酯(2.1 g，78%）。MS (LCMS) m/z363.47 [M+H] ⁺。 ¹H NMR (400 MHz, CDCl ₃ ) δ 8.11 (dd, J= 7.6, 2.0 Hz, 2H), 6.32 (dd, J= 7.6, 2.0 Hz, 2H), 4.10 (t, J= 7.6 Hz, 2H), 3.89 (dd, J= 8.4, 5.2 Hz, 2H) 3.48 (t, J= 4.8 Hz, 4H), 3.41-3.37 (m, 1H), 2.38 (t, J= 4.8 Hz, 4H), 1.49 (s, 9H). Preparation Step 1 of Intermediate 46 : To 4-(Azines-3-yl)piperene

- To a solution of tertiary-butyl 1-carboxylate (1.8 g, 7.46 mmol) and 1-fluoro-4-nitrobenzene (1.05 g, 7.46 mmol) in DMF (18 mL) was added K ₂ CO ₃ (1.55 g, 11.2 mmol), and the reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with ice-cold water (25 mL). The resulting material was collected by filtration, triturated with pentane (5 mL) and further dried under vacuum for 30 min to afford Boc- intermediate 46 , 4-(1-(4-nitrophenyl)azepine-3- base) piperpe

- tert-butyl 1-carboxylate (2.1 g, 78%). MS (LCMS) m/z 363.47 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (dd, J = 7.6, 2.0 Hz, 2H), 6.32 (dd, J = 7.6, 2.0 Hz, 2H), 4.10 (t, J = 7.6 Hz, 2H) , 3.89 (dd, J = 8.4, 5.2 Hz, 2H) 3.48 (t, J = 4.8 Hz, 4H), 3.41-3.37 (m, 1H), 2.38 (t, J = 4.8 Hz, 4H), 1.49 (s , 9H).

之TFA鹽（1.51 g，76%）。MS (LCMS) m/z263.34 [M+H] ⁺。 中間物47 5-(4-(1-(4-胺基苯基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Preparation of Intermediate 46 Step 2: To a stirred solution of Boc- Intermediate 46 (2.00 g, 5.52 mmol) in dichloromethane (20 mL) at 0 °C was added trifluoroacetic acid (4.25 mL) and the mixture was Stir at room temperature for 3 hours. The reaction solution was concentrated and the residue was triturated with diethyl ether (10 mL) to give 1-(1-(4-nitrophenyl)azepine-3-yl)piper

TFA salt (1.51 g, 76%). MS (LCMS) m/z 263.34 [M+H] ⁺ . Intermediate 47 5-(4-(1-(4-aminophenyl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

-1-基)-2 -(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（180 mg，64%及64%，兩步驟）。MS (LCMS) m/z489.59 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 7.68 (d, J= 8.4 Hz, 1H), 7.35 (d, J= 2.0 Hz, 1H), 7.26 (dd, J= 8.8, 2.0 Hz, 1H), 6.48 (d, J= 8.4 Hz, 2H), 6.24 (d, J= 8.4 Hz, 2H), 5.07 (dd, J= 12.8, 5.2 Hz, 1H), 4.13 (t, J= 8.0 Hz, 2H), 3.81 (t, J= 6.4 Hz, 2H), 3.50 (br s, 4H), 3.46 - 3.35 (m, 1H), 2.94 - 2.83 (m, 1H), 2.65 - 2.50 (m, 5H), 2.52 - 2.38 (m, 1H), 2.08 - 1.99 (m, 1H)。 中間物48 3-(4-(4-(1-(4-胺基苯基)吖呾-3-基)哌

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 47 was prepared by substituting Intermediate 46 for Intermediate 37 following a similar procedure as described for Intermediate 39 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 47 , 5-(4-(1-(4-aminophenyl)azepine-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (180 mg, 64% and 64%, two steps). MS (LCMS) m/z 489.59 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 7.68 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 6.48 (d, J = 8.4 Hz, 2H), 6.24 (d, J = 8.4 Hz, 2H), 5.07 (dd, J = 12.8, 5.2 Hz, 1H), 4.13 ( t, J = 8.0 Hz, 2H), 3.81 (t, J = 6.4 Hz, 2H), 3.50 (br s, 4H), 3.46 - 3.35 (m, 1H), 2.94 - 2.83 (m, 1H), 2.65 - 2.50 (m, 5H), 2.52 - 2.38 (m, 1H), 2.08 - 1.99 (m, 1H). Intermediate 48 3-(4-(4-(1-(4-aminophenyl)azan-3-yl)piper

-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（180 mg，21%及96%，兩步驟）。MS (LCMS) m/z475.64 [M+H] ⁺。 中間物49 3-(5-(4-(1-(4-胺基苯基)吖呾-3-基)哌

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 48 was prepared by substituting Intermediate 46 for Intermediate 37 following the procedure described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 48 , 3-(4-(4-(1-(4-aminophenyl)azepine-3-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 21% and 96%, two steps). MS (LCMS) m/z 475.64 [M+H] ⁺ . Intermediate 49 3-(5-(4-(1-(4-aminophenyl)azan-3-yl)piper

-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（180 mg，41%及66%，兩步驟）。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.01 (s, 1H, NH), 7.95 (s, 1H), 7.53 (d, J= 8.8 Hz, 1H), 7.09 (s, 1H), 7.07 (d, J= 8.8 Hz, 2H), 6.68 (d, J= 8.0 Hz, 2H), 6.33 (d, J= 8.4 Hz, 2H), 5.05 (dd, J= 13.2, 4.8 Hz, 1H), 4.33 (d, J= 17.2 Hz, 1H), 4.21 (d, J= 17.2 Hz, 1H), 3.87 (t, J= 6.4 Hz, 2H), 3.53 (t, J= 6.4 Hz, 2H), 3.19 (br s, 4H), 3.28 - 3.15 (m, 1H), 2.95 - 2.83 (m, 1H), 2.70 - 2.50 (m, 5H), 2.45 - 2.33 (m, 1H), 1.99 - 1.92 (m, 1H)。 中間物50 2-(4-硝基苯基)-6-(哌啶-4-基)-2,6-二氮雜螺[3.3]庚烷

Intermediate 49 was prepared by substituting Intermediate 46 for Intermediate 37 following the procedure described for Intermediate 41 . Intermediate 49 , 3-(5-(4-(1-(4-aminophenyl)azan-3-yl)piperene was obtained

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (180 mg, 41% and 66%, two steps). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.01 (s, 1H, NH), 7.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 7.07 ( d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 8.4 Hz, 2H), 5.05 (dd, J = 13.2, 4.8 Hz, 1H), 4.33 ( d, J = 17.2 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H), 3.87 (t, J = 6.4 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 3.19 (br s , 4H), 3.28 - 3.15 (m, 1H), 2.95 - 2.83 (m, 1H), 2.70 - 2.50 (m, 5H), 2.45 - 2.33 (m, 1H), 1.99 - 1.92 (m, 1H). Intermediate 50 2-(4-nitrophenyl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane

Intermediate 50 was prepared by substituting intermediate 26 with 2-(4-nitrophenyl) using a similar two-step procedure as described in intermediate 27 , using tertiary-butyl 4-oxopiperidine-1-carboxylate -2,6-diazaspiro[3.3] (reference: WO 2021/255212) was prepared by reaction. The reaction mixture was concentrated and the residue was diluted with saturated aqueous sodium bicarbonate (100 mL), and extracted with 10% MeOH/DCM (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give crude. The crude was triturated with diethyl ether (80 mL) to give 2-(4-nitrophenyl)-6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane (1.59 g, 97% and 85%, two steps). MS (LCMS) m/z 303.41 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d _{6 )} δ 8.04 (d, J = 9.2 Hz, 2H), 6.42 (d, J = 9.2 Hz, 2H ), 4.09 (s, 4H), 3.24 (s, 4H), 2.89 (br d, J = 12.4 Hz, 2H), 2.39 (t, J = 10.8 Hz, 2H), 2.01 - 1.90 (m, 1H), 1.54 (d, J = 10.4 Hz, 2H), 1.03 -0.94 (m, 2H). Intermediate 51 5-(4-(6-(4-aminophenyl)-2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Intermediate 51 was prepared by substituting Intermediate 50 for Intermediate 37 following a similar procedure as described for Intermediate 39 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford Intermediate 51 , 5-(4-(6-(4-aminophenyl)-2,6-diazaspiro[ 3.3] Hept-2-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.340 g, 46 % and 86%, two steps). MS (LCMS) m/z 529.404 [M+H] ⁺ . Intermediate 52 3-(4-(4-(6-(4-aminophenyl)-2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-1- Pendantoxyisoindolin-2-yl)piperidine-2,6-dione

Intermediate 52 was prepared by substituting Intermediate 50 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 52 , 3-(4-(4-(6-(4-aminophenyl)-2,6-diazepine Heterospiro[3.3]hept-2-yl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (0.155 g, 34% and 99 %, two steps). MS (LCMS) m/z 515.70 [M+H] ⁺ . Intermediate 53 1-(4-nitrophenyl)-4-(piperidin-4-yl)piper

取代2-(4-硝基苯基)-2,6-二氮雜螺[3.3]庚烷與4-側氧哌啶-1-羧酸三級丁酯反應而製備。獲得 中間物 53，1-(4-硝基苯基)-4-(哌啶-4 -基)哌

（1.61 g，64%及86%，兩步驟）。MS (LCMS) m/z291.33 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d , J= 9.2 Hz, 2H), 7.01 (d, J= 9.2 Hz, 2H), 3.42 (t, J= 4.8 Hz, 4H), 2.95 (br d, J= 12.4 Hz, 2H), 2.60 (t, J= 4.8 Hz, 4H), 2.40 (t, J= 11.6 Hz, 2H), 2.35 - 2.23 (m, 1H), 1.70 (br d, J= 9.2 Hz, 2H), 1.33 - 1.20 (m, 2H)。 中間物54 5-(4-(4-(4-胺基苯基)哌

-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮

Intermediate 53 was prepared by following a similar two-step procedure as described in Intermediate 42 , using 1-(4-nitrophenyl)piperene

Substituted 2-(4-nitrophenyl)-2,6-diazaspiro[3.3]heptane and 4-side oxygen piperidine-1-carboxylic acid tertiary butyl reaction to prepare. Intermediate 53 , 1-(4-nitrophenyl)-4-(piperidin-4-yl)piper was obtained

(1.61 g, 64% and 86%, two steps). MS (LCMS) m/z 291.33 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d , J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H ), 3.42 (t, J = 4.8 Hz, 4H), 2.95 (br d, J = 12.4 Hz, 2H), 2.60 (t, J = 4.8 Hz, 4H), 2.40 (t, J = 11.6 Hz, 2H) , 2.35 - 2.23 (m, 1H), 1.70 (br d, J = 9.2 Hz, 2H), 1.33 - 1.20 (m, 2H). Intermediate 54 5-(4-(4-(4-aminophenyl)piperene

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

-1-基)哌啶-1-基)-2 -(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（0.220 g，61%及66%，兩步驟）。MS (LCMS) m/z517.43 [M+H] ⁺。 中間物55 3-(4-(4-(4-(4-胺基苯基)哌

-1-基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 54 was prepared by substituting Intermediate 53 for Intermediate 37 following a similar procedure as described for Intermediate 39 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 54 , 5-(4-(4-(4-aminophenyl)piperene

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.220 g, 61% and 66 %, two steps). MS (LCMS) m/z 517.43 [M+H] ⁺ . Intermediate 55 3-(4-(4-(4-(4-aminophenyl)piperene

-1-yl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)哌啶-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（72 mg，39%及25%，兩步驟）。MS (LCMS) m/z503.70 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 10.99 (s, 1H, NH), 7.43 (t, J= 7.6 Hz, 1H), 7.30 (d, J= 7.6 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.68 (d, J= 8.8 Hz, 2H), 6.49 (d , J= 8.4 Hz, 2H), 5.12 (dd, J= 13.4, 5.0 Hz, 1H), 4.45 (d, J= 17.2 Hz, 1H), 4.30 (d, J= 17.2 Hz, 1H), 3.52 - 3.39 (m, 2H), 3.33 (br s, 4H), 2.95 (br s, 4H), 2.80 - 2.70 (m, 2H), 2.70 - 2.60 (m, 3H), 2.60 - 2.38 (m, 1H), 2.05 - 1.95 (m, 1H), 1.95 - 1.85 (m, 2H), 1.68 - 1.54 (m, 2H)。 中間物56 6-(4-(4-硝基苯基)哌

-1-基)-2 -氮雜螺[3.3]庚烷

Intermediate 55 was prepared by substituting Intermediate 53 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 55 , 3-(4-(4-(4-(4-aminophenyl)piperene

-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (72 mg, 39% and 25%, two steps). MS (LCMS) m/z 503.70 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.99 (s, 1H, NH), 7.43 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.49 (d , J = 8.4 Hz, 2H), 5.12 (dd, J = 13.4, 5.0 Hz, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.52 - 3.39 (m, 2H), 3.33 (br s, 4H), 2.95 (br s, 4H), 2.80 - 2.70 (m , 2H), 2.70 - 2.60 (m, 3H), 2.60 - 2.38 (m, 1H), 2.05 - 1.95 (m, 1H), 1.95 - 1.85 (m, 2H), 1.68 - 1.54 (m, 2H). Intermediate 56 6-(4-(4-nitrophenyl)piperene

-1-yl)-2-azaspiro[3.3]heptane

反應而製備。獲得 中間物 56，6-(4-(4-硝基苯基)哌

-1-基)-2-氮雜螺[3.3]庚烷（0.680 g，72%及90%，兩步驟）。MS (LCMS) m/z303.70 [M+H] ⁺。 中間物57 3- (4-(6-(4-(4-胺基苯基)哌

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 56 was obtained by following a similar two-step procedure as described in Intermediate 53 , using substituted 4-oxo of 6-oxo-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl tertiary butyl piperidine-1-carboxylate and 1-(4-nitrophenyl) piperidine

prepared by reaction. Intermediate 56 , 6-(4-(4-nitrophenyl)piperene was obtained

-1-yl)-2-azaspiro[3.3]heptane (0.680 g, 72% and 90%, two steps). MS (LCMS) m/z 303.70 [M+H] ⁺ . Intermediate 57 3-(4-(6-(4-(4-aminophenyl)piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)-2 -氮雜螺[3.3]庚-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（350 mg，45%及84%，兩步驟）。MS (LCMS) m/z529.32 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H, NH), 7.31 (t, J= 7.6 Hz, 1H), 7.05 (d, J= 7.6 Hz, 1H), 6.67 (d, J= 8.8 Hz, 2H), 6.53 (d, J= 7.6 Hz, 1H), 6.48 (d, J= 8.8 Hz, 2H), 5.10 (dd, J= 13.2, 5.2 Hz, 1H), 4.42 (d, J= 16.8 Hz, 1H), 4.27 (d, J= 16.8 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.93 - 3.84 (m, 2H), 2.95 (br s, 4H), 3.00 - 2.90 (m, 1H), 2.70 – 2.55 (m, 2H), 2.47 -2.37 (m, 1H), 2.36 (br s, 4H), 2.37 - 2.25 (m, 2 H), 2.08 - 1.86 (m, 3H)。 中間物58 3-(5-(6-(4-(4-胺基苯基)哌

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 57 was prepared by substituting Intermediate 56 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 57 , 3-(4-(6-(4-(4-aminophenyl)piperene

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (350 mg, 45% and 84%, two steps). MS (LCMS) m/z 529.32 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H, NH), 7.31 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.67 (d , J = 8.8 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 8.8 Hz, 2H), 5.10 (dd, J = 13.2, 5.2 Hz, 1H), 4.42 (d , J = 16.8 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.93 - 3.84 (m, 2H), 2.95 (br s, 4H), 3.00 - 2.90 (m, 1H), 2.70 – 2.55 (m, 2H), 2.47 -2.37 (m, 1H), 2.36 (br s, 4H), 2.37 - 2.25 (m, 2H), 2.08 - 1.86 (m, 3H) . Intermediate 58 3-(5-(6-(4-(4-aminophenyl)piperene

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮（0.305 g，28%及67%，兩步驟）。MS (LCMS) m/z515.32 [M+H] ⁺。 中間物59 2-(1-(4-硝基苯基)哌啶-4 -基)-2,6-二氮雜螺[3.3]庚烷

Intermediate 58 was prepared by substituting Intermediate 56 for Intermediate 37 following a similar procedure as described for Intermediate 41 . Intermediate 58 , 3-(5-(6-(4-(4-aminophenyl)piperene) was obtained

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (0.305 g, 28% and 67%, two steps). MS (LCMS) m/z 515.32 [M+H] ⁺ . Intermediate 59 2-(1-(4-nitrophenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane

-1-羧酸三級丁酯與1-氟-4-硝基苯反應而製備。 中間物 53，2-(1-(4-硝基苯基)哌啶-4-基)-2,6-二氮雜螺[3.3]庚烷（1.32 g，93%及98%，兩步驟）。MS (LCMS) m/z303.41 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 8.03 (dd, J= 7.6, 2.0 Hz, 2H), 6.99 (dd, J= 7.6, 2.0 Hz, 2H), 3.86-3.78 (m, 2H), 3.53 (br s, 2H), 3.16 (br s, 4H), 3.18 - 3.05 (m, 2H), 2.23 - 2.16 (m, 1H), 1.69 - 1.64 (m, 2H), 1.23 - 1.13 (m, 2H)。 中間物60 3-(4-(6-(1-(4-胺基苯基)哌啶-4 -基)-2,6-二氮雜螺[3.3]庚-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 59 was prepared by following a similar two-step procedure as described in Intermediate 46 using 6-(piperidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tris Grade butyl ester substituted 4-(azene-3-yl)piperene

-1-Carboxylic acid tertiary butyl ester reacts with 1-fluoro-4-nitrobenzene to prepare. Intermediate 53 , 2-(1-(4-nitrophenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]heptane (1.32 g, 93% and 98%, two steps ). MS (LCMS) m/z 303.41 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 8.03 (dd, J = 7.6, 2.0 Hz, 2H), 6.99 (dd, J = 7.6, 2.0 Hz, 2H), 3.86-3.78 (m, 2H) , 3.53 (br s, 2H), 3.16 (br s, 4H), 3.18 - 3.05 (m, 2H), 2.23 - 2.16 (m, 1H), 1.69 - 1.64 (m, 2H), 1.23 - 1.13 (m, 2H). Intermediate 60 3-(4-(6-(1-(4-aminophenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)-1- Pendantoxyisoindolin-2-yl)piperidine-2,6-dione

Intermediate 60 was prepared by substituting Intermediate 59 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 60 , 3-(4-(6-(1-(4-aminophenyl)piperidin-4-yl) -2,6-diazaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (350 mg, 45% and 93 %, two steps). MS (LCMS) m/z 515.70 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.98 (s, 1H, NH), 7.31 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.67 (d , J = 8.8 Hz, 2H), 6.56 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.8 Hz, 2H) 5.09 (dd, J = 13.2, 5.2 Hz, 1H), 4.44 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 16.8 Hz, 1H), 4.07 - 4.00 (m, 4H), 3.32 - 3.18 (m, 5H), 2.97 - 2.88 (m, 1H), 2.70 - 2.40 (m, 3H), 2.07 - 1.93 (m, 3H), 1.72 - 1.63 (m, 2H), 1.32 - 1.20 (m, 3H). Intermediate 61 1-(Azines-3-ylmethyl)-4-(4-nitrophenyl)piper

（710 mg，47%及97%，兩步驟）。MS (LCMS) m/z277.28 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d, J= 9.6 Hz, 2H), 7.02 (d, J= 9.6 Hz, 2H), 3.71 (t, J= 8.4 Hz, 2H), 3.45 - 3.38 (m, 6H), 2.95 - 2.85 (m, 1H), 2.56 (d, J= 7.2 Hz, 2H), 2.48 - 2.41 (m, 4H). 中間物62 3-(4-(3-((4-(4-胺基苯基)哌

-1-基)甲基)吖呾-1-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮

Intermediate 61 was obtained by substituting tertiary-butyl 3-(iodomethyl)azene-1-carboxylate for 4-(iodomethyl)piperidine-1-carboxylate following a similar procedure as described for Intermediate 37. Acid tertiary butyl ester to prepare. Intermediate 61 , 1-(azan-3-ylmethyl)-4-(4-nitrophenyl)piperene

(710 mg, 47% and 97%, two steps). MS (LCMS) m/z 277.28 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.05 (d, J = 9.6 Hz, 2H), 7.02 (d, J = 9.6 Hz, 2H), 3.71 (t, J = 8.4 Hz, 2H), 3.45 - 3.38 (m, 6H), 2.95 - 2.85 (m, 1H), 2.56 (d, J = 7.2 Hz, 2H), 2.48 - 2.41 (m, 4H). Intermediate 62 3-(4-(3-( (4-(4-Aminophenyl)piperene

-1-yl)methyl)azan-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

-1-基)甲基)氮雜環丁-1-基)-1-側氧基異吲哚啉-2-基)哌啶2,6-二酮（220 mg，24%及86%，兩步驟）。MS (LCMS) m/z489.40 [M+H] ⁺。 中間物63 ( R)-甲磺酸(1-(4-((2-烯丙基-1-(7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)甲酯

Intermediate 62 was prepared by substituting Intermediate 61 for Intermediate 37 following a similar procedure as described for Intermediate 40 . The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford intermediate 62 , 3-(4-(3-((4-(4-aminophenyl)piper

-1-yl)methyl)azetidin-1-yl)-1-oxoisoindoline-2-yl)piperidine 2,6-dione (220 mg, 24% and 86%, two steps). MS (LCMS) m/z 489.40 [M+H] ⁺ . Intermediate 63 ( R )-methanesulfonic acid (1-(4-((2-allyl-1-(7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-4 -yl) methyl ester

Intermediate 63 was prepared in Step 1 similarly to the preparation of Intermediate 8 , using (1-(4-aminophenyl)piperidin-4-yl)methanol (ref: WO 2009/029998) in place of 2-(4- Aminophenyl)ethanol to give ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ] in 35% yield Pyridin-2-yl)-6-((4-(4-(hydroxymethyl)piperidin-1-yl)phenyl)amino)-1,2-dihydro-3 H -pyrazolo[3 ,4- d ]pyrimidin-3-one. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ = 8.77 (br d, J = 3.6 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.47 - 7.38 (m, 2H), 6.95 - 6.87 (m, 2H), 5.68 (tdd, J = 16.8, 10.5, 6.2, Hz, 1H), 5.01 (d, J = 10.1 Hz, 1H), 4.91 (br d, J = 17.0 Hz, 1H), 4.86 - 4.77 (m , 1H), 4.71 - 4.63 (m, 1H), 3.66 (br d, J = 12.0 Hz, 2H), 3.56 (d, J = 6.3 Hz, 2H), 3.09 - 3.00 (m, 1H), 2.90 - 2.81 (m, 1H), 2.71 (br t, J = 11.7 Hz, 2H), 2.38 (ddd, J = 13.3, 8.6, 4.5 Hz, 1H), 2.27 - 2.19 (m, 1H), 2.04 - 1.95 (m, 1H), 1.90 - 1.81 (m, 4H), 1.48 - 1.36 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).

-1-基)丙基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 1）

The preparation step 2 of intermediate 63 was similar to the preparation of intermediate 2 , and intermediate 63 was obtained in 55% yield, methanesulfonic acid ( R )-(1-(4-((2-allyl-1-(7 -Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[ 3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)methyl ester. ¹ H NMR (400 MHz, chloroform-d) δ = 8.97 - 8.86 (m, 1H), 8.10 - 8.03 (m, 1H), 7.79 (br d, J = 8.4 Hz, 1H), 7.46 (br d, J = 8.9 Hz, 2H), 7.36 (br s, 3H), 5.68 - 5.54 (m, 1H), 4.99 (br d, J = 10.0 Hz, 1H), 4.85 (br d, J = 17.1 Hz, 1H), 4.81 - 4.65 (m, 2H), 4.58 - 4.42 (m, 2H), 4.11 - 4.04 (m, 1H), 3.95 - 3.86 (m, 1H), 3.83 - 3.65 (m, 2H), 3.19 - 3.06 (m , 2H), 2.90 - 2.83 (m, 1H), 2.81 (s, 3H), 2.54 - 2.40 (m, 2H), 2.37 - 2.25 (m, 2H), 2.20 - 2.07 (m, 1H), 2.06 - 1.98 (m, 2H), 1.95 - 1.83 (m, 1H), 1.00 (br t, J = 7.3 Hz, 3H). Example 1 4-((3-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopentyl [ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 1 )

-1-基)苯基)胺基)-1H-吡唑并[3,4-d]嘧啶-3(2H)-酮（ 中間物 1）(40 mg，0.078 mmol)、甲磺酸3-((2-(2,6-二側氧基哌啶-3-基)-1,3-二側氧基異吲哚啉-4-基)胺基)丙酯(中間物2)（31.9 mg，0.078 mmol）及碘化鈉（2.339 mg，0.016 mmol）懸浮於二

烷（3 mL）中。接著將DIEA（0.041 mL，0.234 mmol）添加至小瓶，並在90℃下繼續過夜。然後冷卻至室溫，添加水（5 mL）並用二氯甲烷（2 x 15 mL）萃取。將合併的有機層用鹽水洗滌，經硫酸鈉乾燥，並蒸發。將所得殘餘物藉由在使用二氯甲烷-MeOH（0-20%）之Combi-Flash上之矽膠管柱層析法純化。合併純產物流份並蒸發，得到所欲標題產物（11 mg，0.013 mmol，17%產率）。 ¹H NMR (DMSO- d ₆ ) δ：11.06 (s, 1H), 10.12 (br s, 1H), 8.82 (s, 1H), 7.93 (br d, J= 6.7 Hz, 1H), 7.70 (d, J= 8.2 Hz, 1H), 7.53 - 7.65 (m, 3H), 7.15 (d, J= 8.7 Hz, 1H), 7.02 (d, J= 6.8 Hz, 1H), 6.92 (br d, J= 9.0 Hz, 2H), 6.78 (br d, J= 3.3 Hz, 1H), 5.62 - 5.72 (m, 1H), 4.97 - 5.06 (m, 3H), 4.85 (br d, J= 17.1 Hz, 1H), 4.74 (br s, 1H), 4.57 (br d, J=15.5 Hz, 1H), 3.33 - 3.44 (m, 2H), 3.13 (br s, 4H), 2.92 - 3.01 (m, 1H), 2.73 - 2.89 (m, 2H), 2.52 - 2.52 (m, 4H), 2.41 - 2.46 (m, 3H), 2.12 - 2.27 (m, 1H), 1.82 - 2.06 (m, 4H), 1.65 - 1.82 (m, 3H), 0.87 (t, J= 7.4 Hz, 3H); LC/MS (ESI) m/z826.82 [M+H] ⁺。 實例2 4-((6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)己基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 2）

In a 20 mL glass vial with a sealed cap, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-2- Base)-6-((4-(piper

-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one ( Intermediate 1 ) (40 mg, 0.078 mmol), 3- ((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)propyl ester (intermediate 2) (31.9 mg, 0.078 mmol) and sodium iodide (2.339 mg, 0.016 mmol) suspended in two

alkane (3 mL). DIEA (0.041 mL, 0.234 mmol) was then added to the vial and continued at 90 °C overnight. Then cooled to room temperature, added water (5 mL) and extracted with dichloromethane (2 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. The resulting residue was purified by column chromatography on silica gel on Combi-Flash with dichloromethane-MeOH (0-20%). The pure product fractions were combined and evaporated to give the desired title product (11 mg, 0.013 mmol, 17% yield). ¹ H NMR (DMSO- d ₆ ) δ: 11.06 (s, 1H), 10.12 (br s, 1H), 8.82 (s, 1H), 7.93 (br d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.53 - 7.65 (m, 3H), 7.15 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.92 (br d, J = 9.0 Hz , 2H), 6.78 (br d, J = 3.3 Hz, 1H), 5.62 - 5.72 (m, 1H), 4.97 - 5.06 (m, 3H), 4.85 (br d, J = 17.1 Hz, 1H), 4.74 ( br s, 1H), 4.57 (br d, J =15.5 Hz, 1H), 3.33 - 3.44 (m, 2H), 3.13 (br s, 4H), 2.92 - 3.01 (m, 1H), 2.73 - 2.89 (m , 2H), 2.52 - 2.52 (m, 4H), 2.41 - 2.46 (m, 3H), 2.12 - 2.27 (m, 1H), 1.82 - 2.06 (m, 4H), 1.65 - 1.82 (m, 3H), 0.87 (t, J = 7.4 Hz, 3H); LC/MS (ESI) m/z 826.82 [M+H] ⁺ . Example 2 4-((6-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopentyl [ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 2 )

-1-基)-5-側氧戊基)胺基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 3）

Example 2 was prepared by following a similar procedure as described in Example 1 , using Intermediate 3 (35.2 mg, 0.078 mmol) in place of Intermediate 2 to afford the desired title product (8.0 mg, 8.6 µmol, 11% yield) . ¹ H NMR (DMSO- d ₆ ) δ: 11.09 (s, 1H), 10.07 - 10.19 (m, 1H), 8.83 (br s, 1H), 7.87 - 7.94 (m, 1H), 7.69 (br d, J = 8.2 Hz, 1H), 7.65 (br d, J = 2.2 Hz, 1H), 7.56 - 7.62 (m, 3H), 7.48 - 7.54 (m, 1H), 7.07 - 7.13 (m, 1H), 6.88 - 7.05 (m, 4H), 6.53 (t, J = 6.0 Hz, 1H), 5.61 - 5.72 (m, 1H), 4.98 - 5.09 (m, 4H), 4.68 - 4.89 (m, 3H), 4.51 - 4.62 (m , 1H), 3.71 - 3.82 (m, 1H), 3.53 - 3.68 (m, 1H), 3.05 - 3.24 (m, 5H), 2.84 - 3.04 (m, 4H), 2.74 - 2.81 (m, 1H), 2.67 (s, 1H), 2.55 - 2.63 (m, 2H), 2.30 - 2.40 (m, 4H), 2.12 - 2.28 (m, 3H), 1.99 - 2.10 (m, 3H), 1.81 - 1.97 (m, 2H) , 0.77 - 0.97 (m, 5H); LC/MS (ESI) m/z 869.3 [M+H] ⁺ . Example 3 3-(4-((5-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl ) piperpe

-1-yl)-5-oxopentyl)amino)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 3 )

-1-基)苯基)胺基)-1H-吡唑并[3,4-d]嘧啶-3(2 H)-酮（ 中間物 1）(40 mg，0.078 mmol)、5-((2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-4-基)胺基)戊酸（ 中間物 6）(28.0 mg，0.078 mmol)、HATU(44.5 mg，0.117 mmol)溶解於DMF（1.0 ml）中。接著將DIEA (0.068 ml，0.390 mmol)添加至反應混合物。在室溫下繼續反應16小時。LCMS（ESI）分析偵測到所欲產物。接著將濾液用水（3 mL）稀釋並用EtOAc（2 x 15 mL）萃取。將合併的有機層用鹽水洗滌，並經硫酸鈉乾燥，並蒸發。接著利用二氯甲烷-MeOH（0-20%）以矽膠管柱層析法純化（化合物在約15% MeOH洗提）。合併純產物流份且蒸發，得到所欲的產物3-(4-((5-(4-(4-((2-烯丙基-1-((R)-7-乙基-7-羥基-6,7-二氫-5H-環戊[b]吡啶-2-基)-3-側氧基-2,3-二氫-1H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)哌

-1-基)-5-側氧戊基)胺基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（36 mg，0.041 mmol，53%產率）。 ¹H NMR (DMSO- d ₆ ) δ：11.00 (s, 1H), 10.15 (br s, 1H), 8.83 (s, 1H), 7.88 - 7.96 (m, 1H), 7.69 (d, J= 8.2 Hz, 1H), 7.60 (br s, 2H), 7.28 (t, J= 7.8 Hz, 1H), 6.90 - 6.97 (m, 3H), 6.74 - 6.79 (m, 1H), 5.58 - 5.72 (m, 2H), 4.97 - 5.14 (m, 3H), 4.85 (br d, J= 18.3 Hz, 1H), 4.74 (br s, 1H), 4.50 - 4.65 (m, 1H), 4.18 - 4.26 (m, 1H), 4.06 - 4.17 (m, 2H), 3.53 - 3.66 (m, 4H), 3.13 - 3.20 (m, 4H), 2.87 - 3.10 (m, 5H), 2.72 - 2.84 (m, 1H), 2.53 - 2.68 (m, 2H), 2.39 - 2.46 (m, 2H), 2.15 - 2.38 (m, 2H), 1.82 - 2.07 (m, 4H), 1.65 - 1.76 (m, 1H), 1.49 (br d, J= 7.3 Hz, 1H), 0.77 - 0.97 (m, 5H); LC/MS (ESI) m/z854.3 [M+H] ⁺。 實例4 (2 S,4 R)-1-(( RS)-2-(8-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-8-側氧辛醯胺)-3,3-二甲基丁醯基)-4-羥基- N-(( S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯啶-2-羧醯胺（ 化合物 4）

In a 6 mL glass vial with a sealed cap, (R)-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-2- Base)-6-((4-(piper

-1-yl)phenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3( 2H )-one ( Intermediate 1 ) (40 mg, 0.078 mmol), 5-(( 2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanoic acid ( Intermediate 6 ) (28.0 mg, 0.078 mmol), HATU (44.5 mg, 0.117 mmol) was dissolved in DMF (1.0 ml). Then DIEA (0.068 ml, 0.390 mmol) was added to the reaction mixture. The reaction was continued for 16 hours at room temperature. LCMS (ESI) analysis detected the desired product. The filtrate was then diluted with water (3 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated. It was then purified by silica gel column chromatography using dichloromethane-MeOH (0-20%) (compound eluted at about 15% MeOH). The pure product fractions were combined and evaporated to give the desired product 3-(4-((5-(4-(4-((2-allyl-1-((R)-7-ethyl-7- Hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)piperidine

-1-yl)-5-oxopentyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (36 mg, 0.041 mmol, 53% yield ). ¹ H NMR (DMSO- d ₆ ) δ: 11.00 (s, 1H), 10.15 (br s, 1H), 8.83 (s, 1H), 7.88 - 7.96 (m, 1H), 7.69 (d, J = 8.2 Hz , 1H), 7.60 (br s, 2H), 7.28 (t, J = 7.8 Hz, 1H), 6.90 - 6.97 (m, 3H), 6.74 - 6.79 (m, 1H), 5.58 - 5.72 (m, 2H) , 4.97 - 5.14 (m, 3H), 4.85 (br d, J = 18.3 Hz, 1H), 4.74 (br s, 1H), 4.50 - 4.65 (m, 1H), 4.18 - 4.26 (m, 1H), 4.06 - 4.17 (m, 2H), 3.53 - 3.66 (m, 4H), 3.13 - 3.20 (m, 4H), 2.87 - 3.10 (m, 5H), 2.72 - 2.84 (m, 1H), 2.53 - 2.68 (m, 2H), 2.39 - 2.46 (m, 2H), 2.15 - 2.38 (m, 2H), 1.82 - 2.07 (m, 4H), 1.65 - 1.76 (m, 1H), 1.49 (br d, J = 7.3 Hz, 1H ), 0.77 - 0.97 (m, 5H); LC/MS (ESI) m/z 854.3 [M+H] ⁺ . Example 4 (2 S ,4 R )-1-(( RS )-2-(8-(4-(4-((2-allyl-1-(( R )-7-ethyl-7- Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ] pyrimidin-6-yl)amino)phenyl)piperidine

-1-yl)-8-oxoctylamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazole-5- base) phenyl) ethyl) pyrrolidine-2-carboxamide ( compound 4 )

-1-基)-10-側氧癸醯胺基)-3,3-二甲基丁醯基)-4-羥基- N-(( S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯啶-2-羧醯胺（ 化合物 5）

Example 4 was prepared by following a similar procedure described in Example 3 , using Intermediate 4 (46.9 mg, 0.078 mmol) in place of Intermediate 6 to give the desired title product (37 mg, 0.033 mmol, 42% yield ). LC/MS (ESI) m/z 1096.4 [M+H] ⁺ . Example 5 (2 S ,4 R )-1-(( RS )-2-(10-(4-(4-((2-allyl-1-(( R )-7-ethyl-7- Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ] pyrimidin-6-yl)amino)phenyl)piperidine

-1-yl)-10-oxodecylamino)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazole-5 -yl)phenyl)ethyl)pyrrolidine-2-carboxamide ( compound 5 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 6）

Example 5 was prepared by following a similar procedure as described in Example 3, using Intermediate 5 (49.1 mg, 0.078 mmol) in place of Intermediate 6 to give the desired title product (58 mg, 0.049 mmol, 62% yield ). LC/MS (ESI) m/z 1124.4 [M+H] ⁺ . Example 6 3-(5-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenethyl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 6 )

烷（1 mL）中之混合物添加3-(1-側氧基-5-哌

-1-基-異吲哚啉-2-基)哌啶-2,6-二酮（參考文獻：Chem. Euro. Journal 20 20,16818）（142.6 mg，322.3 µmol，TFA鹽）、DIEA (05.6 µL、537 µmol)及NaI(1.61 mg，10.7 µmol)。在N ₂下，將混合物在100℃下攪拌12小時。LCMS顯示起始材料完全耗盡，並偵測到所欲產物。將反應混合物過濾，並將濾液藉由製備型HPLC純化，得到 化合物 6 ，3-(5-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并-[3,4- d]嘧啶-6-基)胺基)苯乙基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（24.5 mg，產率28%，97.96%純度）。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 10.94 (br s, 1H), 10.21 (br s, 1H), 8.87 (s, 1H), 7.91 (br d, J =8.1 Hz, 1H), 7.77 - 7.59 (m, 3H), 7.53 (br d, J =8.5 Hz, 1H), 7.21 (br d, J =8.1 Hz, 2H), 7.08 (s, 2H), 5.75 - 5.61 (m, 1H), 5.10 - 4.97 (m, 3H), 4.86 (br d, J =17.1 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.56 (br dd, J =15.6, 5.8 Hz, 1H), 4.31 (s, 1H), 4.23 (s, 1H), 3.30 - 3.27 (m, 4H), 2.99 - 2.84 (m, 3H), 2.80 - 2.70 (m, 4H), 2.59 (br d, J =5.5 Hz, 5H), 2.37 (br dd, J =13.3, 4.3 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.89 (br dd, J =13.6, 7.1 Hz, 1H), 1.70 (br dd, J =13.9, 7.3 Hz, 1H), 0.86 (br t, J =7.3 Hz, 3H)；LCMS (ESI): m/z = 783.4 (M+H) ⁺，RT：2.673 min. 實例7 3-(5-(4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 7）

At 20°C, methanesulfonic acid ( R )-4-((2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ] Pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenethyl ester ( intermediate 9 ) (60.0 g, 107 µmol, 98.59% purity) in two

To the mixture in alkanes (1 mL) was added 3-(1-oxo-5-piper

-1-yl-isoindolin-2-yl)piperidine-2,6-dione (reference: Chem. Euro. Journal 20 20, 16818) (142.6 mg, 322.3 µmol, TFA salt), DIEA ( 05.6 µL, 537 µmol) and NaI (1.61 mg, 10.7 µmol). The mixture was stirred at 100 °C for 12 h under _N2 . LCMS showed complete consumption of starting material and detection of desired product. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC to obtain compound 6 , 3-(5-(4-(4-((2-allyl-1-(( R )-7-ethyl- 7-Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo-[3,4 - d ]pyrimidin-6-yl)amino)phenethyl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24.5 mg, 28% yield, 97.96% purity). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.94 (br s, 1H), 10.21 (br s, 1H), 8.87 (s, 1H), 7.91 (br d, J = 8.1 Hz, 1H), 7.77 - 7.59 (m, 3H), 7.53 (br d, J = 8.5 Hz, 1H), 7.21 (br d, J = 8.1 Hz, 2H), 7.08 (s, 2H), 5.75 - 5.61 (m, 1H) , 5.10 - 4.97 (m, 3H), 4.86 (br d, J = 17.1 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.56 (br dd, J = 15.6, 5.8 Hz, 1H), 4.31 (s , 1H), 4.23 (s, 1H), 3.30 - 3.27 (m, 4H), 2.99 - 2.84 (m, 3H), 2.80 - 2.70 (m, 4H), 2.59 (br d, J = 5.5 Hz, 5H) , 2.37 (br dd, J = 13.3, 4.3 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.89 (br dd, J = 13.6, 7.1 Hz, 1H), 1.70 (br dd, J = 13.9, 7.3 Hz, 1H), 0.86 (br t, J = 7.3 Hz, 3H); LCMS (ESI): m/z = 783.4 (M+H) ⁺ , RT: 2.673 min. Example 7 3-(5-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 7 )

-1-基)苯基)胺基)-1,2-二氫-3 H-吡唑并[3,4- d]嘧啶-3-酮（ 中間物 1）（0.100 g，195 µmol）於二

烷（2 mL）中之溶液添加DIEA（86.8 mg，672 µmol）、NaI（3.36 mg，22.4 µmol）及甲磺酸(1-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-5-基)哌啶-4-基)甲酯（ 中間物 11）（97.5 mg，224 µmol）。將反應在100℃下攪拌12小時。LCMS顯示反應完成並偵測到所欲產物。將反應過濾，並將濾液濃縮，得到殘餘物，將該殘餘物藉由製備型HPLC純化，得到 化合物 7 ，3-(3-(5-(4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并-[3,4- d]嘧啶-6-基)胺基)苯乙基)哌

-1-基)甲基-哌啶-1基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（0.021 g，產率10%，92%純度）。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 10.93 (br s, 1H), 10.24 - 9.96 (m, 1H), 8.83 (s, 1H), 7.94 (br d, J =6.9 Hz, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.59 (br s, 2H), 7.49 (d, J =8.9 Hz, 1H), 6.93 (br d, J =8.9 Hz, 2H), 6.67 - 6.60 (m, 2H), 5.74 - 5.62 (m, 1H), 5.06 (s, 1H), 5.05 - 4.97 (m, 2H), 4.86 (br d, J =17.3 Hz, 1H), 4.82 - 4.68 (m, 1H), 4.57 (br dd, J =15.7, 4.9 Hz, 1H), 4.36 - 4.15 (m, 2H), 3.53 (br t, J =8.2 Hz, 1H), 3.46 - 3.39 (m, 1H), 3.31 (br s, 1H), 3.12 (br s, 4H), 3.02 - 2.84 (m, 3H), 2.83 - 2.74 (m, 1H), 2.61 - 2.54 (m, 5H), 2.49 - 2.35 (m, 4H), 2.26 - 2.12 (m, 2H), 2.07 - 1.84 (m, 3H), 1.78 - 1.58 (m, 4H), 0.88 (t, J =7.3 Hz, 3H)；LCMS (ESI): m/z = 852.3 (M+H) ⁺，RT：2.055 min. 實例8 5-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 8）

At 20°C, to ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)- 6-((4-(piper

-1-yl)phenyl)amino)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one ( intermediate 1 ) (0.100 g, 195 µmol) in two

A solution in alkane (2 mL) was added with DIEA (86.8 mg, 672 µmol), NaI (3.36 mg, 22.4 µmol) and methanesulfonic acid (1-(2-(2,6-dioxopiperidine-3- yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl ester ( intermediate 11 ) (97.5 mg, 224 µmol). The reaction was stirred at 100 °C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC to give compound 7 , 3-(3-(5-(4-((4-(4-((2- Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2, 3-Dihydro-1 H -pyrazolo-[3,4- d ]pyrimidin-6-yl)amino)phenethyl)piper

-1-yl)methyl-piperidin-1 yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.021 g, 10% yield, 92% purity) . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.93 (br s, 1H), 10.24 - 9.96 (m, 1H), 8.83 (s, 1H), 7.94 (br d, J = 6.9 Hz, 1H) , 7.70 (d, J = 8.1 Hz, 1H), 7.59 (br s, 2H), 7.49 (d, J = 8.9 Hz, 1H), 6.93 (br d, J = 8.9 Hz, 2H), 6.67 - 6.60 ( m, 2H), 5.74 - 5.62 (m, 1H), 5.06 (s, 1H), 5.05 - 4.97 (m, 2H), 4.86 (br d, J = 17.3 Hz, 1H), 4.82 - 4.68 (m, 1H ), 4.57 (br dd, J = 15.7, 4.9 Hz, 1H), 4.36 - 4.15 (m, 2H), 3.53 (br t, J = 8.2 Hz, 1H), 3.46 - 3.39 (m, 1H), 3.31 ( br s, 1H), 3.12 (br s, 4H), 3.02 - 2.84 (m, 3H), 2.83 - 2.74 (m, 1H), 2.61 - 2.54 (m, 5H), 2.49 - 2.35 (m, 4H), 2.26 - 2.12 (m, 2H), 2.07 - 1.84 (m, 3H), 1.78 - 1.58 (m, 4H), 0.88 (t, J = 7.3 Hz, 3H); LCMS (ESI): m/z = 852.3 ( M+H) ⁺ , RT: 2.055 min. Example 8 5-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-di Hydrogen -5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amine base) phenyl) piperazine

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 8 )

-1-基)苯基)胺基)-1,2-二氫-3 H-吡唑并[3,4- d]嘧啶-3-酮（ 中間物 1）(0.120 g，234 µmol）及2-(2,6-二側氧基-3-哌啶基)-5-氟-異吲哚啉-1,3-二酮（97.0 mg，351 µmol）於DMSO（2 mL）中之溶液添加DIEA（83.5 µL，468 µmol）。將反應在60℃下攪拌12小時。LCMS顯示反應完成並偵測到所欲產物。將反應藉由製備型HPLC直接純化，得到 化合物 8，5-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（45 mg，產率25.%，97.08%純度）。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ: 11.22 - 10.99 (m, 1H), 10.27 - 10.00 (m, 1H), 8.84 (s, 1H), 7.94 (br d, J =7.5 Hz, 1H), 7.72 (t, J =7.9 Hz, 2H), 7.63 (br d, J =5.6 Hz, 2H), 7.43 (d, J =1.8 Hz, 1H), 7.34 (dd, J =8.7, 1.9 Hz, 1H), 7.01 (br d, J =9.0 Hz, 2H), 5.68 (tdd, J =16.8, 10.6, 5.9 Hz, 1H), 5.12 - 5.06 (m, 2H), 5.01 (dd, J =10.3, 0.9 Hz, 1H), 4.86 (br d, J =17.1 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.58 (br dd, J =15.7, 5.8 Hz, 1H), 3.63 (br d, J =5.0 Hz, 4H), 3.28 (br d, J =4.0 Hz, 4H), 3.01 - 2.75 (m, 3H), 2.62 (br d, J =2.8 Hz, 1H), 2.59 - 2.55 (m, 1H), 2.21 (m, 1H), 2.08 - 1.99 (m, 2H), 1.95 - 1.83 (m, 1H), 1.71 (dd, J =13.6, 7.4 Hz, 1H), 0.88 (t, J =7.4 Hz, 3H)；LCMS (ESI): m/z = 769.2 (M+H) ⁺，RT：2.389 min. 實例9 3-(5-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苄基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 9）

At 20°C, to ( R )-2-allyl-1-(7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)- 6-((4-(piper

-1-yl)phenyl)amino)-1,2-dihydro- 3H -pyrazolo[3,4- d ]pyrimidin-3-one ( intermediate 1 ) (0.120 g, 234 µmol) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (97.0 mg, 351 µmol) in DMSO (2 mL) Add DIEA (83.5 µL, 468 µmol). The reaction was stirred at 60 °C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was directly purified by preparative HPLC to obtain compound 8 , 5-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7- Dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl) Amino)phenyl)piperene

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (45 mg, yield 25.%, 97.08% purity). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 11.22 - 10.99 (m, 1H), 10.27 - 10.00 (m, 1H), 8.84 (s, 1H), 7.94 (br d, J = 7.5 Hz, 1H ), 7.72 (t, J = 7.9 Hz, 2H), 7.63 (br d, J = 5.6 Hz, 2H), 7.43 (d, J = 1.8 Hz, 1H), 7.34 (dd, J = 8.7, 1.9 Hz, 1H), 7.01 (br d, J = 9.0 Hz, 2H), 5.68 (tdd, J = 16.8, 10.6, 5.9 Hz, 1H), 5.12 - 5.06 (m, 2H), 5.01 (dd, J = 10.3, 0.9 Hz, 1H), 4.86 (br d, J = 17.1 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.58 (br dd, J = 15.7, 5.8 Hz, 1H), 3.63 (br d, J = 5.0 Hz, 4H), 3.28 (br d, J = 4.0 Hz, 4H), 3.01 - 2.75 (m, 3H), 2.62 (br d, J = 2.8 Hz, 1H), 2.59 - 2.55 (m, 1H), 2.21 (m, 1H), 2.08 - 1.99 (m, 2H), 1.95 - 1.83 (m, 1H), 1.71 (dd, J = 13.6, 7.4 Hz, 1H), 0.88 (t, J = 7.4 Hz, 3H); LCMS (ESI): m/z = 769.2 (M+H) ⁺ , RT: 2.389 min. Example 9 3-(5-(4-(4-((2-allyl-1-(( R )- 7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo [3,4- d ]pyrimidin-6-yl)amino)benzyl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 9 )

-1-基-異吲哚啉-2-基)哌啶-2,6-二酮（參考文獻：Chem. Euro. Journal 2020,16818）（74.6 mg，169 µmol，TFA鹽）及TEA（46.6 mg，460 µmol）。隨後將AcOH（17.5 µL，307 µmol）逐滴添加反應，並將反應在20℃下攪拌12小時。隨後將NaBH ₃CN (19.3 mg，307 µmol）在20℃下添加至反應，並將反應在20℃下攪拌額外12小時。LCMS顯示反應完成並且主峰係所欲產物。將反應濃縮，得到殘餘物，將該殘餘物藉由製備型HPLC(NH ₄HCO ₃條件）純化，得到 化合物 9，3-(5-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并-[3,4- d]嘧啶-6-基)胺基)苯乙基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（20.5 mg，產率17%，97.83%純度）。LCMS (ESI ⁺)： m/z= 769.5 (M+H) ⁺，RT：1.935分鐘。1H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (br s, 1H), 10.27 (br s, 1H), 8.89 (s, 1H), 7.92 (d, J= 8.1 Hz, 1H), 7.74 - 7.67 (m, 3H), 7.52 (d, J= 9.1 Hz, 1H), 7.29 (d, J= 8.5 Hz, 2H), 7.08 (s, 1H), 7.05 (d, J= 8.1 Hz, 1H), 5.68 (tdd, J= 17, 10.6, 6.0 Hz, 1H), 5.07 - 4.97 (m, 3H), 4.86 (dd, J= 17, 1.3 Hz, 1H),4.75 (br dd, J= 17, 4.2 Hz, 1H), 4.56 (br dd, J= 16.0, 6.0 Hz, 1H), 4.36 - 4.17 (m, 2H), 3.49 (m, 2H), 3.30 - 3.24 (m, 4H), 3.03 - 2.73 (m, 3H), 2.61 - 2.55 (m, 1H), 2.52 (br d, J= 1.8 Hz, 4H), 2.42 - 2.34 (m, 1H), 2.25 - 2.16 (m, 1H), 2.07 - 1.84 (m, 3H), 1.77 - 1.64 (m, 1H), 0.87 (t, J=7.4 Hz, 3H)。 實例10 3-(5-(4-(3-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)丙基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 10）

To a solution of intermediate 13 (70.0 g, 153 µmol) in DCE (3 mL) and MeOH (0.5 mL) was added 3-(1-oxo-5-piperene at 20 °C

-1-yl-isoindolin-2-yl)piperidine-2,6-dione (reference: Chem. Euro. Journal 2020, 16818) (74.6 mg, 169 µmol, TFA salt) and TEA (46.6 mg, 460 µmol). AcOH (17.5 µL, 307 µmol) was then added dropwise to the reaction, and the reaction was stirred at 20 °C for 12 h. NaBH ₃ CN (19.3 mg, 307 μmol) was then added to the reaction at 20° C., and the reaction was stirred at 20° C. for an additional 12 hours. LCMS showed the reaction was complete and the main peak was the desired product. The reaction was concentrated to give a residue which was purified by preparative HPLC ( _{NH4HCO3 condition} ) to give compound 9 , 3-(5-(4-(4-((2-allyl-1 -(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1 H -pyrazolo-[3,4- d ]pyrimidin-6-yl)amino)phenethyl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20.5 mg, 17% yield, 97.83% purity). LCMS (ESI ⁺ ): m/z = 769.5 (M+H) ⁺ , RT: 1.935 min. 1H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (br s, 1H), 10.27 (br s, 1H), 8.89 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 - 7.67 (m, 3H), 7.52 (d, J = 9.1 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.08 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 5.68 (tdd, J = 17, 10.6, 6.0 Hz, 1H), 5.07 - 4.97 (m, 3H), 4.86 (dd, J = 17, 1.3 Hz, 1H), 4.75 (br dd, J = 17, 4.2 Hz , 1H), 4.56 (br dd, J = 16.0, 6.0 Hz, 1H), 4.36 - 4.17 (m, 2H), 3.49 (m, 2H), 3.30 - 3.24 (m, 4H), 3.03 - 2.73 (m, 3H), 2.61 - 2.55 (m, 1H), 2.52 (br d, J = 1.8 Hz, 4H), 2.42 - 2.34 (m, 1H), 2.25 - 2.16 (m, 1H), 2.07 - 1.84 (m, 3H ), 1.77 - 1.64 (m, 1H), 0.87 (t, J =7.4 Hz, 3H). Example 10 3-(5-(4-(3-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Propyl)piperene

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 10 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮24.5 mg，產率24%，95.32%純度。LCMS (ESI ⁺)： m/z= 797.5 (M+H) ⁺，RT：2.789分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 10.96 (br s, 1H), 10.2 (br s, 1H), 8.87 (s, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.80 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 1H), 7.52 (d, J= 8.8 Hz, 1H), 7.18 (d, J= 8.3 Hz, 2H), 7.07 (s, 1H), 7.06 (d, J= 8.0 Hz, 1H), 5.75 - 5.60 (m, 1H), 5.02 -5.00 (m, 2H), 5.02 (d, J= 10 Hz, 1H), 4.85 (br d, J= 17.2 Hz, 1H), 4.76 (br d, J= 12.0 Hz, 1H), 4.56 (br dd, J= 16.0, 6.1 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.24 - 4.16 (m, 1H), 3.35 - 3.25 (m, 4H), 3.02 - 2.84 (m, 2H), 2.82 - 2.73 (m, 1H), 2.61 - 2.45 (m, 7H), 2.40 - 2.30 (m, 3H), 2.24 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.90 - 1.75 (m, 1H), 1.80 - 1.64 (m, 3H), 0.86 (t, J= 7.3 Hz, 3H)。 製備型HPLC 方法： 儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B%0.0 15 8.0 75 8.1 75 8.2 100 10.2 100 10.3 15 11.5 15 實例11 4-((3-(4-(4-((2-烯丙基-1-(6-(2-羥基丙-2-基)吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)丙基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 11）

The synthesis procedure of Example 10 is the same as that of Example 6 , using Intermediate 13 (70.0 mg, 121 μmol) to replace Intermediate 9 . After preparative HPLC (NH ₄ HCO ₃ conditions), compound 10 was obtained, 3-(5-(4-(3-(4-((2-allyl-1-(( R )-7-ethyl -7-Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4 - d ]pyrimidin-6-yl)amino)phenyl)propyl)piperene

-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione 24.5 mg, yield 24%, purity 95.32%. LCMS (ESI ⁺ ): m/z = 797.5 (M+H) ⁺ , RT: 2.789 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.96 (br s, 1H), 10.2 (br s, 1H), 8.87 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.07 (s , 1H), 7.06 (d, J = 8.0 Hz, 1H), 5.75 - 5.60 (m, 1H), 5.02 -5.00 (m, 2H), 5.02 (d, J = 10 Hz, 1H), 4.85 (br d , J = 17.2 Hz, 1H), 4.76 (br d, J = 12.0 Hz, 1H), 4.56 (br dd, J = 16.0, 6.1 Hz, 1H), 4.36 - 4.29 (m, 1H), 4.24 - 4.16 ( m, 1H), 3.35 - 3.25 (m, 4H), 3.02 - 2.84 (m, 2H), 2.82 - 2.73 (m, 1H), 2.61 - 2.45 (m, 7H), 2.40 - 2.30 (m, 3H), 2.24 - 2.15 (m, 1H), 2.05 - 1.93 (m, 2H), 1.90 - 1.75 (m, 1H), 1.80 - 1.64 (m, 3H), 0.86 (t, J = 7.3 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitoring Wavelength: 220 nm and 254 nm time B% 0.0 15 8.0 75 8.1 75 8.2 100 10.2 100 10.3 15 11.5 15 Example 11 4-((3-(4-(4-((2-allyl-1-( 6-(2-Hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl )amino)phenyl)piperidine

-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 11 )

-1-基)丙基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（30 mg，16%產率，96.039%純度）。LCMS (ESI ⁺)： m/z= 800.2 (M+H) ⁺，RT：2.033分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (br s, 1H, NH), 10.24 - 10.06 (m, 1H, NH), 8.83 (s, 1H), 8.05 (br t, J= 7.0 Hz, 1H), 7.76 (br d, J= 7.6 Hz, 1H), 7.63 - 7.50 (m, 4H), 7.16 (br d, J= 8.5 Hz, 1H), 7.03 (d, J= 7.0 Hz, 1H), 6.93 (br d, J= 8.7 Hz, 2H), 6.78 (br t, J= 5.7 Hz, 1H, NH), 5.67 (tdd, J= 16.7, 10.9, 5.6 Hz, 1H), 5.34 (s, 1H), 5.08 - 4.96 (m, 2H), 4.83 (br d, J= 17.0 Hz, 1H), 4.71 - 4.63 (m, 2H), 3.50 - 3.35 (m, 6H), 3.20 - 3.07 (m, 4H), 2.94 - 2.75 (m, 1H), 2.65 – 2.50 (m, 2H), 2.50 - 2.45 (m, 1H), 2.16 - 1.95 (m, 2H), 1.86 - 1.74 (m, 2H), 1.47 (s, 6H)。 實例12 4-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-5-基)苯甲醯胺（ 化合物 12）

Example 11 was prepared by reacting Intermediate 2 with Intermediate 1 using Intermediate 15 (49.1 mg, 0.078 mmol) in place of Intermediate 1 following a similar procedure as described in Example 1 . The reaction was concentrated under reduced pressure to give a residue, which _was purified by preparative HPLC ( _NH3H2O / _{NH4HCO3 conditions} identical to Example 10 ) to give compound 11 , 4-(( 3-(4-(4-((2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-3-oxo-2,3-dihydro -1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (30 mg, 16% yield, 96.039% purity). LCMS (ESI ⁺ ): m/z = 800.2 (M+H) ⁺ , RT: 2.033 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (br s, 1H, NH), 10.24 - 10.06 (m, 1H, NH), 8.83 (s, 1H), 8.05 (br t, J = 7.0 Hz, 1H), 7.76 (br d, J = 7.6 Hz, 1H), 7.63 - 7.50 (m, 4H), 7.16 (br d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H ), 6.93 (br d, J = 8.7 Hz, 2H), 6.78 (br t, J = 5.7 Hz, 1H, NH), 5.67 (tdd, J = 16.7, 10.9, 5.6 Hz, 1H), 5.34 (s, 1H), 5.08 - 4.96 (m, 2H), 4.83 (br d, J = 17.0 Hz, 1H), 4.71 - 4.63 (m, 2H), 3.50 - 3.35 (m, 6H), 3.20 - 3.07 (m, 4H ), 2.94 - 2.75 (m, 1H), 2.65 - 2.50 (m, 2H), 2.50 - 2.45 (m, 1H), 2.16 - 1.95 (m, 2H), 1.86 - 1.74 (m, 2H), 1.47 (s , 6H). Example 12 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridine -2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)benzamide ( Compound 12 )

-1-基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-5-基)苯甲醯胺（24.9 mg，產率29%，98%純度）。LCMS (ESI ⁺)： m/z= 908.4 (M+H) ⁺，RT：2.896分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.00 (br s, 1H, NH), 10.51 (s, 1H, NH), 10.16 (br s, 1H, NH), 8.83 (s, 1H), 8..13 (s, 1H), 8.09 (s, 1H), 8.03 - 7.89 (m, 2H), 7.83 (d, J= 8.5 Hz, 1H), 7.72 (dd, J= 8.2, 1.8 Hz, 2H), 7.68 - 7.55 (m, 2H), 7.35 (d, J= 8.5 Hz, 1H), 7.01 (br d, J= 8.8 Hz, 2H), 5.67 (tdd, J= 16.8, 10.5, 5.9 Hz, 1H), 5.10 (dd, J= 13.4, 5.1 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J= 10.3 Hz, 1H), 4.86 (br d, J= 17.0 Hz, 1H), 4.82 - 4.67 (m, 1H), 4.64 - 4.53 (m, 1H), 4.52 - 4.42 (m, 1H), 4.38 - 4.30 (m, 1H), 3.45 - 3.20 (m, 8H), 3.05 - 2.86 (m, 2H), 2.84 - 2.73 (m, 1H), 2.65 - 2.56 (m, 1H), 2.40 (br dd, J= 13.2, 4.5 Hz, 1H), 2.26 - 2.15 (m, 1H), 2.09 - 1.97 (m, 2H), 1.90 (br dd, J= 13.5, 7.2 Hz, 1H), 1.71 (br dd, J= 13.6, 7.3 Hz, 1H), 0.87 (t, J= 7.3 Hz, 3H)。 製備型HPLC 方法： 儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75×30 mm×3 um 流速：25 mL/min 監測器波長：220 nm及254 nm 時間B%0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 實例13 4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-5-基)苯甲醯胺（ 化合物 13）

To a solution of intermediate 16 (75 mg, 93 µmol, 83% purity) in DMF (2 mL) at 20 °C was added 3-(5-amino-1-oxo-isoindoline-2 -yl)piperidine-2,6-dione (48.4 mg, 187 µmol), 1-methylimidazole (19.2 mg, 233 µmol) and hexafluorophosphate [chloro(dimethylamine)methylene]-di Methyl-ammonium (65.5 mg, 233 µmol). The mixture was stirred at 40 °C for 12 h under _N2 . LCMS showed the reaction was complete and the desired compound was detected. The reaction mixture was poured into H ₂ O (2 mL) and extracted with EA (3 x 15 mL). The organic phase was washed with brine (15 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to give compound 12 , 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)benzamide ( 24.9 mg, 29% yield, 98% purity). LCMS (ESI ⁺ ): m/z = 908.4 (M+H) ⁺ , RT: 2.896 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.00 (br s, 1H, NH), 10.51 (s, 1H, NH), 10.16 (br s, 1H, NH), 8.83 (s, 1H), 8..13 (s, 1H), 8.09 (s, 1H), 8.03 - 7.89 (m, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.72 (dd, J = 8.2, 1.8 Hz, 2H ), 7.68 - 7.55 (m, 2H), 7.35 (d, J = 8.5 Hz, 1H), 7.01 (br d, J = 8.8 Hz, 2H), 5.67 (tdd, J = 16.8, 10.5, 5.9 Hz, 1H ), 5.10 (dd, J = 13.4, 5.1 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J = 10.3 Hz, 1H), 4.86 (br d, J = 17.0 Hz, 1H) , 4.82 - 4.67 (m, 1H), 4.64 - 4.53 (m, 1H), 4.52 - 4.42 (m, 1H), 4.38 - 4.30 (m, 1H), 3.45 - 3.20 (m, 8H), 3.05 - 2.86 ( m, 2H), 2.84 - 2.73 (m, 1H), 2.65 - 2.56 (m, 1H), 2.40 (br dd, J = 13.2, 4.5 Hz, 1H), 2.26 - 2.15 (m, 1H), 2.09 - 1.97 (m, 2H), 1.90 (br dd, J = 13.5, 7.2 Hz, 1H), 1.71 (br dd, J = 13.6, 7.3 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75×30 mm×3 um Flow rate: 25 mL/min Monitor wavelength: 220 nm and 254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 13 4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyridine Azolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)benzyl Amide ( compound 13 )

-1-基)甲基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-5-基)苯甲醯胺（21.5 mg，31%產率，97.5%純度）。LCMS (ESI ⁺)： m/z= 922.2 (M+H) ⁺，RT：2.120分鐘。 ¹H NMR (400 MHz, DMSO-d ₆) δ = 10.98 (br s, 1H, MH), 10.62 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 8.13 (s, 1H), 8.07 (d, J= 1.5 Hz, 1H), 7.98 - 7.87 (m, 2H), 7.83 (dd, J= 8.4, 1.2 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.65 - 7.50 (m, 2H), 6.93 (br d, J= 8.9 Hz, 2H), 5.66 (tdd, J= 16.8, 10.6, 5.9 Hz, 1H), 5.10 (dd, J= 13.3, 5.1 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (dd, J= 10.4, 2.4 Hz, 1H), 4.85 (br d, J= 17.1 Hz, 1H), 4.75 (br d, J= 10.0 Hz, 1H), 4.56 (br dd, J= 15.6, 5.0 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.38 - 4.29 (m, 1H), 3.72 (s, 2H), 3.14 (br s, 4H), 3.03 - 2.86 (m, 2H), 2.82 - 2.72 (m, 1H), 2.65 - 2.55 (m, 5H), 2.44 - 2.33 (m, 1H), 2.24 - 2.15 (m, 1H), 2.01 (ddd, J= 13.2, 8.1, 5.4 Hz, 2H), 1.89 (br dd, J= 13.6, 7.4 Hz, 1H), 1.70 (dd, J= 13.6, 7.4 Hz, 1H), 0.86 (t, J= 7.4 Hz, 3H)。 實例14 4-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-4-基)苯甲醯胺（化合物 14）

Example 13 was prepared by substituting Intermediate 17 (56.2 mg, 73.4 µmol) for Intermediate 16 after purification following a similar procedure as described in Example 12 to afford the desired title product, 4-((4-( 4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3- Oxy-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)benzyl Amide (21.5 mg, 31% yield, 97.5% purity). LCMS (ESI ⁺ ): m/z = 922.2 (M+H) ⁺ , RT: 2.120 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 10.98 (br s, 1H, MH), 10.62 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 8.13 (s, 1H), 8.07 (d, J = 1.5 Hz, 1H), 7.98 - 7.87 (m, 2H), 7.83 (dd, J = 8.4, 1.2 Hz, 1H), 7.76 - 7.66 (m, 3H) , 7.65 - 7.50 (m, 2H), 6.93 (br d, J = 8.9 Hz, 2H), 5.66 (tdd, J = 16.8, 10.6, 5.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (dd, J = 10.4, 2.4 Hz, 1H), 4.85 (br d, J = 17.1 Hz, 1H), 4.75 (br d, J = 10.0 Hz, 1H ), 4.56 (br dd, J = 15.6, 5.0 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.38 - 4.29 (m, 1H), 3.72 (s, 2H), 3.14 (br s, 4H), 3.03 - 2.86 (m, 2H), 2.82 - 2.72 (m, 1H), 2.65 - 2.55 (m, 5H), 2.44 - 2.33 (m, 1H), 2.24 - 2.15 (m, 1H), 2.01 (ddd, J = 13.2, 8.1, 5.4 Hz, 2H), 1.89 (br dd, J = 13.6, 7.4 Hz, 1H), 1.70 (dd, J = 13.6, 7.4 Hz, 1H), 0.86 (t, J = 7.4 Hz, 3H ). Example 14 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridine -2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)benzamide ( Compound 14 )

-1-基)-3-氯- N-(2-(2,6-二側氧基哌啶-3-基)-1-側氧異吲哚啉-4-基)苯甲醯胺（22.2 mg，產率23%，95%純度）。LCMS (ESI ⁺)： m/z= 908.4 (M+H) ⁺，RT：2.894分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) = 11.00 (br s, 1H, NH), 10.34 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.84 (s, 1H), 8.08 (d, J= 1.8 Hz, 1H), 8.00 - 7.90 (m, 2H), 7.71 (dd, J= 10.2, 1.0 Hz, 2H), 7.68 - 7.52 (m, 4H), 7.34 (d, J= 8.6 Hz, 1H), 7.01 (br d, J= 8.8 Hz, 2H), 5.75 - 5.61 (m, 1H), 5.15 (dd, J= 13.2, 5.1 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J= 10.3 Hz, 1H), 4.86 (br d, J= 17.0 Hz, 1H), 4.83- 4.68 (m, 1H), 4.64 - 4.53 (m, 1H), 4.49 - 4.36 (m, 2H), 3.40 – 3.30 (m, 4H), 3.30 – 3.20 (m, 4H), 3.04 - 2.85 (m, 2H), 2.84 - 2.73 (m, 1H), 2.58 (br d, J= 17.6 Hz, 2H), 2.45 - 2.35 (m, 1H), 2.25 - 2.17 (m, 1H), 2.08 - 1.96 (m, 2H), 1.95 - 1.85 (m, 1H), 1.71 (br dd, J= 13.6, 7.3 Hz, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 實例15 4-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-3-氯- N-(3-(2,6-二側氧基哌啶-3-基)苯并呋喃-5-基)苯甲醯胺（ 化合物 15）

Example 14 was substituted for 3-(5-amino-1-oxo-isoindolin-2-yl) by following a similar procedure described in Example 12 , using Intermediate 16 (56.2 mg, 73.4 µmol) Piperidine-2,6-dione, prepared by reacting with 3-(4-amino-1-oxo-isoindoline-2-yl)piperidine-2,6-dione, gives the desired The title product 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridine -2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chloro- N- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl)benzamide ( 22.2 mg, 23% yield, 95% purity). LCMS (ESI ⁺ ): m/z = 908.4 (M+H) ⁺ , RT: 2.894 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) = 11.00 (br s, 1H, NH), 10.34 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.84 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.00 - 7.90 (m, 2H), 7.71 (dd, J = 10.2, 1.0 Hz, 2H), 7.68 - 7.52 (m, 4H), 7.34 (d, J = 8.6 Hz, 1H), 7.01 (br d, J = 8.8 Hz, 2H), 5.75 - 5.61 (m, 1H), 5.15 (dd, J = 13.2, 5.1 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J = 10.3 Hz, 1H), 4.86 (br d, J = 17.0 Hz, 1H), 4.83- 4.68 (m, 1H), 4.64 - 4.53 (m, 1H), 4.49 - 4.36 (m, 2H), 3.40 – 3.30 (m, 4H), 3.30 – 3.20 (m, 4H), 3.04 - 2.85 (m, 2H), 2.84 - 2.73 (m, 1H), 2.58 (br d, J = 17.6 Hz, 2H ), 2.45 - 2.35 (m, 1H), 2.25 - 2.17 (m, 1H), 2.08 - 1.96 (m, 2H), 1.95 - 1.85 (m, 1H), 1.71 (br dd, J = 13.6, 7.3 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). Example 15 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridine -2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-3-chloro- N- (3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)benzamide ( compound 15 )

-1-基)-3-氯- N-(3-(2,6-二側氧基哌啶-3-基)苯并呋喃-5-基)苯甲醯胺（31.2 mg，產率34%，97%純度）。LCMS (ESI ⁺)： m/z= 893.4 (M+H) ⁺，RT：3.074分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 10.95 (br s, 1H, NH), 10.26 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.83 (s, 1H), 8.09 (d, J= 1.9 Hz, 1H), 8.00 (d, J= 1.6 Hz, 1H), 8.06 - 7.92 (m, 2H), 7.91 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.56 (d, J= 8.9 Hz, 1H), 7.33 (d, J= 8.5 Hz, 1H), 7.01 (br d, J= 8.9 Hz, 2H), 5.67 (br dd, J= 16.9, 10.5 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J= 10.0 Hz, 1H), 4.86 (br d, J= 17.3 Hz, 1H), 4.82 - 4.68 (m, 1H), 4.59 (br d, J= 4.8 Hz, 1H), 4.14 (dd, J= 12.0, 4.9 Hz, 1H), 3.40 - 3.25 (m, 8H), 3.03 - 2.93 (m, 1H), 2.86 - 2.72 (m, 2H), 2.65 - 2.58 (m, 1H), 2.37 - 2.25 (m, 1H), 2.25 - 2.10 (m, 2H), 2.08 - 1.98 (m, 1H), 1.90 (br dd, J= 13.8, 7.3 Hz, 1H), 1.77 - 1.65 (m, 1H), 0.87 (br t, J= 7.4 Hz, 3H)。 製備型HPLC 方法： 儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B%0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 實例16 4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)-3-氯- N-(3-(2,6-二側氧基哌啶-3-基)苯并呋喃-5-基)苯甲醯胺（ 化合物 16）

Example 15 was obtained by substituting 3- (5 - amino- 1 -oxo-isoindoline- 2-yl)piperidine-2,6-dione, prepared by reaction with 3-(5-aminobenzofuran-3-yl)piperidine-2,6-dione (ref. WO 2021/047764) , to obtain the desired title product compound 15 , 4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl ) piperpe

-1-yl)-3-chloro- N- (3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)benzamide (31.2 mg, yield 34 %, 97% purity). LCMS (ESI ⁺ ): m/z = 893.4 (M+H) ⁺ , RT: 3.074 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.95 (br s, 1H, NH), 10.26 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.83 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 8.06 - 7.92 (m, 2H), 7.91 (s, 1H), 7.71 (d, J = 8.1 Hz, 1H ), 7.68 - 7.60 (m, 2H), 7.56 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.01 (br d, J = 8.9 Hz, 2H), 5.67 ( br dd, J = 16.9, 10.5 Hz, 1H), 5.06 (s, 1H, OH), 5.00 (br d, J = 10.0 Hz, 1H), 4.86 (br d, J = 17.3 Hz, 1H), 4.82 - 4.68 (m, 1H), 4.59 (br d, J = 4.8 Hz, 1H), 4.14 (dd, J = 12.0, 4.9 Hz, 1H), 3.40 - 3.25 (m, 8H), 3.03 - 2.93 (m, 1H ), 2.86 - 2.72 (m, 2H), 2.65 - 2.58 (m, 1H), 2.37 - 2.25 (m, 1H), 2.25 - 2.10 (m, 2H), 2.08 - 1.98 (m, 1H), 1.90 (br dd, J = 13.8, 7.3 Hz, 1H), 1.77 - 1.65 (m, 1H), 0.87 (br t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitoring Wavelength: 220 nm and 254 nm Time B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 Example 16 4-((4-(4-((2-allyl-1-(( R ) -7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazole And[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperene

-1-yl)methyl)-3-chloro- N- (3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)benzamide ( compound 16 )

-1-基)甲基)-3-氯- N-(3-(2,6-二側氧基哌啶-3-基)苯并呋喃-5-基)苯甲醯胺（30.3 mg，產率23%，93%純度）。LCMS (ESI ⁺)： m/z= 907.3 (M+H) ⁺，RT：3.122分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (s, 1H, NH), 10.36 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s, 1H), 8.06 (d, J= 1.6 Hz, 1H), 7.99 (d, J= 1.6 Hz, 1H), 7.95 (dd, J= 8.0, 1.6 Hz, 1H), 7.95 -7.90 (m, 1H), 7.91 (s, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.66 (dd, J= 9.2, 2.0 Hz, 1H), 7.57 (br d, J= 9.0 Hz, 2H), 6.93 (br d, J= 9.0 Hz, 2H), 5.75 - 5.59 (m, 1H), 5.04 (s, 1H), 4.99 (d, J= 10.1 Hz, 1H), 4.85 (br d, J= 17.1 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.56 (br dd, J= 14.4, 4.6 Hz, 1H), 4.14 (dd, J= 12.1, 4.9 Hz, 1H), 3.71 (s, 2H), 3.20 - 3.10 (m, 4H), 3.01 - 2.91 (m, 1H), 2.85 - 2.71 (m, 2H), 2.68 - 2.60 (m, 1H), 2.62 (br s, 4H), 2.36 - 2.23 (m, 1H), 2.23 - 2.09 (m, 2H), 2.07 - 1.96 (m, 1H), 1.88 (qd, J= 13.8, 7.1 Hz, 1H), 1.76 - 1.64 (m, 1H), 0.86 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3 µm 流速：25 mL/min 監測器波長：220/254 nm 時間B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 實例17 4-(4-(6-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)-2,6-二氮雜螺[3.3]庚-2-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 17）

Example 16 was obtained by following a similar procedure described in Example 15 , using Intermediate 17 (90.0 mg, 132 µmol) in place of Intermediate 16 , with 3-(5-aminobenzofuran-3-yl)piperidine- 2,6-diketone (reference WO 2021/047764) was prepared by reaction to obtain the desired title product compound 16 , 4-((4-(4-((2-allyl-1-(( R )- 7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo [3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)-3-chloro- N- (3-(2,6-dioxopiperidin-3-yl)benzofuran-5-yl)benzamide (30.3 mg, Yield 23%, 93% purity). LCMS (ESI ⁺ ): m/z = 907.3 (M+H) ⁺ , RT: 3.122 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (s, 1H, NH), 10.36 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 -7.90 (m, 1H), 7.91 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 9.2, 2.0 Hz, 1H), 7.57 (br d, J = 9.0 Hz , 2H), 6.93 (br d, J = 9.0 Hz, 2H), 5.75 - 5.59 (m, 1H), 5.04 (s, 1H), 4.99 (d, J = 10.1 Hz, 1H), 4.85 (br d, J = 17.1 Hz, 1H), 4.80 – 4.70 (m, 1H), 4.56 (br dd, J = 14.4, 4.6 Hz, 1H), 4.14 (dd, J = 12.1, 4.9 Hz, 1H), 3.71 (s, 2H), 3.20 - 3.10 (m, 4H), 3.01 - 2.91 (m, 1H), 2.85 - 2.71 (m, 2H), 2.68 - 2.60 (m, 1H), 2.62 (br s, 4H), 2.36 - 2.23 (m, 1H), 2.23 - 2.09 (m, 2H), 2.07 - 1.96 (m, 1H), 1.88 (qd, J = 13.8, 7.1 Hz, 1H), 1.76 - 1.64 (m, 1H), 0.86 (t , J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3 µm Flow rate: 25 mL/min Monitor Wavelength: 220/254 nm Time B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 Example 17 4-(4-(6-(4-((2-allyl-1-(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H- Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 17 )

-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 18）

To a solution of Intermediate 7 (66.8 mg, 161 µmol) in Tol. (1.5 mL) was added a solution of Intermediate 20 (150 mg, 241 µmol) in DMF (1.5 mL) and DIEA (86.0 µL, 482 µmol). The reaction was then stirred at 20°C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was directly purified without work-up. The reaction was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to afford the title compound 17 , 4-(4-(6-(4-((2-allyl-1-(( R )-7-ethane Base-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3, 4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2,6-di oxypiperidin-3-yl)isoindoline-1,3-dione (18.7 mg, 14% yield, 100.00% purity). LCMS (ESI ⁺ ): m/z = 864.2 (M+H) ⁺ , RT: 2.159 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.79 (s, 1H), 7.88 (br d, J = 8.2 Hz , 1H), 7.71 -7.64 (m, Hz, 2H), 7.58 - 7.45 (m, 2H), 7.33 (d, J = 6.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 6.42 ( br d, J = 8.7 Hz, 2H), 5.66 (tdd, J = 16.8, 10.5, 6.0 Hz, 1H), 5.09 (dd, J = 12.9, 5.5 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (dd, J = 10.2, 1.0 Hz, 1H), 4.85 (dd, J = 18.4, 1.2 Hz, 1H), 4.80 - 4.66 (m, 1H), 4.55 (br dd, J = 15.2, 4.4 Hz, 1H ), 3.85 (s, 4H), 3.66 - 3.56 (m, 2H), 3.29 (br s, 4H), 3.02 - 2.86 (m, 4H), 2.85 - 2.74 (m, 1H), 2.64 - 2.54 (m, 2H), 2.26 - 2.14 (m, 2H), 2.06 - 1.97 (m, 2H), 1.89 (br dd, J = 13.6, 7.4 Hz, 1H), 1.81 - 1.64 (m, 3H), 1.44 - 1.30 (m , 2H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C 1875*30 mm*3 um Flow rate: 25 mL/min Monitor Wavelength: 220/254 nm Time B% 0.0 15 8.0 45 8.1 45 8.2 100 10.2 100 10.3 15 11.5 15 Example 18 4-(4-(4-(4-((2-allyl-1-(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H- Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 18 )

-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮。LCMS (ESI ⁺)：m/z = 852.3 (M+H) ⁺，RT：2.116分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s, 1H), 8.00 - 7.90 (m, 1H), 7.72 - 7.65 (m, 2H), 7.65 - 7.52 (m, 2H), 7.33 (d, J= 6.9 Hz, 1H), 7.32 (d, J= 6.9 Hz, 1H), 6.92 (br d, J= 9.1 Hz, 2H), 5.75 - 5.58 (m, 1H), 5.09 (dd, J= 12.6, 5.4 Hz, 1H), 5.05 (s, 1H, OH), 4.99 (br d, J= 10.0 Hz, 1H), 4.84 (br d, J= 16.9 Hz, 1H), 4.79 - 4.66 (m, 1H), 4.63 - 4.48 (m, 1H), 3.76 (br d, J= 11.2 Hz, 2H), 3.11 (br s, 4H), 3.01 - 2.83 (m, 4H), 2.83 - 2.74 (m, 1H), 2.68 (br s, 4H), 2.59 - 2.52 (m, 2H), 2.25 - 2.15 (m, 1H), 2.10 - 2.00 (m, 2H), 1.97 - 1.83 (m, 3H), 1.77 - 1.58 (m, 3H), 1.22 (s, 1H), 0.86 (br t, J= 7.3 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH3CN 管柱：Phenomenex C 1875*30 mm*3 um 流速：25 mL/min 監測器波長：220 nm及254 nm 時間B% 0.0 15 8.0 45 8.1 45 8.2 100 10.2 100 10.3 15 11.5 15 實例19 4-(6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-2-氮雜螺[3.3]庚-2-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 19）

Example 18 was prepared by reacting Intermediate 18 with Intermediate 1 in place of Intermediate 19 under standard reductive amination conditions following a similar procedure as described in Intermediate 20 , Step 1. LCMS showed the reaction was complete and the desired product was detected. The reaction was directly purified by preparative HPLC (NH ₄ HCO ₃ .H ₂ O conditions) to obtain 98.27% purity of compound 18 , 4-(4-(4-(4-((2-allyl-1- (( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. LCMS (ESI ⁺ ): m/z = 852.3 (M+H) ⁺ , RT: 2.116 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s, 1H), 8.00 - 7.90 (m, 1H), 7.72 - 7.65 (m, 2H), 7.65 - 7.52 (m, 2H), 7.33 (d, J = 6.9 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 6.92 (br d, J = 9.1 Hz, 2H), 5.75 - 5.58 (m, 1H), 5.09 (dd, J = 12.6, 5.4 Hz, 1H), 5.05 (s, 1H, OH), 4.99 (br d, J = 10.0 Hz, 1H), 4.84 (br d, J = 16.9 Hz, 1H), 4.79 - 4.66 (m, 1H), 4.63 - 4.48 (m, 1H), 3.76 (br d, J = 11.2 Hz, 2H), 3.11 (br s, 4H ), 3.01 - 2.83 (m, 4H), 2.83 - 2.74 (m, 1H), 2.68 (br s, 4H), 2.59 - 2.52 (m, 2H), 2.25 - 2.15 (m, 1H), 2.10 - 2.00 ( m, 2H), 1.97 - 1.83 (m, 3H), 1.77 - 1.58 (m, 3H), 1.22 (s, 1H), 0.86 (br t, J = 7.3 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH3CN Column: Phenomenex C 1875*30 mm*3 um Flow rate: 25 mL/min Monitor Wavelength: 220 nm and 254 nm Time B% 0.0 15 8.0 45 8.1 45 8.2 100 10.2 100 10.3 15 11.5 15 Example 19 4-(6-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyridine Azolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Compound 19 )

-1-基)-2-氮雜螺[3.3]庚-2-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（50.3 mg，產率26%，99%純度）。LCMS (ESI ⁺)： m/z= 864.5 (M+H) ⁺，RT：2.950分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.06 (br s, 1H, NH), 10.12 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (br d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.1 Hz, 1H), 7.65 - 7.48 (m, 3H), 7.11 (d, J= 7.0 Hz, 1H), 6.92 (br d, J= 8.9 Hz, 2H), 6.76 (d, J= 8.5 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.05 (dd, J= 5.6, 6.8 Hz, 1H), 5.05 (s, 1H), 5.00 (d, J= 9.6 Hz, 1H), 4.85 (br d, J= 17.0 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.64 - 4.50 (m, 1H), 4.23 (br s, 2H), 4.11 (br s, 2H), 3.09 (br s, 4H), 3.01 - 2.72 (m, 3H), 2.70 - 2.53 (m, 2H), 2.44 - 2.29 (m, 6H), 2.26 - 2.14 (m, 1H), 2.10 - 1.96 (m, 4H), 1.95 - 1.83 (m, 1H), 1.75 - 1.63 (m, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：沃特世Xbridge Prep OBD C18 150*40 mm*10 um 流速：25 mL/min 監測器波長：220/254 nm 時間B% 0.0 45 8.0 65 8.1 65 8.2 100 10.2 100 10.3 45 11.5 45 實例20 3-(5-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)甲基)哌

-1-基)-1-側氧異吲哚啉-2-基))哌啶-2,6-二酮（ 化合物 20）

Example 19 was prepared by reacting Intermediate 1 with Intermediate 1 using Intermediate 21 (35.2 mg, 0.078 mmol) in place of Intermediate 18 under standard reductive amination conditions following a similar procedure as described for Intermediate 18 . The reaction was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to obtain the desired compound 29 , 4-(6-(4-(4-((2-allyl-1-(( R )-7- Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3 ,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (50.3 mg, 26% yield, 99% purity). LCMS (ESI ⁺ ): m/z = 864.5 (M+H) ⁺ , RT: 2.950 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.06 (br s, 1H, NH), 10.12 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (br d, J = 8.0 Hz , 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.65 - 7.48 (m, 3H), 7.11 (d, J = 7.0 Hz, 1H), 6.92 (br d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.5 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.05 (dd, J = 5.6, 6.8 Hz, 1H), 5.05 (s, 1H), 5.00 (d, J = 9.6 Hz , 1H), 4.85 (br d, J = 17.0 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.64 - 4.50 (m, 1H), 4.23 (br s, 2H), 4.11 (br s, 2H) , 3.09 (br s, 4H), 3.01 - 2.72 (m, 3H), 2.70 - 2.53 (m, 2H), 2.44 - 2.29 (m, 6H), 2.26 - 2.14 (m, 1H), 2.10 - 1.96 (m , 4H), 1.95 - 1.83 (m, 1H), 1.75 - 1.63 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Waters Xbridge Prep OBD C18 150*40 mm*10 um Flow rate : 25 mL/min Monitor Wavelength: 220/254 nm Time B% 0.0 45 8.0 65 8.1 65 8.2 100 10.2 100 10.3 45 11.5 45 Example 20 3-(5-(4-((1-(4-((2 -Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2 ,3-Dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azepine-3-yl)methyl)piper

-1-yl)-1-oxoisoindolin-2-yl))piperidine-2,6-dione ( compound 20 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮14 mg（產率13%，98%純度）。LCMS (ESI ^-): m/z= 822.4 (M-H) ^-，RT：2.673分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (br s, 1H, NH), 10.10 (br s, 1H), 8.79 (s, 1H), 7.90 (br d, J= 8.2 Hz, 1H), 7.68 (d, J= 8.1 Hz, 1H), 7.52 (br d, J= 9.1 Hz, 2H), 7.55 - 7.45 (m, 1H), 7.08 (s, 1H), 7.07 (d, J= 7.6 Hz, 1H), 6.42 (d, J= 8.1 Hz, 2H), 5.66 (tdd, J= 16.8, 10.5, 5.9 Hz, 1H), 5.05 (dd, J= 5.2, 13.2 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (dd, J= 1.0, 10.0 Hz, 1H), 4.85 (br d, J= 17.2 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.56 (br dd, J= 13.2, 4.0 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.25 - 4.15 (m, 1H), 3.93 (br t, J= 7.3 Hz, 2H), 3.47 (br t, J= 6.2 Hz, 2H), 3.29 (s, 4H), 3.01 - 2.85 (m, 3H), 2.82 - 2.72 (m, 1H), 2.68 - 2.55 (m, 3H), 2.55 (br s, 4H), 2.40 - 2.28 (m, 1H), 2.25 - 2.16 (m, 1H), 2.05 - 1.85 (m, 3H), 1.70 (dd, J= 13.5, 7.4 Hz, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 實例21 4-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 21）

The synthesis procedure of Example 20 is the same as that of Example 6 , using Intermediate 22 (70.0 mg, 121 mmol) to replace Intermediate 9 . After preparative HPLC (NH ₄ HCO ₃ conditions), compound 20 was obtained, 3-(5-(4-((1-(4-((2-allyl-1-(( R )-7-ethane Base-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3, 4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)methyl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 14 mg (13% yield, 98% purity). LCMS (ESI ^- ): m/z = 822.4 (MH) ^- , RT: 2.673 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 10.94 (br s, 1H, NH), 10.10 (br s, 1H), 8.79 (s, 1H), 7.90 (br d, J = 8.2 Hz, 1H ), 7.68 (d, J = 8.1 Hz, 1H), 7.52 (br d, J = 9.1 Hz, 2H), 7.55 - 7.45 (m, 1H), 7.08 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 8.1 Hz, 2H), 5.66 (tdd, J = 16.8, 10.5, 5.9 Hz, 1H), 5.05 (dd, J = 5.2, 13.2 Hz, 1H), 5.04 (s , 1H, OH), 4.99 (dd, J = 1.0, 10.0 Hz, 1H), 4.85 (br d, J = 17.2 Hz, 1H), 4.80 - 4.69 (m, 1H), 4.56 (br dd, J = 13.2 , 4.0 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.25 - 4.15 (m, 1H), 3.93 (br t, J = 7.3 Hz, 2H), 3.47 (br t, J = 6.2 Hz, 2H) , 3.29 (s, 4H), 3.01 - 2.85 (m, 3H), 2.82 - 2.72 (m, 1H), 2.68 - 2.55 (m, 3H), 2.55 (br s, 4H), 2.40 - 2.28 (m, 1H ), 2.25 - 2.16 (m, 1H), 2.05 - 1.85 (m, 3H), 1.70 (dd, J = 13.5, 7.4 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min monitoring Wavelength: 220 nm and 254 nm Time B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 Example 21 4-(4-((1-(4-((2-allyl-1-( ( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 21 )

-1-基)異吲哚啉-1,3-二酮（參考文獻： J. Med. Chem, 2021, 54, 12381)反應。在製備型HPLC（NH ₄HCO ₃條件）之後，得到 化合物 21，4-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮0.014 g，產率12%及97.08%純度。LCMS (ESI ^-)： m/z= 838.3 (M-H) ^-，RT：2.061分鐘。 ¹H NMR (400 MHz, DMSO- d ₆) δ = 11.09 (br s, 1H, NH), 10.06 (br s, 1H, NH), 8.79 (s, 1H), 7.90 (br d, J= 8.0 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.59 - 7.41 (m, 2H), 7.37 (d, J= 7.2 Hz, 1H), 7.35 (d, J= 8.4 Hz, 1H), 6.42 (br d, J= 8.6 Hz, 2H), 5.73 - 5.59 (m, 1H), 5.10 (dd, J= 5.6, 12.8 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J= 10.3 Hz, 1H), 4.85 (br d, J= 17.5 Hz, 1H), 4.80 - 4.67 (m, 1H), 4.64 - 4.49 (m, 1H), 3.93 (br t, J= 7.2 Hz, 2H), 3.46 (br t, J= 6.0 Hz, 2H), 3.47 – 3.25 (br s, 4H), 3.01 - 2.90 (m, 2H), 2.95 - 2.73 (m, 2H), 2.70 - 2.60 (m, 2H), 2.58 (br s, 4H), 2.57 - 2.53 (m, 1H), 2.52 - 2.45 (m, 1H), 2.20 (ddd, J= 13.4, 8.1, 5.6 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.89 (br dd, J= 13.7, 7.4 Hz, 1H), 1.76 - 1.64 (m, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 實例22 5-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 22）

The synthesis procedure of Example 21 is the same as that of Example 6 , using Intermediate 22 (70.0 mg, 121 mmol) to replace Intermediate 9 and 2-(2,6-two-side oxypiperidin-3-yl)-4-(piper

-1-yl) isoindoline-1,3-dione (reference: J. Med. Chem , 2021 , 54 , 12381) reaction. After preparative HPLC (NH ₄ HCO ₃ conditions), compound 21 was obtained, 4-(4-((1-(4-((2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 0.014 g, yield 12% and purity 97.08%. LCMS (ESI ^- ): m/z = 838.3 (MH) ^- , RT: 2.061 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.09 (br s, 1H, NH), 10.06 (br s, 1H, NH), 8.79 (s, 1H), 7.90 (br d, J = 8.0 Hz , 1H), 7.74 - 7.65 (m, 2H), 7.59 - 7.41 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.42 (br d , J = 8.6 Hz, 2H), 5.73 - 5.59 (m, 1H), 5.10 (dd, J = 5.6, 12.8 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J = 10.3 Hz , 1H), 4.85 (br d, J = 17.5 Hz, 1H), 4.80 - 4.67 (m, 1H), 4.64 - 4.49 (m, 1H), 3.93 (br t, J = 7.2 Hz, 2H), 3.46 ( ( br s, 4H), 2.57 - 2.53 (m, 1H), 2.52 - 2.45 (m, 1H), 2.20 (ddd, J = 13.4, 8.1, 5.6 Hz, 1H), 2.09 - 1.96 (m, 2H), 1.89 (br dd, J = 13.7, 7.4 Hz, 1H), 1.76 - 1.64 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min monitoring Wavelength: 220 nm and 254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 22 5-(4-((1-(4-((2-allyl-1-( ( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 22 )

-1-基)異吲哚啉-1,3-二酮（參考文獻：J. Med. Chem, 2021, 64, 12831-12854）反應。在製備型HPLC（NH ₄HCO ₃條件）之後，得到 化合物 22，5-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮10 mg，產率11%及97.15%純度。LCMS (ESI ^-): m/z= 836.4 (M-H) ^-，RT：2.824分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.10(br s, 1H, NH), 10.06 (br s, 1H), 8.79 (s, 1H), 7.89 (br d, J= 7.9 Hz, 1H), 7.68 (d, J= 8.2 Hz, 2H), 7.52 (br s, 2H), 7.35 (s, 1H), 7.26 (dd, J= 8.6, 1.7 Hz, 1H), 6.42 (br d, J= 8.5 Hz, 2H), 5.77 - 5.56 (m, 1H), 5.07 (dd, J= 5.4, 13.0 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J= 10.0 Hz, 1H), 4.85 (br d, J= 17.2 Hz, 1H), 4.83 - 4.67 (m, 1H), 4.63 - 4.48 (m, 1H), 3.92 (br t, J= 7.3 Hz, 2H), 3.52 - 3.37 (m, 6H), 3.05 - 2.88 (m, 2H), 2.88 - 2.83 (m, 1H), 2.83 - 2.71 (m, 1H), 2.68 - 2.60 (m, 3H), 2.58 - 2.51 (m, 5H), 2.26 - 2.14 (m, 1H), 2.07 - 1.96 (m, 2H), 1.94 - 1.82 (m, 1H), 1.78 - 1.61 (m, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B% 0.0 25 8.0 45 8.1 45 8.2 100 10.2 100 10.3 25 11.5 25 實例23 3-(5-(4-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 23）

The synthesis procedure of Example 22 is the same as that of Example 6 , using Intermediate 22 (70.0 mg, 121 mmol) to replace Intermediate 9 and 2-(2,6-two-side oxypiperidin-3-yl)-5-(piper

-1-yl) isoindoline-1,3-dione (reference: J. Med. Chem, 2021, 64, 12831-12854). After preparative HPLC (NH ₄ HCO ₃ conditions), compound 22 was obtained, 5-(4-((1-(4-((2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 10 mg, yield 11% and purity 97.15%. LCMS (ESI ^- ): m/z = 836.4 (MH) ^- , RT: 2.824 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.10(br s, 1H, NH), 10.06 (br s, 1H), 8.79 (s, 1H), 7.89 (br d, J = 7.9 Hz, 1H ), 7.68 (d, J = 8.2 Hz, 2H), 7.52 (br s, 2H), 7.35 (s, 1H), 7.26 (dd, J = 8.6, 1.7 Hz, 1H), 6.42 (br d, J = 8.5 Hz, 2H), 5.77 - 5.56 (m, 1H), 5.07 (dd, J = 5.4, 13.0 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J = 10.0 Hz, 1H) , 4.85 (br d, J = 17.2 Hz, 1H), 4.83 - 4.67 (m, 1H), 4.63 - 4.48 (m, 1H), 3.92 (br t, J = 7.3 Hz, 2H), 3.52 - 3.37 (m , 6H), 3.05 - 2.88 (m, 2H), 2.88 - 2.83 (m, 1H), 2.83 - 2.71 (m, 1H), 2.68 - 2.60 (m, 3H), 2.58 - 2.51 (m, 5H), 2.26 - 2.14 (m, 1H), 2.07 - 1.96 (m, 2H), 1.94 - 1.82 (m, 1H), 1.78 - 1.61 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min monitoring Detector wavelength: 220 nm and 254 nm Time B% 0.0 25 8.0 45 8.1 45 8.2 100 10.2 100 10.3 25 11.5 25 Example 23 3-(5-(4-(1-(4-((2-allyl-1 -(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)piper

-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 23 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（5.0 mg，5.9 µmol，產率6%，98%純度）。LCMS (ESI ⁺)： m/z= 838.4 (M+H) ⁺，RT：2.004分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 13.78 - 13.74 (m, 1H), 10.94 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.99 - 7.88 (m, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.65 - 7.42 (m, 2H), 7.52 (d, J= 8.8 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J= 7.2 Hz, 1H), 6.93 (br d, J= 8.8 Hz, 2H), 5.76 - 5.59 (m, 1H), 5.05 (dd, J= 5.2, 13.0 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J= 10.4 Hz, 1H), 4.86 (br d, J= 17.1 Hz, 1H), 4.83 - 4.69 (m, 1H), 4.65 - 4.50 (m, 1H), 4.38 - 4.15 (m, 2H), 4.16 - 4.14 (m, 1H), 3.70 (br d, J= 11.4 Hz, 2H), 3.28 (br s, 4H), 3.04 - 2.83 (m, 2H), 2.82 - 2.73 (m, 1H), 2.65 (br s, 4H), 2.65 - 2.58 (m, 2H), 2.58 - 2.53 (m, 1H), 2.45 - 2.30 (m, 2H), 2.27 - 2.14 (m, 1H), 2.09 - 1.82 (m, 5H), 1.78 - 1.65 (m, 1H), 1.63 - 1.48 (m, 2H), 0.87 (br t, J= 7.3 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3 µm 流速：25 mL/min 監測器波長：220/254 nm 時間B% 0.0 15 8.0 45 8.1 45 8.2 100 10.2 100 10.3 15 11.5 15 實例24 4-(6-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)-2,6-二氮雜螺[3.3]庚-2-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 24）

To a mixture of Intermediate 23 (58.1 mg, 116 µmol) in DMF (1.5 mL) was added Intermediate 7 (40.0 mg, 96.3 µmol) and DIEA (17.2 µL, 96.3 µmol) at 20 °C. Next, the reaction was stirred at 20 °C for 12 h under _N2 . LCMS showed the reaction was complete and the desired product was detected. The reaction was subjected to preparative HPLC (NH ₄ HCO ₃ conditions) to obtain compound 23 , 3-(5-(4-(1-(4-((2-allyl-1-(( R )-7- Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3 ,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.0 mg, 5.9 µmol, 6% yield, 98% purity). LCMS (ESI ⁺ ): m/z = 838.4 (M+H) ⁺ , RT: 2.004 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 13.78 - 13.74 (m, 1H), 10.94 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.99 - 7.88 (m, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.65 - 7.42 (m, 2H), 7.52 (d, J = 8.8 Hz, 1H), 7.06 (s, 1H), 7.05 ( d, J = 7.2 Hz, 1H), 6.93 (br d, J = 8.8 Hz, 2H), 5.76 - 5.59 (m, 1H), 5.05 (dd, J = 5.2, 13.0 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (br d, J = 10.4 Hz, 1H), 4.86 (br d, J = 17.1 Hz, 1H), 4.83 - 4.69 (m, 1H), 4.65 - 4.50 (m, 1H), 4.38 - 4.15 (m, 2H), 4.16 - 4.14 (m, 1H), 3.70 (br d, J = 11.4 Hz, 2H), 3.28 (br s, 4H), 3.04 - 2.83 (m, 2H), 2.82 - 2.73 (m, 1H), 2.65 (br s, 4H), 2.65 - 2.58 (m, 2H), 2.58 - 2.53 (m, 1H), 2.45 - 2.30 (m, 2H), 2.27 - 2.14 (m, 1H), 2.09 - 1.82 (m, 5H), 1.78 - 1.65 (m, 1H), 1.63 - 1.48 (m, 2H), 0.87 (br t, J = 7.3 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3 µm Flow rate: 25 mL/min Monitor Wavelength: 220/254 nm Time B% 0.0 15 8.0 45 8.1 45 8.2 100 10.2 100 10.3 15 11.5 15 Example 24 4-(6-(1-(4-((2-allyl-1-(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H- Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 24 )

-1-基)吖呾--1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 25）

Example 24 was obtained by following a similar procedure described in Example 18 , under standard reductive amination conditions, using 2-(2,6-dioxopiperidin-3-yl)-4-(2,6- Diazaspiro[3.3]hept-2-yl)isoindoline-1,3-dione (reference: WO 2021/194318) was prepared by reacting intermediate 18 with intermediate 24 . After preparative HPLC purification, the desired title product compound 24 was obtained, 4-(6-(1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy- 6,7-Dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidine- 6-yl)amino)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)-2-(2,6-two-side oxypiperidine- 3-yl)isoindoline-1,3-dione (15 mg, 15.47% yield, 100% purity). LCMS (ESI ⁺ ): m/z = 864.3 (M+H) ⁺ , RT: 2.091 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.06 (br s, 1H, NH), 10.10 (m, 1H, NH), 8.81 (s, 1H), 7.97 - 7.88 (m, 1H), 7.69 (br d, J = 8.9 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 7.0 Hz, 1H), 6.91 ( br d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.6 Hz, 1H), 5.72 - 5.61 (m, 1H), 5.05 (dd, J = 5.2, 13.0 Hz, 1H), 5.04 (s, 1H, OH), 5.00 (br d, J = 10.4 Hz, 1H), 4.90 - 4.81 (m, 1H), 4.80 - 4.69 (m, 1H), 4.61 - 4.50 (m, 1H), 4.26 (s, 4H ), 3.56 - 3.45 (m, 2H), 3.29 (s, 4H), 3.02 - 2.91 (m, 1H), 2.91 - 2.76 (m, 2H), 2.75 - 2.65 (m, 2H), 2.63 - 2.52 (m , 2H), 2.26 - 2.15 (m, 1H), 2.15 - 2.07 (m, 1H), 2.06 - 1.96 (m, 2H), 1.95 - 1.84 (m, 1H), 1.77 - 1.65 (m, 3H), 1.33 - 1.20 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H). Example 25 4-(3-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan--1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 25 )

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（52 mg，產率39.87%，97%純度）。LCMS (ESI ⁺)： m/z= 824.2 (M+H) ⁺，RT：2.074分鐘。 ¹H NMR (400 MHz, DMSO-d ₆) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (br d, J= 7.7 Hz, 1H), 7.69 (d, J= 8.2 Hz, 1H), 7.60 (d, J= 8.2 Hz, 1H), 7.58 (d, J= 8.2 Hz, 2H), 7.13 (d, J= 6.9 Hz, 1H), 6.93 (br d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.6 Hz, 1H), 5.67 (tdd, J= 16.8, 10.6, 5.9 Hz, 1H), 5.06 (dd, J= 5.2, 13.0 Hz, 1H), 5.05 (s, 1H, OH), 4.99 (d, J= 9.9 Hz, 1H), 4.85 (br d, J= 16.9 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.56 (br dd, J= 15.5, 5.0 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.03 (br dd, J= 8.5, 4.6 Hz, 2H), 3.31 (br s, 2H), 3.14 (br s, 4H), 3.02 - 2.92 (m, 1H), 2.91 - 2.72 (m, 2H), 2.63 - 2.53 (m, 1H), 2.52 (br d, J= 1.8 Hz, 4H), 2.25 - 2.15 (m, 1H), 2.07 - 1.97 (m, 2H), 1.89 (br dd, J= 13.6, 7.3 Hz, 1H), 1.70 (dd, J= 13.6, 7.3 Hz, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法： 儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B%0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 實例26 4-(4-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 26）

Example 25 was prepared by reacting Intermediate 1 with Intermediate 1 in place of Intermediate 18 using Intermediate 25 under standard reductive amination conditions following a similar procedure as described in Example 18 . The reaction was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to obtain the desired compound 25 , 4-(3-(4-(4-((2-allyl-1-(( R )-7- Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3 ,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (52 mg, yield 39.87% , 97% purity). LCMS (ESI ⁺ ): m/z = 824.2 (M+H) ⁺ , RT: 2.074 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (br d, J = 7.7 Hz , 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 6.9 Hz, 1H ), 6.93 (br d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.6 Hz, 1H), 5.67 (tdd, J = 16.8, 10.6, 5.9 Hz, 1H), 5.06 (dd, J = 5.2 , 13.0 Hz, 1H), 5.05 (s, 1H, OH), 4.99 (d, J = 9.9 Hz, 1H), 4.85 (br d, J = 16.9 Hz, 1H), 4.78 - 4.73 (m, 1H), 4.56 (br dd, J = 15.5, 5.0 Hz, 1H), 4.37 - 4.25 (m, 2H), 4.03 (br dd, J = 8.5, 4.6 Hz, 2H), 3.31 (br s, 2H), 3.14 (br s, 4H), 3.02 - 2.92 (m, 1H), 2.91 - 2.72 (m, 2H), 2.63 - 2.53 (m, 1H), 2.52 (br d, J = 1.8 Hz, 4H), 2.25 - 2.15 (m , 1H), 2.07 - 1.97 (m, 2H), 1.89 (br dd, J = 13.6, 7.3 Hz, 1H), 1.70 (dd, J = 13.6, 7.3 Hz, 1H), 0.87 (t, J = 7.4 Hz , 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitoring Wavelength: 220 nm and 254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 26 4-(4-(1-(4-((2-allyl-1-(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H- Pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 26 )

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（0.019 g，產率13.41%，98%純度）。LCMS (ESI ⁺)：m/z = 629.2 (M+H) ⁺，RT：0.656分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (br s, 1H, NH), 10.07 (br s, 1H, NH), 8.80 (s, 1H), 7.90 (br d, J= 8.0 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.60 - 7.42 (m, 2H), 7.40 - 7.30 (m, 2H), 6.34 (d, J= 8.8 Hz, 2H), 5.67 (tdd, J= 16.8, 10.6, 5.9 Hz, 1H), 5.09 (dd, J= 5.4, 12.8 Hz, 1H), 5.07 (s, 1H, OH), 4.99 (d, J= 9.6 Hz, 1H), 4.85 (br d, J= 17.2 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.60 - 4.50 (m, 1H), 3.96 (t, J= 6.8 Hz, 2H), 3.52 (t, J= 6.0 Hz, 2H), 3.43 - 3.35 (m, 1H), 3.30 - 3.20 (m, 4H), 3.02 - 2.75 (m, 3H), 2.64 - 2.53 (m, 2H), 2.55 (br s, 4H), 2.22 - 2.11 (m, 1H), 2.08 - 1.97 (m, 2H), 1.95 -1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 0.87 (t, J= 7.6 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C 1875*30 mm*3 um 流速：25 mL/min 監測器波長：220/254 nm 時間B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 實例27 4-(3-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 27）

Example 26 was prepared following a similar procedure described in Example 17 , using Intermediate 27 in place of Intermediate 20 to react Intermediate 7 . The reaction mixture was directly purified without work-up. _The reaction was purified by preparative HPLC ( _NH4HCO3 conditions) to afford the title compound 26 , 4-(4-(1-(4-((2-allyl-1-(( R )-7-ethane Base-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3, 4-d]pyrimidin-6-yl)amino)phenyl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.019 g, 13.41% yield, 98% purity). LCMS (ESI ⁺ ): m/z = 629.2 (M+H) ⁺ , RT: 0.656 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (br s, 1H, NH), 10.07 (br s, 1H, NH), 8.80 (s, 1H), 7.90 (br d, J = 8.0 Hz , 1H), 7.72 - 7.65 (m, 2H), 7.60 - 7.42 (m, 2H), 7.40 - 7.30 (m, 2H), 6.34 (d, J = 8.8 Hz, 2H), 5.67 (tdd, J = 16.8 , 10.6, 5.9 Hz, 1H), 5.09 (dd, J = 5.4, 12.8 Hz, 1H), 5.07 (s, 1H, OH), 4.99 (d, J = 9.6 Hz, 1H), 4.85 (br d, J = 17.2 Hz, 1H), 4.80 - 4.73 (m, 1H), 4.60 - 4.50 (m, 1H), 3.96 (t, J = 6.8 Hz, 2H), 3.52 (t, J = 6.0 Hz, 2H), 3.43 - 3.35 (m, 1H), 3.30 - 3.20 (m, 4H), 3.02 - 2.75 (m, 3H), 2.64 - 2.53 (m, 2H), 2.55 (br s, 4H), 2.22 - 2.11 (m, 1H ), 2.08 - 1.97 (m, 2H), 1.95 -1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C 1875*30 mm*3 um Flow rate: 25 mL/min Monitor Wavelength: 220/254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 27 4-(3-((4-(4-((2-allyl-1-( ( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 27 )

-1-基)甲基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（12 mg，產率16%，98.87%純度）。LCMS (ESI ^-): m/z= 836.5 (M-H) ^-，RT：2.907分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 7.7 Hz, 1H), 7.69 (d, J= 8.1 Hz, 1H), 7.65 - 7.49 (m, 3H), 7.11 (d, J= 6.9 Hz, 1H), 6.92 (br d, J= 8.9 Hz, 2H), 6.79 (d, J= 8.6 Hz, 1H), 5.74 - 5.59 (m, 1H), 5.09 - 5.02 (m, 1H), 5.05 (s, 1H, OH), 5.00 (br d, J= 10.1 Hz, 1H), 4.85 (br d, J= 17.6 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.57 (br dd, J= 15.0, 5.4 Hz, 1H), 4.42 - 4.25 (m, 2H), 3.91 - 3.82 (m, 2H), 3.45 - 3.35 (m, 2H), 3.10 (br s, 4H), 3.04 - 2.93 (m, 2H), 2.86 - 2.74 (m, 2H), 2.68 - 2.63 (m, 2H), 2.56 - 2.55 (m, 4H), 2.26 - 2.15 (m, 1H), 2.06 - 1.95 (m, 2H), 1.89 (br dd, J= 13.6, 7.3 Hz, 1H), 1.77 - 1.66 (m, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法： 儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B%0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 實例28 5-(3-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 28）

The synthesis procedure of Example 27 is the same as that of Example 7 , using Intermediate 28 (0.08 g, 179.01 μmol, 94.30% purity) to replace Intermediate 11 and Intermediate 1 to react. The mixture was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to give the desired compound 27 , 4-(3-((4-(4-((2-allyl-1-(( R )-7 -Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[ 3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (12 mg, yield 16% yield, 98.87% purity). LCMS (ESI ^- ): m/z = 836.5 (MH) ^- , RT: 2.907 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J = 7.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.65 - 7.49 (m, 3H), 7.11 (d, J = 6.9 Hz, 1H), 6.92 (br d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.6 Hz, 1H), 5.74 - 5.59 (m, 1H), 5.09 - 5.02 (m, 1H), 5.05 (s, 1H, OH), 5.00 (br d, J = 10.1 Hz, 1H) , 4.85 (br d, J = 17.6 Hz, 1H), 4.80 - 4.71 (m, 1H), 4.57 (br dd, J = 15.0, 5.4 Hz, 1H), 4.42 - 4.25 (m, 2H), 3.91 - 3.82 (m, 2H), 3.45 - 3.35 (m, 2H), 3.10 (br s, 4H), 3.04 - 2.93 (m, 2H), 2.86 - 2.74 (m, 2H), 2.68 - 2.63 (m, 2H), 2.56 - 2.55 (m, 4H), 2.26 - 2.15 (m, 1H), 2.06 - 1.95 (m, 2H), 1.89 (br dd, J = 13.6, 7.3 Hz, 1H), 1.77 - 1.66 (m, 1H) , 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitoring Detector wavelength: 220 nm and 254 nm Time B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 Example 28 5-(3-((4-(4-((2-allyl-1-( ( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 28 )

-1-基)甲基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（40 mg，產率16.51%，98.60%純度）。LCMS (ESI ^-): m/z = 836.4 (M-H) ^-，RT：2.836分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.05 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 7.6 Hz, 1H), 7.70 (d, J= 8.1 Hz, 1H), 7.64 (d, J= 8.3 Hz, 1H), 7.63 - 7.52 (m, 2H), 6.93 (br d, J= 9.1 Hz, 2H), 6.79 (d, J= 2.0 Hz, 1H), 6.65 (dd, J= 8.5, 2.0 Hz, 1H), 5.67 (tdd, J= 16.8, 10.5, 5.9 Hz, 1H), 5.05 (dd, J= 5.4, 12.8 Hz, 1H), 5.05 (s, 1H, OH), 4.98 (dd, J= 1.0, 9.6 Hz, 1H), 4.86 (dd, J= 17.2, 1.0 Hz, 1H), 4.82 – 4.70 (m, 1H), 4.57 (br dd, J= 15.7, 4.6 Hz, 1H), 4.16 (t, J= 8.2 Hz, 2H), 3.72 (dd, J= 8.2, 5.5 Hz, 2H), 3.30 (br s, 2H), 3.10 (br s, 4H), 3.06 - 2.90 (m, 1H), 2.89 - 2.73 (m, 1H), 2.70 - 2.64 (m, 2H), 2.56 (br s, 4H), 2.60 - 2.50 (m, 2H), 2.20 (ddd, J= 13.5, 8.2, 5.7 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.89 (br dd, J= 13.6, 7.4 Hz, 1H), 1.71 (dd, J= 13.6, 7.4 Hz, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃水溶液；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220 nm及254 nm 時間B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 實例294-((1'-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)-[1,3'-雙吖呾]-3-基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 29）

The synthesis procedure of Example 28 is the same as that of Example 27 , using Intermediate 29 (0.08 g, 179.01 μmol, 94.30% purity) to replace Intermediate 28 and Intermediate 1 to react. The mixture was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to give the desired compound 28 , 5-(3-((4-(4-((2-allyl-1-(( R )-7 -Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[ 3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (40 mg, produced 16.51% yield, 98.60% purity). LCMS (ESI ^- ): m/z = 836.4 (MH) ^- , RT: 2.836 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.05 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J = 7.6 Hz , 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.63 - 7.52 (m, 2H), 6.93 (br d, J = 9.1 Hz, 2H), 6.79 (d, J = 2.0 Hz, 1H), 6.65 (dd, J = 8.5, 2.0 Hz, 1H), 5.67 (tdd, J = 16.8, 10.5, 5.9 Hz, 1H), 5.05 (dd, J = 5.4, 12.8 Hz, 1H), 5.05 (s, 1H, OH), 4.98 (dd, J = 1.0, 9.6 Hz, 1H), 4.86 (dd, J = 17.2, 1.0 Hz, 1H), 4.82 – 4.70 (m, 1H ), 4.57 (br dd, J = 15.7, 4.6 Hz, 1H), 4.16 (t, J = 8.2 Hz, 2H), 3.72 (dd, J = 8.2, 5.5 Hz, 2H), 3.30 (br s, 2H) , 3.10 (br s, 4H), 3.06 - 2.90 (m, 1H), 2.89 - 2.73 (m, 1H), 2.70 - 2.64 (m, 2H), 2.56 (br s, 4H), 2.60 - 2.50 (m, 2H), 2.20 (ddd, J = 13.5, 8.2, 5.7 Hz, 1H), 2.07 - 1.96 (m, 2H), 1.89 (br dd, J = 13.6, 7.4 Hz, 1H), 1.71 (dd, J = 13.6 , 7.4 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ aqueous solution; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min monitoring Wavelength: 220 nm and 254 nm Time B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 Example 29 4-((1'-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyridine Azolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-[1,3'-biazine]-3-yl)amino)-2-(2,6-two sides Oxypiperidin-3-yl)isoindoline-1,3-dione ( Compound 29 )

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 30）

Example 29 was prepared following a similar procedure described in Example 26 , using Intermediate 30 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was directly purified by preparative HPLC (FA conditions) without work-up to give compound 29 , 4-((1'-(4-((2-allyl-1-(( R )-7 -Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[ 3,4- d ]pyrimidin-6-yl)amino)phenyl)-[1,3'-diazepine]-3-yl)amino)-2-(2,6-two side oxypiper pyridin-3-yl)isoindoline-1,3-dione (25.9 mg, 53% yield, 100.00% purity). LCMS (ESI ⁺ ): m/z = 810.1 (M+H) ⁺ , RT: 2.126 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.10 (br s, 1H), 10.05 (br s, 1H), 8.79 (s, 1H), 7.89 (br d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.593 (t, J = 8.0 Hz, 1H), 7.52 (br s, 2H), 7.10 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 6.8 Hz, 1H), 6.42 (br d, J = 8.6 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.07 (dd, J = 5.2, 12.8 Hz , 1H), 5.04 (s, 1H), 4.99 (br d, J = 9.9 Hz, 1H), 4.85 (br d, J = 17.4 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.62 - 4.49 ( m, 1H), 4.40 - 4.25 (m, 1H), 3.92 - 3.78 (m, 2H), 3.70 (br t, J = 6.7 Hz, 2H), 3.61 (br d, J = 3.0 Hz, 3H), 3.10 (br t, J = 6.5 Hz, 2H), 3.01 - 2.83 (m, 2H), 2.81 - 2.71 (m, 1H), 2.64 - 2.52 (m, 2H), 2.25 - 2.13 (m, 1H), 2.10 - 1.96 (m, 2H), 1.89 (br dd, J = 13.6, 7.4 Hz, 1H), 1.70 (dd, J = 13.6, 7.3 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Waters Xbridge BEH C 18100*30 mm*10 um Flow rate: 25 mL/min Monitor Wavelength: 220&254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 30 4-(3-(4-(2-allyl-1-(( R )- 7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo [3,4- d ]pyrimidin-6-yl)piper

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 30 )

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（24 mg，產率25%，98.78%純度）。LCMS (ESI ^-): m/z = 731.3 (M-H) ^-，RT：2.798分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.04 (br s, 1H, NH), 8.79 (s, 1H), 7.83 (d, J= 8.1 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.58 (dd, J= 7.2, 8.4 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 8.8 Hz, 1H), 5.72 - 5.55 (m, 1H), 5.05 (dd, J= 5.6, 12.8 Hz, 1H), 5.04 (s, 1H), 4.98 (br d, J= 10.3 Hz, 1H), 4.83 (br d, J= 17.5 Hz, 1H), 4.74 (br dd, J= 15.9, 5.5 Hz, 1H), 4.53 (br dd, J= 15.9, 6.3 Hz, 1H), 4.35 - 4.28 (m, 2H), 4.05 - 3.98 (m, 2H), 3.97 - 3.75 (m, 2H), 3.33 - 3.20 (m, 1H), 3.01 - 2.83 (m, 2H), 2.81 - 2.71 (m, 1H), 2.64 - 2.52 (m, 2H), 2.43 (br s, 4H), 2.20 (ddd, J= 13.5, 8.2, 5.7 Hz, 1H), 2.05 - 1.96 (m, 2H), 1.92 - 1.84 (m, 1H), 1.70 (dd, J= 13.6, 7.3 Hz, 1H), 0.87 (t, J= 7.4 Hz, 3H)。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃於水中；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220&254 nm 時間B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 實例31 4-(4-(1-(2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 31）

Example 30 was prepared by reacting Intermediate 25 with Intermediate 31 in place of Intermediate 18 under standard reductive amination conditions following a procedure similar to that described in Example 18 . The reaction was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to obtain the desired compound 30 , 4-(3-(4-(2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)piper

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (24 mg, yield 25% , 98.78% purity). LCMS (ESI ^- ): m/z = 731.3 (MH) ^- , RT: 2.798 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.04 (br s, 1H, NH), 8.79 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.58 (dd, J = 7.2, 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.72 - 5.55 (m, 1H ), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 5.04 (s, 1H), 4.98 (br d, J = 10.3 Hz, 1H), 4.83 (br d, J = 17.5 Hz, 1H), 4.74 (br dd, J = 15.9, 5.5 Hz, 1H), 4.53 (br dd, J = 15.9, 6.3 Hz, 1H), 4.35 - 4.28 (m, 2H), 4.05 - 3.98 (m, 2H), 3.97 - 3.75 (m, 2H), 3.33 - 3.20 (m, 1H), 3.01 - 2.83 (m, 2H), 2.81 - 2.71 (m, 1H), 2.64 - 2.52 (m, 2H), 2.43 (br s, 4H), 2.20 (ddd, J = 13.5, 8.2, 5.7 Hz, 1H), 2.05 - 1.96 (m, 2H), 1.92 - 1.84 (m, 1H), 1.70 (dd, J = 13.6, 7.3 Hz, 1H), 0.87 ( t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitor wavelength: 220&254 nm Time B% 0.0 25 8.0 55 8.1 55 8.2 100 10.2 100 10.3 25 11.5 25 Example 31 4-(4-(1-(2-allyl-1-(( R )-7-ethyl Base-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3, 4- d ]pyrimidin-6-yl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 31 )

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（22 mg，產率20%，99.45%純度）。LCMS (ESI ^-): m/z= 731.3 (M-H) ^-，RT：2.708分鐘。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (s, 1H, NH), 8.77 (s, 1H), 7.83 (d, J= 8.2 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.40 - 7.29 (m, 2H), 5.69 - 5.58 (m, 1H), 5.09 (dd, J= 12.8, 5.4 Hz, 1H), 5.04 (s, 1H), 4.98 (d, J= 10.1 Hz, 1H), 4.83 (br d, J= 17.2 Hz, 1H), 4.73 (br dd, J= 15.9, 5.5 Hz, 1H), 4.54 (br dd, J= 16.0, 5.6 Hz, 1H), 4.27 - 4.09 (m, 2H), 4.07 - 3.89 (m, 2H), 3.38 - 3.32 (m, 4H), 2.97 - 2.85 (m, 2H), 2.81 - 2.70 (m, 1H), 2.65 - 2.55 (m, 1H), 2.57 (br s, 4H), 2.25 - 2.13 (m, 1H), 2.07 - 1.96 (m, 2H), 1.88 (br dd, J= 13.6, 7.4 Hz, 1H), 1.78 - 1.63 (m, 1H), 0.86 (t, J= 7.4 Hz, 3H)。 實例32 4-(4-(1-(2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 32）

Example 31 was prepared following a similar procedure as described in Example 26 , using Intermediate 32 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was filtered, and the filter cake was collected by suction filtration and dried in vacuo to give compound 31 , 4-(4-(1-(2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (22 mg, 20% yield, 99.45% purity). LCMS (ESI ^- ): m/z = 731.3 (MH) ^- , RT: 2.708 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.08 (s, 1H, NH), 8.77 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.74 - 7.64 (m, 2H) , 7.40 - 7.29 (m, 2H), 5.69 - 5.58 (m, 1H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H), 5.04 (s, 1H), 4.98 (d, J = 10.1 Hz, 1H ), 4.83 (br d, J = 17.2 Hz, 1H), 4.73 (br dd, J = 15.9, 5.5 Hz, 1H), 4.54 (br dd, J = 16.0, 5.6 Hz, 1H), 4.27 - 4.09 (m , 2H), 4.07 - 3.89 (m, 2H), 3.38 - 3.32 (m, 4H), 2.97 - 2.85 (m, 2H), 2.81 - 2.70 (m, 1H), 2.65 - 2.55 (m, 1H), 2.57 (br s, 4H), 2.25 - 2.13 (m, 1H), 2.07 - 1.96 (m, 2H), 1.88 (br dd, J = 13.6, 7.4 Hz, 1H), 1.78 - 1.63 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H). Example 32 4-(4-(1-(2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridine- 2-yl)-3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)azan-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 32 )

Example 32 was prepared following a similar procedure described in Example 26 , using Intermediate 33 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was filtered, and the filter cake was collected by suction filtration and dried in vacuo to give compound 32 , 4-(4-(3-((2-allyl-1-(( R )-7-ethyl- 7-Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ] pyrimidin-6-yl) amino) azil-1-yl) piperidin-1-yl)-2-(2,6-two side oxypiperidin-3-yl) isoindoline-1 ,3-Diketone (46 mg, 24% yield, 95.4% purity). LCMS (ESI ⁺ ): m/z = 747.2 (M+H) ⁺ , RT: 2.017 min. ¹ H NMR (400 MHz, DMSO- d ₆ , 80°C) δ = 11.07 (br s, 1H, NH), 8.69 (s, 1H), 8.31 - 8.07 (m, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.75 - 7.56 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 5.71 (ddd, J = 16.8, 6.1, 4.2 Hz , 1H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H), 5.01 (dd, J = 10.1, 1.2 Hz, 1H), 4.92 (dd, J = 17.2, 1.2 Hz, 1H), 4.72 (s, 1H), 4.73 - 4.62 (m, 1H), 4.58 - 4.51 (m, 1H), 4.50 - 4.38 (m, 1H), 3.68 - 3.53 (m, 4H), 3.05 - 2.93 (m, 4H), 2.93 - 2.75 (m, 3H), 2.70 - 2.52 (m, 2H), 2.35 - 2.18 (m, 2H), 2.13 - 2.03 (m, 2H), 1.98 - 1.86 (m, 1H), 1.83 - 1.70 (m, 3H ), 1.50 - 1.37 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A : 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitor Wavelength: 220&254 nm Time B% 0.0 20 8.0 55 8.1 55 8.2 100 10.2 100 10.3 20 11.5 20 Example 33 4-(4-(6-((2-allyl-1-(( R )-7- Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3 ,4- d ]pyrimidin-6-yl)amino)-2-azaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2,6-two-side oxypiperidine -3-yl)isoindoline-1,3-dione ( compound 33 )

Example 33 was prepared following a similar procedure described in Example 26 , using Intermediate 34 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was filtered, and the filter cake was collected by suction filtration and dried in vacuo to obtain compound 33 , 4-(4-(6-((2-allyl-1-(( R )-7-ethyl- 7-Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ] pyrimidin-6-yl)amino)-2-azaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2,6-two-side oxypiperidine-3- base) isoindoline-1,3-dione (0.0359 g, 37% yield, 98.52% purity). LCMS (ESI ⁺ ): m/z = 787.5 (M+H) ⁺ , RT: 2.713 min. ¹ H NMR (400 MHz, DMSO- d ₆ , 80°C) δ = 10.78 (br s, 1H, NH), 8.66 (s, 1H), 8.14 - 7.91 (m, 1H), 7.82 (br d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.9 Hz,1H), 7.64 (d, J = 7.9 Hz,1H), 7.31 (d, J = 9.2 Hz,1H), 7.29 (d, J = 7.2 Hz ,1H), 5.68 (tdd, J = 16.8, 10.6, Hz, 1H), 5.04 (br dd, J = 12.8, 5.4, 1H), 5.00 (br d, J = 10.4 Hz, 1H), 4.91 (br d , J = 17.5 Hz, 1H), 4.71 (s, 1H), 4.75 - 4.62 (m, 1H), 4.61 - 4.46 (m, 1H), 4.33 - 4.11 (m, 1H), 3.65 - 3.52 (m, 2H ), 3.21 (br s, 2H), 3.09 (br s, 2H), 3.03 - 2.95 (m, 4H), 2.95 - 2.71 (m, 2H), 2.70 - 2.54 (m, 1H), 2.47 - 2.34 (m , 2H), 2.24 - 2.15 (m, 4H), 2.13 - 2.00 (m, 2H), 2.00 - 1.85 (m, 1H), 1.80 - 1.70 (m, 3H), 1.45 - 1.33 (m, 2H), 0.89 (br t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Waters Xbridge Prep OBD C18 150*40 mm*10um Flow rate: 25 mL/min Monitor Wavelength: 220&254 nm Time B% 0.0 30 8.0 70 8.1 70 8.2 100 10.2 100 10.3 30 11.5 30 Example 34 4-(6-(4-((2-allyl-1-(( R ) -7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazole And[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl)-2-(2,6-two side oxy piperidin-3-yl)isoindoline-1,3-dione ( compound 34 )

Example 34 was prepared following a similar procedure as described in Example 26 , using Intermediate 35 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was filtered, and the filter cake was collected by suction filtration and dried in vacuo to obtain compound 34 , 4-(6-(4-((2-allyl-1-(( R )-7-ethyl- 7-Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl)-2-(2,6-two side oxypiperidin-3-yl ) isoindoline-1,3-dione (7.6 mg, 23% yield, 97.36% purity). LCMS (ESI ⁺ ): m/z = 781.4 (M+H) ⁺ , RT: 2.927 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.07 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (br d, J = 8.1 Hz , 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 8.3, 7.0 Hz, 1H), 7.62 - 7.47 (m, 2H), 7.15 (d, J = 7.0 Hz, 1H) , 6.83 (d, J = 8.5 Hz, 1H), 6.46 (br d, J = 8.8 Hz, 2H), 5.66 (tdd, J = 16.8, 10.5, 6.0, Hz, 1H), 5.06 (dd, J = 12.8 , 5.6 Hz, 1H), 5.04 (s, 1H), 4.99 (d, J = 9.4 Hz, 1H), 4.85 (br d, J = 17.1 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.62 - 4.51 (m, 1H), 4.40 (s, 4H), 3.98 (s, 4H), 3.02 - 2.90 (m, 1H), 2.90 - 2.72 (m, 2H), 2.62 - 2.53 (m, 2H), 2.25 - 2.16 (m, 1H), 2.06 - 1.97 (m, 2H), 1.89 (br dd, J = 13.6, 7.4 Hz, 1H), 1.70 (dd, J = 13.7, 7.4 Hz, 1H), 0.87 (t, J = 7.4 Hz, 3H). Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitor Wavelength: 220&254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 35 4-(6-((1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyridine Azolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 35 )

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 36）

Example 35 was prepared by reacting Intermediate 24 with Intermediate 36 in place of Intermediate 18 under standard reductive amination conditions following a similar procedure as described in Example 18 . After preparative HPLC purification, the desired title product compound 35 , 4-(6-((1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy- 6,7-Dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidine- 6-yl)amino)phenyl)piperidin-4-yl)amino)-2-azaspiro[3.3]hept-2-yl)-2-(2,6-two-side oxypiperidine- 3-yl)isoindoline-1,3-dione (15.0 mg, 22% yield, 100% purity). LCMS (ESI ⁺ ): m/z = 878.40 (M+H) ⁺ , RT: 2.133 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.06 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.80 (s, 1H), 7.97 - 7.87 (m, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.54 (br dd, J = 8.4, 7.1 Hz, 3H), 7.10 (d, J = 6.9 Hz, 1H), 6.90 (br d, J = 8.9 Hz, 2H ), 6.74 (d, J = 8.5 Hz, 1H), 5.73 - 5.58 (m, 1H), 5.08 - 4.93 (m, 2H), 4.98 (dd, J = 17.2, 1.0 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.78 - 4.68 (m, 1H), 4.63 - 4.50 (m, 1H), 4.20 (s, 2H), 4.09 (s, 2H), 3.63 - 3.50 (m, 2H), 3.31 - 3.22 (m, 3H), 3.02 - 2.70 (m, 2H), 2.70 - 2.60 (m, 2H), 2.60 - 2.53 (m, 2H), 2.47 - 2.43 (m, 2H), 2.24 - 2.15 (m, 1H), 2.07 - 1.92 (m, 4H), 1.91 - 1.78 (m, 3H), 1.76 - 1.63 (m, 1H), 1.40 – 1.25 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H) . Example 36 4-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta [ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-two-side oxypiperidin-3-yl)isoindoline-1,3-dione ( compound 36 )

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（99 mg，17%）。MS (LCMS) m/z866.68 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.04 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 7.6 Hz, 1H), 7.70(d, J= 8.0 Hz, 1H), 7.68 (dd, J= 8.8, 6.8 Hz, 1H), 7.58 (br s, 2H), 7.34 (d, J= 10.0 Hz, 1H), 7.32 (d, J= 7.2 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 5.71-5.63 (m, 1H), 5.08 (dd, J= 13.2, 7.2 Hz, 1H), 5.05 (s, 1H, OH), 5.00 (d, J= 10.0 Hz, 1H), 4.86 (d, J= 16.8 Hz, 1H), 4.83 - 4.68 (m, 1H), 4.64 - 4.52 (m, 1H), 3.71 (br d, J= 11.2 Hz, 2H), 3.15 - 3.05 (m, 4H), 3.05 - 2.70 (m, 6H), 2.65 - 2.48 (m, 4H), 2.30 - 2.18 (m, 3H), 2.10 - 1.95 (m, 2H), 1.93 - 1.65 (m, 6H), 1.40 - 1.28 (m, 2H), 0.87 (t, J= 7.6 Hz, 3H)。 實例37 5-(4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 37）

Example 36 was prepared following a similar procedure described in Example 26 , using Intermediate 38 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography using 0 to 10% MeOH/DCM to give the desired product, which was further purified by reverse phase HPLC (column/size: X-SELECT-CSH C18 (19 *250*5 µ); mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; gradient (time/%B): 0.01/15, 1/15, 10/35, 14/39, 14.1/100, 18/100, 18.1/15, 21/15. Flow rate: 18 mL/min; Solubility: ACN + THF + water), to obtain compound 36 , 4-(4-((4-(4-((2-allyl Base-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3- Dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (99 mg, 17 %). MS (LCMS) m/z 866.68 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.04 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J = 7.6 Hz, 1H ), 7.70(d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.8, 6.8 Hz, 1H), 7.58 (br s, 2H), 7.34 (d, J = 10.0 Hz, 1H), 7.32 ( d, J = 7.2 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.71-5.63 (m, 1H), 5.08 (dd, J = 13.2, 7.2 Hz, 1H), 5.05 (s, 1H , OH), 5.00 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 16.8 Hz, 1H), 4.83 - 4.68 (m, 1H), 4.64 - 4.52 (m, 1H), 3.71 (br d , J = 11.2 Hz, 2H), 3.15 - 3.05 (m, 4H), 3.05 - 2.70 (m, 6H), 2.65 - 2.48 (m, 4H), 2.30 - 2.18 (m, 3H), 2.10 - 1.95 (m , 2H), 1.93 - 1.65 (m, 6H), 1.40 - 1.28 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H). Example 37 5-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta [ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)piperidin-1-yl)-2-(2,6-two-side oxypiperidin-3-yl)isoindoline-1,3-dione ( compound 37 )

-1-基)甲基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（22 mg，7%）。MS (LCMS) m/z864.64 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.1 (s, 1H), 10.15 (br s, 1H), 8.82 (s, 1H), 8.43 (br s, 1H), 7.93 (d, J= 8.0 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.65 (d, J= 8.4 Hz, 1H), 7.58 (br s, 1H), 7.31 (br s, 1H), 7.24 (d, J= 8.8 Hz, 1H), 6.92 (d, J= 8.8 Hz, 2H), 5.72-5.60 (m, 1H), 5.05 (dd, J= 13.2, 6.8 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (d, J= 10.4 Hz, 1H), 4.86 (d, J= 16.8 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.61 - 4.52 (m, 1H), 4.07 (d, J= 13.2 Hz, 2H), 3.11 (br s, 4H), 3.04 - 2.92 (m, 3H), 2.92 - 2.73 (m, 2H), 2.70 - 2.50 (m, 6H), 2.27 - 2.15 (m, 3H), 2.08 - 1.97 (m, 2H), 1.96 - 1.79 (m, 4H), 1.75 - 1.68 (m, 1H), 1.23 - 1.12 (m, 2H), 0.87 (t, J= 7.6 Hz, 3H)。 實例38 3-(4-(4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 38）

Example 37 was prepared following a similar procedure described in Example 26 , using Intermediate 39 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by reverse phase HPLC (column/size: X-Select-C18 (19*150 mm) 5 µ; mobile phase A: 0.1% formic acid in water (aq), mobile phase B: acetonitrile; gradient (Time/%B): 0/10, 2/10, 10/40, 12.5/43, 12.6/100, 15/100, 15.1/10, 18/10. Flow rate: 18 mL/min; Solubility: THF + ACN+water) to give compound 37 , 5-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-di Hydrogen -5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amine base) phenyl) piperazine

-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (22 mg, 7 %). MS (LCMS) m/z 864.64 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.1 (s, 1H), 10.15 (br s, 1H), 8.82 (s, 1H), 8.43 (br s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.58 (br s, 1H), 7.31 (br s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 5.72-5.60 (m, 1H), 5.05 (dd, J = 13.2, 6.8 Hz, 1H), 5.04 (s, 1H, OH) , 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 16.8 Hz, 1H), 4.82 - 4.70 (m, 1H), 4.61 - 4.52 (m, 1H), 4.07 (d, J = 13.2 Hz, 2H), 3.11 (br s, 4H), 3.04 - 2.92 (m, 3H), 2.92 - 2.73 (m, 2H), 2.70 - 2.50 (m, 6H), 2.27 - 2.15 (m, 3H), 2.08 - 1.97 (m, 2H), 1.96 - 1.79 (m, 4H), 1.75 - 1.68 (m, 1H), 1.23 - 1.12 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H). Example 38 3-(4-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl ) piperpe

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 38 )

-1-基)甲基)哌啶-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（130.1 mg，29%）。MS (LCMS) m/z852.74 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 8.0 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.58 (br s, 2H), 7.43 (dd, J= 8.0, 7.2 Hz, 1H), 7.29 (d, J= 7.2 Hz, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.93 (d, J= 9.2 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.11 (dd, J= 8.0, 5.2 Hz, 1H), 5.05 (s, 1H, OH), 4.99 (d, J= 9.6 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.62 - 4.50 (m, 1H), 4.43 (d, J= 17.2 Hz, 1H), 4.29 (d, J= 17.2 Hz, 1H), 3.47 - 3.35 (m, 2H), 3.11 (br s, 4H), 3.03 - 2.86 (m, 2H), 2.83 - 2.70 (m, 3H), 2.70 - 2.50 (m, 2H), 2.50 - 2.40 (m, 4H), 2.25 (d, J= 6.8 Hz, 2H), 2.28 - 2.16 (m, 1H), 2.05 - 1.95 (m, 2H), 1.95 - 1.81 (m, 3H), 1.80 - 1.65 (m, 2H), 1.35 - 1.20 (m, 2H), 0.87 (t, J= 7.6 Hz, 3H)。 實例39 3-(5-(4-((4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)甲基)哌啶-1-基)-1-側氧異吲哚啉-2-基)-1-甲基哌啶-2,6-二酮（ 化合物 39）

Example 38 was prepared following a similar procedure described in Example 26 , using Intermediate 40 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with DCM (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography using 0 to 10% MeOH/DCM as eluent to give an enriched product (310 mg), which was further purified by reverse phase HPLC (column/size : X-Select C18 (19*250 mm) 5 µ; mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; gradient (time/%B): 0.01/15, 1/15, 10/15, 14.5 /100, 14.6/100, 18/100, 18.1/15, 20.5/15. Solubility: ACN + water + THF; flow rate: 16 mL/min), to obtain compound 38 , 3-(4-(4-((4 -(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)- 3-oxo-2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (130.1 mg, 29%). MS (LCMS) m/z 852.74 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.98 (s, 1H, NH), 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J = 8.0 Hz, 1H ), 7.70 (d, J = 8.0 Hz, 1H), 7.58 (br s, 2H), 7.43 (dd, J = 8.0, 7.2 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.17 ( d, J = 8.0 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.11 (dd, J = 8.0, 5.2 Hz, 1H), 5.05 (s, 1H , OH), 4.99 (d, J = 9.6 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.62 - 4.50 (m, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.29 (d, J = 17.2 Hz, 1H), 3.47 - 3.35 (m, 2H), 3.11 (br s, 4H), 3.03 - 2.86 (m, 2H), 2.83 - 2.70 ( m, 3H), 2.70 - 2.50 (m, 2H), 2.50 - 2.40 (m, 4H), 2.25 (d, J = 6.8 Hz, 2H), 2.28 - 2.16 (m, 1H), 2.05 - 1.95 (m, 2H), 1.95 - 1.81 (m, 3H), 1.80 - 1.65 (m, 2H), 1.35 - 1.20 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H). Example 39 3-(5-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl ) piperpe

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindoline-2-yl)-1-methylpiperidine-2,6-dione ( compound 39 )

-1-基)甲基)哌啶-1-基)-1-側氧異吲哚啉-2-基)-1-甲基哌啶-2,6-二酮（0.109 g，23%）。MS (LCMS) m/z864.38 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.67 - 7.54 (m, 2H), 7.51 (d, J= 9.2 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J= 8.0 Hz, 1H), 6.92 (d, J= 8.8 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.11 (dd, J= 13.4, 5.0 Hz, 1H), 5.04 (s, 1H), 4.99 (d, J= 10.4 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.62 - 4.52 (m, 1H), 4.32 (d, J= 16.8 Hz, 1H), 4.19 (d, J= 16.8 Hz, 1H), 3.89 (d, J= 12.4 Hz, 2H), 3.11 (br s, 4H), 3.00 (s, 3H), 3.02 - 2.92 (m, 2H), 2.88 - 2.65 (m, 4H), 2.62 - 2.50 (m, 4H), 2.42 - 2.30 (m, 1H), 2.25 - 2.15 (m, 3H), 2.06 - 1.95 (m, 3H), 1.97 - 1.87 (m, 1H), 1.87 - 1.77 (m, 2H), 1.75 - 1.65 (m, 1H), 1.25 - 1.19 (m, 2H), 0.87 (t, J= 7.6 Hz, 3H)。 實例40 5-(3-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 40）

Example 39 was prepared following a similar procedure described in Example 26 , using Intermediate 41 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (50 mL) and extracted with DCM (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude was purified by flash chromatography using 0 to 10% MeOH/DCM as eluent to afford the enriched product (0.180 g). This was further purified by reverse phase HPLC to obtain compound 39 , 3-(5-(4-((4-(4-((2-allyl-1-(( R )-7-ethyl-7 -Hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (0.109 g, 23%) . MS (LCMS) m/z 864.38 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.15 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz , 1H), 7.67 - 7.54 (m, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.06 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 5.04 (s, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.86 ( d, J = 17.2 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.62 - 4.52 (m, 1H), 4.32 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H ), 3.89 (d, J = 12.4 Hz, 2H), 3.11 (br s, 4H), 3.00 (s, 3H), 3.02 - 2.92 (m, 2H), 2.88 - 2.65 (m, 4H), 2.62 - 2.50 (m, 4H), 2.42 - 2.30 (m, 1H), 2.25 - 2.15 (m, 3H), 2.06 - 1.95 (m, 3H), 1.97 - 1.87 (m, 1H), 1.87 - 1.77 (m, 2H) , 1.75 - 1.65 (m, 1H), 1.25 - 1.19 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H). Example 40 5-(3-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 40 )

-1-基)吖呾-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（121 mg，19%）。MS (LCMS) m/z822.59 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J= 7.2 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.58 (br s, 2H), 6.94 (d, J= 9.2 Hz, 2H), 6.82 (d, J= 1.6 Hz, 1H), 6.69 (dd, J= 8.4, 1.6 Hz, 1H), 5.74 - 5.62 (m, 1H), 5.06 (dd, J= 8.4, 5.2 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (d, J= 10.4 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.62 - 4.52 (m, 1H), 4.15 (t, J= 8.0 Hz, 2H), 3.97 – 3.88 (m 2H), 3.43 - 3.37 (m, 1H), 3.15 (br s, 4H), 3.05 - 2.73 (m, 3H), 2.70 - 2.49 (m, 6H), 2.26 - 2.16 (m, 1H), 2.08 - 1.97 (m, 2H), 1.96 - 1.84 (m, 1H), 1.76 -1.65 (m, 1H), 0.87 (t, J= 7.6 Hz, 3H)。 實例41 3-(4-(3-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)哌

-1-基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 41）

Example 40 was prepared following a similar procedure described in Example 26 , using Intermediate 43 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to afford the product (220 mg), which was further purified by reverse phase HPLC (column/size: X- SELECT-CSH C18 (19*250*5 µ); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/30, 15.3/ 30, 15.4/100, 17.5/100, 17.6/10, 20.5/10. Flow rate: 17 mL/min, solubility: ACN + THF + water), to obtain compound 40 , 5-(3-(4-(4-( (2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo -2,3-Dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (121 mg, 19%). MS (LCMS) m/z 822.59 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H) , 7.70 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.58 (br s, 2H), 6.94 (d, J = 9.2 Hz, 2H), 6.82 (d, J = 1.6 Hz, 1H), 6.69 (dd, J = 8.4, 1.6 Hz, 1H), 5.74 - 5.62 (m, 1H), 5.06 (dd, J = 8.4, 5.2 Hz, 1H), 5.04 (s, 1H, OH), 4.99 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.62 - 4.52 (m, 1H), 4.15 (t, J = 8.0 Hz, 2H), 3.97 – 3.88 (m 2H), 3.43 - 3.37 (m, 1H), 3.15 (br s, 4H), 3.05 - 2.73 (m, 3H), 2.70 - 2.49 (m, 6H), 2.26 - 2.16 (m, 1H), 2.08 - 1.97 (m, 2H), 1.96 - 1.84 (m, 1H), 1.76 -1.65 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H). Example 41 3-(4-(3-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)azan-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 41 )

-1-基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（141 mg，27%）。MS (LCMS) m/z810.4 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.33 (t, J= 7.6 Hz, 1H), 7.06 (d, J= 7.6 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 6.59 (d, J= 7.6 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.10 (dd, J= 8.0, 5.2 Hz, 1H), 5.02 (s, 1H), 5.00 (d, J= 10.4 Hz, 1H), 4.80 (d, J= 16.8 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.49 (d, J= 17.0 Hz, 1H), 4.32 (d, J= 17.0 Hz, 1H), 4.10 (dt, J= 6.8, 6.8 Hz, 2H), 3.87 (dt, J= 9.6, 6.8 Hz, 2H), 3.38 - 3.28 (m, 1H), 3.14 (br s, 4H), 3.00 -2.88 (m, 2H), 2.86 - 2.72 (m, 1H), 2.70 - 2.45 (m, 6H), 2.26 - 2.16 (m, 1H), 2.07 - 1.97 (m, 2H), 1.95 - 1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 0.87 (t, J= 7.6 Hz, 3H)。 實例42 3-(5-(3-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 42）

Example 41 was prepared following a similar procedure described in Example 26 , using Intermediate 44 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-Select C18 (19*250 mm) 5 µ; mobile phase A: 0.1% formic acid aqueous solution (aq); mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 1/10, 12/30, 18/30 , 18.1/100, 22/100, 22.1/10, 24/10; Solubility: ACN+water+THF; Flow rate: 18 mL/min, obtain Compound 41 , 3-(4-(3-(4-(4- ((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopent[b]pyridin-2-yl)-3-oxo Base-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (141 mg, 27%). MS (LCMS) m/z 810.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.81 (s , 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 7.6 Hz, 1H), 5.73 - 5.60 (m, 1H), 5.10 (dd, J = 8.0, 5.2 Hz, 1H), 5.02 (s, 1H), 5.00 (d, J = 10.4 Hz, 1H), 4.80 (d, J = 16.8 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.49 (d, J = 17.0 Hz, 1H), 4.32 (d, J = 17.0 Hz, 1H), 4.10 (dt, J = 6.8, 6.8 Hz, 2H), 3.87 (dt, J = 9.6, 6.8 Hz, 2H), 3.38 - 3.28 (m, 1H), 3.14 (br s, 4H), 3.00 -2.88 (m, 2H), 2.86 - 2.72 (m, 1H), 2.70 - 2.45 (m, 6H), 2.26 - 2.16 (m, 1H), 2.07 - 1.97 (m, 2H), 1.95 - 1.85 (m, 1H), 1.75 - 1.65 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H) . Example 42 3-(5-(3-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)azan-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 42 )

-1-基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（30 mg，9%）。MS (LCMS) m/z808.62 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.0 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J= 7.6 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.58 (br s, 2H), 7.51 (d, J= 8.0 Hz, 1H), 6.94 (d, J= 8.8 Hz, 2H), 6.55 (s, 1H), 6.51 (d, J= 8.4 Hz, 1H), 5.72 - 5.61 (m, 1H), 5.05 (s, 1H), 5.03 (dd, J= 8.0, 5.2 Hz, 1H), 4.99 (d, J= 10.4 Hz, 1H), 4.85 (d, J= 18.0 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.32 (d, J= 17.2 Hz, 1H), 4.19 (d, J= 17.2 Hz, 1H), 4.05 (t, J= 7.2 Hz, 2H), 3.81 - 3.73 (m, 2H), 3.40 - 3.28 (m, 1H), 3.14(br s, 4H), 3.03 - 2.85 (m, 2H), 2.83 - 2.72 (m, 1H), 2.60 - 2.49 (m, 5H), 2.42 - 2.30 (m, 1H), 2.27 - 2.16 (m, 1H), 2.06 - 1.86 (m, 3H), 1.76 - 1.65 (m, 1H), 0.87 (t, J= 7.2 Hz, 3H)。 實例43 5-(4-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)吖呾-3-基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 43）

Example 42 was prepared following a similar procedure described in Example 26 , using Intermediate 45 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-SELECT- CSH C18 (19*250*5 µ); mobile phase A: 0.1% formic acid aqueous solution (aq), mobile phase B: acetonitrile; gradient (time/%B): 0.01/15, 1/15, 10/40, 12 /40, 12.1/100, 15/100, 15.1/15, 17/15; flow rate: 18 mL/min; solubility: THF + ACN + water), to obtain compound 42 , 3-(5-(3-(4- (4-((2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3 -oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (30 mg, 9%). MS (LCMS) m/z 808.62 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.0 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H) , 7.69 (d, J = 8.4 Hz, 1H), 7.58 (br s, 2H), 7.51 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.55 (s, 1H ), 6.51 (d, J = 8.4 Hz, 1H), 5.72 - 5.61 (m, 1H), 5.05 (s, 1H), 5.03 (dd, J = 8.0, 5.2 Hz, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.85 (d, J = 18.0 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.19 ( d, J = 17.2 Hz, 1H), 4.05 (t, J = 7.2 Hz, 2H), 3.81 - 3.73 (m, 2H), 3.40 - 3.28 (m, 1H), 3.14(br s, 4H), 3.03 - 2.85 (m, 2H), 2.83 - 2.72 (m, 1H), 2.60 - 2.49 (m, 5H), 2.42 - 2.30 (m, 1H), 2.27 - 2.16 (m, 1H), 2.06 - 1.86 (m, 3H ), 1.76 - 1.65 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 43 5-(4-(1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azene- 3-yl)piperene

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 43 )

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（44 mg，15%）。MS (LCMS) m/z824.66 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 2H), 7.54 (br s, 2H), 7.37 (d, J= 1.2 Hz, 1H), 7.29 (dd, J= 8.4, 1.2 Hz, 1H), 6.45 (d, J= 8.4 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.06 (dd, J= 13.2, 5.6 Hz, 1H), 5.05 (s, 1H), 4.99 (d, J= 9.6 Hz, 1H), 4.85 (d, J= 16.8 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 3.94 (t, J= 7.6 Hz, 2H), 3.63 (t, J= 6.0 Hz, 2H), 3.46 (br s, 4H), 3.35 - 3.15 (m, 1H), 3.05 - 2.72 (m, 3H), 2.70 - 2.49 (m, 6H), 2.25 - 2.18 (m, 1H), 2.10 - 1.98 (m, 2H), 1.95 - 1.85 (m, 1H), 1.78 - 1.64 (m, 1H), 0.87 (t, J= 7.6 Hz, 3H)。 實例44 3-(4-(4-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)吖呾-3-基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 44）

Example 43 was prepared following a similar procedure described in Example 26 , using Intermediate 47 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-Select C18 (19*250 mm) 5 µ; mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; gradient (time/%B): 0.01/20, 1/20, 10/45, 12/45, 12.10/ 100, 14/100, 14.10/20, 16/20. Solubility: ACN + water + THF; flow rate: 18 mL/min), to obtain Compound 43 , 5-(4-(1-(4-((2-ene Propyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3 -Dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azepine-3-yl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (44 mg, 15%). MS (LCMS) m/z 824.66 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.07 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H) , 7.69 (d, J = 8.0 Hz, 2H), 7.54 (br s, 2H), 7.37 (d, J = 1.2 Hz, 1H), 7.29 (dd, J = 8.4, 1.2 Hz, 1H), 6.45 (d , J = 8.4 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.06 (dd, J = 13.2, 5.6 Hz, 1H), 5.05 (s, 1H), 4.99 (d, J = 9.6 Hz, 1H) , 4.85 (d, J = 16.8 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 3.94 (t, J = 7.6 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.46 (br s, 4H), 3.35 - 3.15 (m, 1H), 3.05 - 2.72 (m, 3H), 2.70 - 2.49 (m, 6H), 2.25 - 2.18 (m, 1H), 2.10 - 1.98 (m, 2H), 1.95 - 1.85 (m, 1H), 1.78 - 1.64 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H). Example 44 3-(4-(4-(1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H- Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Azir-3-yl)piperidine

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 44 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（85.5 mg，35%）。MS (LCMS) m/z808.58 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.01 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.80 (s, 1H), 7.90 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.54 (br s, 1H), 7.44 (t, J= 7.6 Hz, 1H), 7.31 (d, J= 7.6 Hz, 1H), 7.17 (d, J= 7.6 Hz, 1H), 6.45 (d, J= 8.4 Hz, 2H), 5.72 - 5.61 (m, 1H), 5.12 (dd, J= 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 4.99 (d, J= 9.2 Hz, 1H), 4.85 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.46 (d, J= 17.2 Hz, 1H), 4.31 (d, J= 17.2 Hz, 1H), 3.94 (t, J= 7.2 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 3.40 - 3.30 (m, 1H), 3.16 - 3.06 (m, 4H), 3.01 - 2.82 (m, 2H), 2.81 - 2.70 (m, 1H), 2.70 - 2.53 (m, 5H), 2.49 - 2.48 (m, 1H), 2.25 - 2.15 (m, 1H), 2.07 -1.95 (m, 2H), 1.95 - 1.84 (m, 1H), 1.76 - 1.66 (m, 1H), 0.87 (t, J= 7.2 Hz, 3H)。 實例45 3-(5-(4-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)吖呾-3-基)哌

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 45）

Example 44 was prepared following a similar procedure described in Example 26 , using Intermediate 48 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-SELECT- CSH C18 (19*250*5 µ); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/25, 18/25, 18.1/100, 21/100, 21.1/100, 24/10; flow rate: 17 mL/min; solubility: ACN + water + THF), to obtain compound 44 , 3-(4-(4-(1-(4- ((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopentyl[ b ]pyridin-2-yl)-3-oxo Base-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (85.5 mg, 35%). MS (LCMS) m/z 808.58 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.01 (s, 1H, NH), 10.1 (br s, 1H, NH), 8.80 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H) , 7.69 (d, J = 8.0 Hz, 1H), 7.54 (br s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.45 (d, J = 8.4 Hz, 2H), 5.72 - 5.61 (m, 1H), 5.12 (dd, J = 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH ), 4.99 (d, J = 9.2 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.46 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.94 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H), 3.40 - 3.30 (m, 1H) , 3.16 - 3.06 (m, 4H), 3.01 - 2.82 (m, 2H), 2.81 - 2.70 (m, 1H), 2.70 - 2.53 (m, 5H), 2.49 - 2.48 (m, 1H), 2.25 - 2.15 ( m, 1H), 2.07 -1.95 (m, 2H), 1.95 - 1.84 (m, 1H), 1.76 - 1.66 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 45 3-(5-(4-(1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H- Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Azir-3-yl)piperidine

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 45 )

-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（26.3 mg，7%）。MS (LCMS) m/z810.69 [M+H] ⁺。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H, NH), 10.06 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (d, J= 8.0 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.52 (d, J= 8.8 Hz, 2H), 7.09 (s, 1H), 7.08 (d, J= 8.0 Hz, 1H), 6.45 (d, J= 8.8 Hz, 2H), 5.72 - 5.61 (m, 1H), 5.05 (dd, J= 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 4.99 (d, J= 10.0 Hz, 1H), 4.85 (d, J= 17.6 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.33 (d, J= 16.8 Hz, 1H), 4.21 (d, J= 16.8 Hz, 1H), 3.94 (t, J= 6.8 Hz, 2H), 3.63 (t, J= 6.0 Hz, 2H), 3.45 - 3.31 (m, 5H), 3.02 - 2.85 (m, 2H), 2.83 - 2.72 (m, 1H), 2.70 - 2.51 (m, 5H), 2.40 - 2.30 (m, 1H), 2.25 - 2.15 (m, 1H), 2.07 - 1.95 (m, 2H), 1.94 - 1.84 (m, 1H), 1.75 - 1.66 (m, 1H), 0.87 (t, J= 7.2 Hz, 3H)。 實例46 5-(4-(6-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)-2,6-二氮雜螺[3.3]庚-2-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 46）

Example 45 was prepared following an analogous procedure described in Example 26 , using Intermediate 49 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-SELECT- CSH C18 (19*250*5 µ); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/25, 18/25, 18.1/100, 21/100, 21.1/100, 24/10; flow rate: 17 mL/min; solubility: ACN + water + THF), to obtain compound 45 , 3-(5-(4-(1-(4- ((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopentyl[ b ]pyridin-2-yl)-3-oxo Base-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)azan-3-yl)piper

-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (26.3 mg, 7%). MS (LCMS) m/z 810.69 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.95 (s, 1H, NH), 10.06 (br s, 1H, NH), 8.80 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H) , 7.69 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.09 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 8.8 Hz, 2H), 5.72 - 5.61 (m, 1H), 5.05 (dd, J = 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 4.99 (d, J = 10.0 Hz, 1H) , 4.85 (d, J = 17.6 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.33 (d, J = 16.8 Hz, 1H), 4.21 (d, J = 16.8 Hz, 1H), 3.94 (t, J = 6.8 Hz, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.45 - 3.31 (m, 5H), 3.02 - 2.85 (m, 2H), 2.83 - 2.72 (m, 1H), 2.70 - 2.51 (m, 5H), 2.40 - 2.30 (m, 1H), 2.25 - 2.15 (m, 1H), 2.07 - 1.95 (m, 2H), 1.94 - 1.84 (m, 1H) , 1.75 - 1.66 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 46 5-(4-(6-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2, 6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Diketone ( compound 46 )

Example 46 was prepared following a similar procedure described in Example 26 , using Intermediate 51 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: X-Select- C18 (19*250 mm)5 µ; mobile phase A: 0.1% formic acid aqueous solution (aq), mobile phase B: acetonitrile; gradient (time/%B): 0.01/15, 1/15, 10/30, 15/ ( _ 2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo- 2,3-Dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl) Piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (65 mg, 15%). MS (LCMS) m/z 864.61 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.05 (s, 1H, NH), 10.04 (br s, 1H, NH), 8.79 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H ), 7.66 (t, J = 8.0 Hz, 2H), 7.51 (br s, 2H), 7.31 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.8, 2.0 Hz, 1H), 6.42 ( d, J = 8.4 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.05 (dd, J = 12.8, 5.6 Hz, 1H), 5.04 (br s, 1H, OH), 4.99 (d, J = 10.0 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 3.90 - 3.80 (m, 6H), 3.33 - 3.25 (m, 4H), 3.20 -3.08 (m, 2H), 3.02 - 2.73 (m, 3H), 2.70 - 2.50 (m, 2H), 2.30 - 2.15 (m, 2H), 2.08 - 1.99 (m, 2H), 1.93 - 1.83 (m, 1H), 1.78 - 1.65 (m, 3H), 1.27 - 1.13 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). Example 47 3-(4-(4-(6-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H- Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) -2,6-diazaspiro[3.3]hept-2-yl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 47 )

-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 48）

Example 47 was prepared following a similar procedure described in Example 26 , using Intermediate 52 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase HPLC (column/size: Omega luna C18 ( 21.2*250 mm) 5 µ; mobile phase A: 0.1% formic acid aqueous solution (aq), mobile phase B: acetonitrile; gradient (time/%B): 0.01/20, 2/20, 10/35, 13.2/35, 13.3/100, 17.5/100, 17.6/20, 19.5/20. Flow rate: 17 mL/min; Solubility: THF+ACN+water), obtain Compound 47 , 3-(4-(4-(6-(4-( (2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo -2,3-Dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-2,6-diazaspiro[3.3]hept-2-yl )piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (43 mg, 17%). MS (LCMS) m/z 850.80 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.05 (s, 1H, NH), 10.04 (br s, 1H, NH), 8.80 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H ), 7.68 (d, J = 8.4 Hz, 1H), 7.51 (br s, 2H), 7.42 (t, J = 8.0 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.42 (d, J = 8.4 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.11 (dd, J = 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 4.99 (d, J = 9.6 Hz, 1H), 4.84 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.42 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 3.85 (br s, 4H), 3.35 - 3.25 (m, 6H), 3.05 - 2.85 (m, 2H), 2.85 - 2.72 (m , 3H), 2.70 - 2.50 (m, 2H), 2.26 - 2.15 (m, 2H), 2.08 - 1.95 (m, 2H), 1.93 - 1.83 (m, 1H), 1.80 - 1.65 (m, 3H), 1.40 - 1.25 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). Example 48 5-(4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ] pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 48 )

-1-基)哌啶-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（65 mg，18%）。MS (LCMS) m/z852.55 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (br d, J= 7.2 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.34 (d, J= 2.0 Hz, 1H), 7.26 (dd, J= 8.8, 2.0 Hz, 1H), 6.91 (d, J= 9.2 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.07 (dd, J= 12.8, 5.2 Hz, 1H), 5.06 (br s, 1H, OH), 4.99 (d, J= 10.0 Hz, 1H), 4.85 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.62 - 4.53 (m, 1H), 4.09 (d, J= 12.4 Hz, 2H), 3.09 (br s, 4H), 3.08 - 2.72 (m, 5H), 2.65 (br s, 4H), 2.70 - 2.50 (m, 3H), 2.25 - 2.16 (m, 1H), 2.08 - 1.99 (m, 2H), 1.97 -1.84 (m, 3H), 1.75 - 1.65 (m, 1H), 1.58 - 1.43 (m, 2H), 0.87 (t, J= 7.6 Hz, 3H)。 實例49 3-(4-(4-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4-d]嘧啶-6-基)胺基)苯基)哌

-1-基)哌啶-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 49）

Example 48 was prepared following a similar procedure described in Example 26 , using Intermediate 54 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase (column/size: X-SELECT 19*250 , 5 um); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 100% ACN, gradient (time/%B): 0/30, 2/30, 15/75, 15.1/98, 17/98, 17.1/30, 20/30; flow rate: 18 mL/min, solubility: THF+ACN+water), obtain compound 48 , 5-(4-(4-(4-((2-allyl-1-( ( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (65 mg, 18%). MS (LCMS) m/z 852.55 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s , 1H), 7.92 (br d, J = 7.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.34 (d, J = 2.0 Hz, 1H), 7.26 (dd, J = 8.8, 2.0 Hz, 1H), 6.91 (d, J = 9.2 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.07 (dd , J = 12.8, 5.2 Hz, 1H), 5.06 (br s, 1H, OH), 4.99 (d, J = 10.0 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m , 1H), 4.62 - 4.53 (m, 1H), 4.09 (d, J = 12.4 Hz, 2H), 3.09 (br s, 4H), 3.08 - 2.72 (m, 5H), 2.65 (br s, 4H), 2.70 - 2.50 (m, 3H), 2.25 - 2.16 (m, 1H), 2.08 - 1.99 (m, 2H), 1.97 -1.84 (m, 3H), 1.75 - 1.65 (m, 1H), 1.58 - 1.43 (m , 2H), 0.87 (t, J = 7.6 Hz, 3H). Example 49 3-(4-(4-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H- Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)piperidin-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 49 )

-1-基)哌啶-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（24.8 mg, 6%）。MS (LCMS) m/z838.61 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 6.8 Hz, 1H), 7.70 (d, J= 8.4 Hz, 1H), 7.58 (br s, 2H), 7.43 (t, J= 7.6 Hz, 1H), 7.31 (d, J= 7.6 Hz, 1H), 7.18 (d, J= 8.0 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.12 (dd, J= 12.8, 5.2 Hz, 1H), 5.06 (br s, 1H, OH), 5.00 (d, J= 10.4 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.55 (m, 1H), 4.45 (d, J= 17.2 Hz, 1H), 4.31 (d, J= 17.2 Hz, 1H), 3.50 - 3.40 (m, 2H), 3.11 (br s, 4H), 3.03 -2.85 (m, 3H), 2.85 - 2.72 (m, 3H), 2.68 (br s, 4H), 2.65 - 2.40 (m, 2H), 2.25 - 2.15 (m, 1H), 2.08 - 1.98 (m, 2H), 1.98 - 1.84 (m, 3H), 1.75-1.55 (m, 3H), 0.87 (t, J= 7.6 Hz, 3H)。 實例50 3-(4-(6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 50）

Example 49 was prepared following a similar procedure described in Example 26 , using Intermediate 55 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude product was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase (column/size: X-SELECT 19*250 , 5 um); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 100% ACN, gradient (time/%B): 0/30, 2/30, 15/75, 15.1/98, 17/98, 17.1/30, 20/30; flow rate: 18 mL/min, solubility: THF+ACN+water), obtain compound 49 , 3-(4-(4-(4-(4-((2-allyl- 1-(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro -1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24.8 mg, 6%). MS (LCMS) m/z 838.61 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s , 1H), 7.93 (br d, J = 6.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.58 (br s, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.72 - 5.60 (m, 1H), 5.12 (dd, J = 12.8, 5.2 Hz, 1H), 5.06 (br s, 1H, OH), 5.00 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H) , 4.60 - 4.55 (m, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.50 - 3.40 (m, 2H), 3.11 (br s, 4H) , 3.03 -2.85 (m, 3H), 2.85 - 2.72 (m, 3H), 2.68 (br s, 4H), 2.65 - 2.40 (m, 2H), 2.25 - 2.15 (m, 1H), 2.08 - 1.98 (m , 2H), 1.98 - 1.84 (m, 3H), 1.75-1.55 (m, 3H), 0.87 (t, J = 7.6 Hz, 3H). Example 50 3-(4-(6-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 50 )

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（49 mg，8%）。MS (LCMS) m/z848.66 [M-H] ^-。 ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (d, J= 7.6 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.57 (br s, 2H), 7.31 (t, J= 7.6 Hz, 1H), 7.05 (d, J= 7.2 Hz, 1H), 6.92 (d, J= 9.2 Hz, 2H), 6.54 (d, J= 8.0 Hz, 1H), 5.72 - 5.60 (m, 1H), 5.10 (dd, J= 12.8, 4.8 Hz, 1H), 5.05 (s, 1H, OH), 5.00 (d, J= 10.4 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.43 (d, J= 17.2 Hz, 1H), 4.28 (d, J= 17.2 Hz, 1H), 4.08 - 4.00 (m, 2H), 3.95 - 3.86 (m, 2H), 3.10 (br s, 4H), 3.03 - 2.85 (m, 2H), 2.84 - 2.73 (m, 1H), 2.70 - 2.44 (m, 3H), 2.41 (br s, 4H), 2.43 - 2.30 (m, 2H), 2.25 - 2.15 (m, 1H), 2.08 - 1.95 (m, 4H), 1.96 - 1.85 (m, 1H), 1.75 - 1.68 (m, 1H), 0.87 (t, J= 7.2 Hz, 3H)。 實例51 3-(5-(6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 51）

Example 50 was prepared following a similar procedure described in Example 26 , using Intermediate 57 in place of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give the crude product which was further purified by reverse phase (column/size: XSELECT C18 9*250 ); mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile, gradient (time/%B): 0.01/10, 2/10, 10/30, 14/30, 14.1/100, 16/100, 16.1 /10, 18.5/10. Flow rate: 17 mL/min, solubility: ACN+THF+water), obtain compound 50 , 3-(4-(6-(4-(4-((2-allyl-1-(( R )-7 -Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[ 3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (49 mg, 8%) . MS (LCMS) m/z 848.66 [MH] ^- . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H ), 7.69 (d, J = 8.0 Hz, 1H), 7.57 (br s, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.54 (d, J = 8.0 Hz, 1H), 5.72 - 5.60 (m, 1H), 5.10 (dd, J = 12.8, 4.8 Hz, 1H), 5.05 (s, 1H, OH ), 5.00 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 4.08 - 4.00 (m, 2H), 3.95 - 3.86 (m, 2H), 3.10 (br s, 4H), 3.03 - 2.85 (m, 2H), 2.84 - 2.73 (m, 1H), 2.70 - 2.44 (m, 3H), 2.41 (br s, 4H), 2.43 - 2.30 (m, 2H), 2.25 - 2.15 (m, 1H), 2.08 - 1.95 (m, 4H), 1.96 - 1.85 (m, 1H), 1.75 - 1.68 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 51 3-(5-(6-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 51 )

-1-基)-2-氮雜螺[3.3]庚-2-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（24 mg, 5%）。MS (LCMS) m/z850.61 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H,NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J= 7.2 Hz, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.57 (br s, 2H), 7.48 (d, J= 8.4 Hz, 1H), 6.92 (d, J= 9.2 Hz, 2H), 6.50 (s, 1H), 6.46 (d, J= 8.4 Hz, 1H), 5.72 - 5.60 (m, 1H), 5.03 (dd, J= 13.2, 4.8 Hz, 1H), 5.03 (br s, 1H, OH), 5.00 (d, J= 9.2 Hz, 1H), 4.86 (d, J= 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.30 (d, J= 17.6 Hz, 1H), 4.17 (d, J= 17.2 Hz, 1H), 3.96 (br s, 2H), 3.84 (br s, 2H), 3.09 (br s, 4H), 3.05 - 2.65 (m, 5H), 2.64 - 2.50 (m, 1H), 2.41 (br s, 4H), 2.42 - 2.30 (m, 2H), 2.25 - 2.15 (m, 1H), 2.14 - 1.84 (m, 5H), 1.76 - 1.65 (m, 1H), 0.87 (t, J= 7.2 Hz, 3H)。 實例52 3-(4-(6-(1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)-2,6-二氮雜螺[3.3]庚-2-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 52）

Example 51 was prepared following a similar procedure as described in Example 26 , using Intermediate 58 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase (column/size: X-Select C18 ( 19*250 mm) 5 µ; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/30, 15/30, 15.1/100 , 17/100, 17.1/10, 20/10; solubility: ACN+water+THF; flow rate: 18 mL/min), to obtain compound 51 , 3-(5-(6-(4-(4-((2 -Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopent[ b ]pyridin-2-yl)-3-oxo-2 ,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)-2-azaspiro[3.3]hept-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (24 mg, 5%) . MS (LCMS) m/z 850.61 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 11.00 (s, 1H,NH), 10.10 (br s, 1H, NH), 8.82 ( s, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.57 (br s, 2H), 7.48 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.50 (s, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.72 - 5.60 (m, 1H), 5.03 (dd, J = 13.2, 4.8 Hz, 1H), 5.03 (br s, 1H, OH), 5.00 (d, J = 9.2 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 ( m, 1H), 4.30 (d, J = 17.6 Hz, 1H), 4.17 (d, J = 17.2 Hz, 1H), 3.96 (br s, 2H), 3.84 (br s, 2H), 3.09 (br s, 4H), 3.05 - 2.65 (m, 5H), 2.64 - 2.50 (m, 1H), 2.41 (br s, 4H), 2.42 - 2.30 (m, 2H), 2.25 - 2.15 (m, 1H), 2.14 - 1.84 (m, 5H), 1.76 - 1.65 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H). Example 52 3-(4-(6-(1-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro-5 H - Cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl) Piperidin-4-yl)-2,6-diazaspiro[3.3]hept-2-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione ( compound 52 )

-1-基)甲基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（ 化合物 53）

Example 52 was prepared following a similar procedure described in Example 26 , using Intermediate 60 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase (column/size: X-Select C18 ( 19*250 mm) 5 µ; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/30, 15/30, 15.1/100 , 17/100, 17.1/10, 20/10; solubility: ACN+water+THF; flow rate: 18 mL/min), to obtain compound 52 , 3-(4-(6-(1-(4-((2 -Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopent[ b ]pyridin-2-yl)-3-oxo-2 ,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)-2,6-diazaspiro[3.3] Hept-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (47 mg, 8%). MS (LCMS) m/z 850.04 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.98 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (d, J = 7.2 Hz, 1H ), 7.69 (d, J = 8.0 Hz, 1H), 7.56 (br s, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 8.0 Hz, 1H), 5.72 - 5.60 (m, 1H), 5.09 (dd, J = 13.2, 5.0 Hz, 1H), 5.05 (br s, 1H, OH), 5.00 (d, J = 10.0 Hz, 1H), 4.86 (d, J = 17.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.50 (m, 1H), 4.42 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 4.12 - 4.02 (m, 4H), 3.55 - 3.40 (m, 2H), 3.33 - 3.20 (m, 3H), 3.02 - 2.85 ( m, 2H), 2.85 - 2.67 (m, 3H), 2.65 - 2.50 (m, 1H), 2.50 - 2.42 (m, 2H), 2.25 - 2.15 (m, 1H), 2.15 - 2.05 (m, 1H), 2.05 - 1.93 (m, 2H), 1.92 - 1.80 (m, 1H), 1.75 - 1.65 (m, 3H), 1.33 - 1.21 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). Example 53 3-(4-(3-((4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl ) piperpe

-1-yl)methyl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( compound 53 )

-1-基)甲基)吖呾-1-基)-1-側氧異吲哚啉-2-基)哌啶-2,6-二酮（39 mg，12%）。MS (LCMS) m/z824.50 [M+H] ⁺; ¹H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s, 1H), 7.93 (br d, J= 7.6 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.31 (t, J= 7.6 Hz, 1H), 7.05 (d, J= 6.8 Hz, 1H), 6.92 (d, J= 9.2 Hz, 2H), 6.56 (d, J= 7.6 Hz, 1H), 5.72 - 5.65 (m, 1H), 5.10 (dd, J= 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 5.00 (dd, J= 10.4, 1.2 Hz, 1H), 4.86 (dd, J= 17.2, 1.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.55 (m, 1H), 4.45 (d, J= 17.2 Hz, 1H), 4.30 (d, J= 16.8 Hz, 1H), 4.17 - 4.07 (m, 2H), 3.72 - 3.63 (m, 2H), 3.10 (br s, 4H), 3.02 - 2.85 (m, 3H), 2.85 - 2.70 (m, 1H), 2.66 (d, J= 11.6 Hz, 2H), 2.70 - 2.55 (m, 1H), 2.55 (br s, 4H), 2.50 - 2.40 (m, 1H), 2.25 - 2.15 (m, 1H), 2.03 - 1.85 (m, 3H), 1.77 - 1.68 (m, 1H), 0.87 (t, J= 7.6 Hz, 3H)。 實例54 4-((6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)己基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 54）

Example 53 was prepared following a similar procedure as described in Example 26 , using Intermediate 62 instead of Intermediate 26 to react Intermediate 7 . The reaction mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with 10% MeOH/DCM (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude. The crude was purified by flash chromatography on silica gel using 0 to 10% methanol/DCM as eluent to give a crude product which was further purified by reverse phase (column/size: X-Select C18 ( 19*250 mm) 5 µ; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; gradient (time/%B): 0.01/10, 2/10, 10/30, 15/30, 15.1/100 , 17/100, 17.1/10, 20/10; Solubility: ACN+water+THF; Flow rate: 18 mL/min), to obtain Compound 53 , 3-(4-(3-((4-(4-(( 2-allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo- 2,3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)methyl)azan-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (39 mg, 12%). MS (LCMS) m/z 824.50 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 11.00 (s, 1H, NH), 10.10 (br s, 1H, NH), 8.82 (s , 1H), 7.93 (br d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 - 7.52 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), 6.92 (d, J = 9.2 Hz, 2H), 6.56 (d, J = 7.6 Hz, 1H), 5.72 - 5.65 (m, 1H), 5.10 (dd, J = 13.2, 5.2 Hz, 1H), 5.05 (br s, 1H, OH), 5.00 (dd, J = 10.4, 1.2 Hz, 1H), 4.86 (dd, J = 17.2, 1.2 Hz, 1H), 4.80 - 4.70 (m, 1H), 4.60 - 4.55 (m, 1H), 4.45 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 4.17 - 4.07 (m, 2H), 3.72 - 3.63 (m, 2H), 3.10 (br s, 4H), 3.02 - 2.85 (m, 3H), 2.85 - 2.70 (m, 1H), 2.66 (d, J = 11.6 Hz, 2H), 2.70 - 2.55 (m , 1H), 2.55 (br s, 4H), 2.50 - 2.40 (m, 1H), 2.25 - 2.15 (m, 1H), 2.03 - 1.85 (m, 3H), 1.77 - 1.68 (m, 1H), 0.87 ( t, J = 7.6 Hz, 3H). Example 54 4-((6-(4-(4-((2-allyl-1-(( R )-7-ethyl-7-hydroxyl-6,7-dihydro- 5H -cyclopenta [ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 54 )

-1-基)異吲哚啉-2-基)哌啶-2,6-二酮反應而製備。將反應在100℃攪拌12小時。LCMS顯示反應完成並偵測到所欲產物。將反應用水（10 mL）稀釋並用EA（3 × 10 mL）萃取。將有機層經Na ₂SO ₄乾燥，並過濾。將濾液濃縮得到殘餘物，將該殘餘物藉由製備型HPLC（NH ₄HCO ₃條件）純化，得到8%產率之 化合物 54，4-((6-(4-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌

-1-基)己基)胺基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮。 ¹H NMR (400 MHz, DMSO- d ₆ ) δ = 11.00 (br s, 1H, NH), 10.08 (br s, 1H, NH), 8.84 (s, 1H), 7.95 (br d, J= 8.0 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.4 Hz, 1H), 7.63 - 7.47 (m, 2H), 7.14 (s, 1H), 7.13 (d, J= 7.6 Hz, 1H), 6.57 (br d, J= 8.6 Hz, 2H), 5.78 - 5.66 (m, 1H), 5.11 (dd, J= 13.2, 5.6 Hz, 1H), 5.10 (s, 1H, OH), 5.05 (d, J= 10.0 Hz, 1H), 4.92 (d, J= 17.5 Hz, 1H), 4.90 - 4.74 (m,1H), 4.70 - 4.54 (m, 1H), 4.39 (d, J= 16.8 Hz, 1H), 4.27 (d, J= 16.8 Hz, 1H), 3.50 (br t, J = 8.1 Hz, 1H), 3.36 (br s, 4H), 3.29 (br d, J = 8.1 Hz, 1H), 3.06 - 2.90 (m, 3H), 2.88 - 2.77 (m, 1H), 2.66 (br d, J = 2.5 Hz, 1H), 2.60 (br s, 4H), 2.52 - 2.44 (m, 3H), 2.36 - 2.17 (m, 3H), 2.11 - 1.86 (m, 4H), 1.82 - 1.65 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H)；LCMS (ESI): m/z = 852.3 (M+H) ⁺，RT：2.019 min。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃於水中；B: CH ₃CN 管柱：沃特世Xbridge BEH C18 100*30 mm*10um 流速：25 mL/分鐘 監測器波長：220&254 nm 時間B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 實例55 5-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮（ 化合物 55）

Example 54 follows a similar procedure described in Example 1 , using Intermediate 63 (35.2 mg, 0.078 mmol) in place of Intermediate 2 and 3-(1-oxo-5-(piper

-1-yl) isoindoline-2-yl) piperidine-2,6-dione reaction and preparation. The reaction was stirred at 100°C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was diluted with water (10 mL) and extracted with EA (3 x 10 mL). The organic layer was dried _{over Na2SO4} , and filtered. The filtrate was concentrated to give a residue, which was purified by preparative HPLC (NH ₄ HCO ₃ condition) to afford compound 54 , 4-((6-(4-(4-((2- Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2, 3-dihydro-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piper

-1-yl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 11.00 (br s, 1H, NH), 10.08 (br s, 1H, NH), 8.84 (s, 1H), 7.95 (br d, J = 8.0 Hz , 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.63 - 7.47 (m, 2H), 7.14 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.57 (br d, J = 8.6 Hz, 2H), 5.78 - 5.66 (m, 1H), 5.11 (dd, J = 13.2, 5.6 Hz, 1H), 5.10 (s, 1H, OH) , 5.05 (d, J = 10.0 Hz, 1H), 4.92 (d, J = 17.5 Hz, 1H), 4.90 - 4.74 (m,1H), 4.70 - 4.54 (m, 1H), 4.39 (d, J = 16.8 Hz, 1H), 4.27 (d, J = 16.8 Hz, 1H), 3.50 (br t, J = 8.1 Hz, 1H), 3.36 (br s, 4H), 3.29 (br d, J = 8.1 Hz, 1H) , 3.06 - 2.90 (m, 3H), 2.88 - 2.77 (m, 1H), 2.66 (br d, J = 2.5 Hz, 1H), 2.60 (br s, 4H), 2.52 - 2.44 (m, 3H), 2.36 - 2.17 (m, 3H), 2.11 - 1.86 (m, 4H), 1.82 - 1.65 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H); LCMS (ESI): m/z = 852.3 (M +H) ⁺ , RT: 2.019 min. Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Waters Xbridge BEH C18 100*30 mm*10um Flow rate: 25 mL/min Monitor Wavelength: 220&254 nm Time B% 0.0 30 8.0 60 8.1 60 8.2 100 10.2 100 10.3 30 11.5 30 Example 55 5-(4-((1-(4-((2-allyl-1 -(( R )-7-Ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2,3-dihydro- 1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( compound 55 )

-1-基)異吲哚啉-1,3-二酮反應而製備。將反應在100℃攪拌12小時。LCMS顯示反應完成並偵測到所欲產物。將反應用水（5 mL）稀釋並用EA（3 ×5 mL）萃取，將有機層經Na ₂SO ₄乾燥，並過濾。將濾液濃縮得到粗產物，將該粗產物藉由製備型HPLC（NH ₄HCO ₃條件)純化，得到15%產率之 化合物 55，5-(4-((1-(4-((2-烯丙基-1-(( R)-7-乙基-7-羥基-6,7-二氫-5 H-環戊[ b]吡啶-2-基)-3-側氧基-2,3-二氫-1 H-吡唑并[3,4- d]嘧啶-6-基)胺基)苯基)哌啶-4-基)甲基)哌

-1-基)-2-(2,6-二側氧基哌啶-3-基)異吲哚啉-1,3-二酮。 ¹H NMR (400 MHz, DMSO- d6) δ = 11.08 (br s, 1H, NH), 10.01 (br s, 1H, NH), 8.78 (s, 1H), 7.89 (br d, J= 8.0 Hz, 1H), 7.70 (d, J= 4.6 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.52 (br s, 2H), 7.35 (br d, J= 1.7 Hz, 1H), 7.27 (dd, J= 8.6, 1.7 Hz, 1H), 6.51 (br d, J= 8.7 Hz, 2H), 5.74 - 5.60 (m, 1H), 5.11 -5.06 (m, 1H), 5.08 (dd, J= 12.8, 5.2 Hz, 1H), 5.05 (s, 1H, OH), 5.00 (d, J= 10.4 Hz, 1H), 4.86 (br d, J= 17.6 Hz, 1H), 4.84 - 4.70 (m, 1H), 4.63 - 4.50 (m, 1H), 3.45 (br s, 4H), 3.30 - 3.17 (m, 2H), 3.01 - 2.83 (m, 4H), 2.81 - 2.74 (m, 1H), 2.61 (br d, J= 2.7 Hz, 1H), 2.57 (br s, 5H), 2.43 (br t, J = 7.0 Hz, 2H), 2.35 - 2.27 (m, 1H), 2.24 - 2.10 (m, 2H), 2.07 - 1.98 (m, 2H), 1.97 - 1.83 (m, 1H), 1.77 - 1.57 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H)；LCMS (ESI): m/z = 866.3 (M+H) ⁺，RT：2.109 min。 製備型HPLC 方法：儀器：Gilson 281半製備型HPLC系统 動相：A：10 mM NH ₄HCO ₃於水中；B: CH ₃CN 管柱：Phenomenex C18 75*30 mm*3um 流速：25 mL/分鐘 監測器波長：220&254 nm 時間B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 實例AMOLT-4、及A-427細胞增生檢定 Example 55 followed a similar procedure described in Example 1 , using Intermediate 63 (35.2 mg, 0.078 mmol) in place of Intermediate 2 and 2-(2,6-dioxopiperidin-3-yl)-5- (Piperin

-1-yl) isoindoline-1,3-dione reaction and preparation. The reaction was stirred at 100°C for 12 hours. LCMS showed the reaction was complete and the desired product was detected. The reaction was diluted with water (5 mL) and extracted with EA (3 x 5 mL), the organic layer was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated to obtain a crude product, which was purified by preparative HPLC (NH ₄ HCO ₃ conditions) to obtain 15% yield of compound 55 , 5-(4-((1-(4-((2- Allyl-1-(( R )-7-ethyl-7-hydroxy-6,7-dihydro- 5H -cyclopenta[ b ]pyridin-2-yl)-3-oxo-2, 3-Dihydro- 1H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-4-yl)methyl)piper

-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione. ¹ H NMR (400 MHz, DMSO- d6 ) δ = 11.08 (br s, 1H, NH), 10.01 (br s, 1H, NH), 8.78 (s, 1H), 7.89 (br d, J = 8.0 Hz, 1H), 7.70 (d, J = 4.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (br s, 2H), 7.35 (br d, J = 1.7 Hz, 1H), 7.27 ( dd, J = 8.6, 1.7 Hz, 1H), 6.51 (br d, J = 8.7 Hz, 2H), 5.74 - 5.60 (m, 1H), 5.11 -5.06 (m, 1H), 5.08 (dd, J = 12.8 , 5.2 Hz, 1H), 5.05 (s, 1H, OH), 5.00 (d, J = 10.4 Hz, 1H), 4.86 (br d, J = 17.6 Hz, 1H), 4.84 - 4.70 (m, 1H), 4.63 - 4.50 (m, 1H), 3.45 (br s, 4H), 3.30 - 3.17 (m, 2H), 3.01 - 2.83 (m, 4H), 2.81 - 2.74 (m, 1H), 2.61 (br d, J = 2.7 Hz, 1H), 2.57 (br s, 5H), 2.43 (br t, J = 7.0 Hz, 2H), 2.35 - 2.27 (m, 1H), 2.24 - 2.10 (m, 2H), 2.07 - 1.98 ( m, 2H), 1.97 - 1.83 (m, 1H), 1.77 - 1.57 (m, 4H), 0.87 (t, J = 7.3 Hz, 3H); LCMS (ESI): m/z = 866.3 (M+H) ⁺ , RT: 2.109 min. Preparative HPLC method: Instrument: Gilson 281 semi-preparative HPLC system Mobile phase: A: 10 mM NH ₄ HCO ₃ in water; B: CH ₃ CN Column: Phenomenex C18 75*30 mm*3um Flow rate: 25 mL/min Monitor wavelength: 220&254 nm Time B% 0.0 35 8.0 65 8.1 65 8.2 100 10.2 100 10.3 35 11.5 35 Example A MOLT-4, and A-427 cell proliferation assay

Cell proliferation was measured using the CellTiter-Glo® Luminescent Cell Viability Assay. The assay involves the direct addition of a single reagent (CellTiter-Glo® Reagent) to cells cultured in serum-supplemented medium. MOLT-4 cells (ATCC, CRL-1582) and A427 cells (ATCC, HTB-53) were cultured according to ATCC recommendations, and seeded at 6,000 cells (for MOLT-4) and 3,000 cells (for A427) per well.

Each compound evaluated was prepared as a DMSO stock solution (10 mM). Compounds were tested in duplicate on each plate and a 10-point serial dilution curve (1 :3 dilution) was used. The highest compound concentration was 10 µM (final) with a final DMSO concentration of 0.1%. Discs were then incubated at 37°C, 5% CO ₂ for 72 hours, followed by equilibration at room temperature for approximately 30 minutes. An equal volume of CellTiter-Glo® Reagent (100 µL) was added to each well. The plates were mixed on an orbital shaker for 2 minutes to induce cell lysis, then incubated at rt for 10 minutes to stabilize the luminescent signal. Luminescence was recorded using a Spectramax i3x (Molecular Devices) plate reader according to the CellTiter-Glo protocol. IC50 determination was performed using nonlinear regression, variable slope (four parameters), inhibitor v. response equation (Prism 9.0). _IC50 values are provided in Table 1. For comparison, Table 1 also includes the _IC50 value of compound ZN-c3. Table 1 Instance# MOLT-4 (nM) A427 (nM) 1 A B 2 A ND 6 A A 7 A A 8 B C 9 C C 10 ND B 11 ND ND 12 A C 13 A C 14 ND ND 15 ND C 16 ND C 17 ND A 18 ND ND 19 ND B 20 ND ND twenty one ND ND twenty two ND C twenty three ND ND twenty four A A 25 C C 26 C C 27 A B 28 ND B 29 ND ND 30 ND C 31 C C 32 ND ND 33 ND C 34 C C 35 A A 36 ND ND 37 ND B 38 A A 39 C C 46 ND A 47 ND A 51 A A 52 ND B 53 ND B ZN-c3 B B For MOLT-4 and A427 CTG IC ₅₀ : A = single IC ₅₀ ≤ 100 nM; B = single IC ₅₀ > 100 nM and < 200 nM; C = single IC ₅₀ ≥ 200 nM. Example B Protein Degradation Assay in MOLT-4 Cells

1.5 million MOLT-4 cells (ATCC, CRL-1582) were incubated with vehicle (DMSO) or indicated compounds at concentrations of 10 µM, 1 µM, 0.1 µM, or 0.01 µM for 5 hours. After treatment, cells were harvested in RIPA lysis buffer supplemented with 1% phosphatase inhibitor and protease inhibitor cocktail and protein concentration was determined by BCA assay. Equal amounts of protein (3.5 µg/lane) from each cell extract were loaded onto 12-230KDa Separation 25 capillary cartridges from ProteinSimple and prepared on a ProteinSimple Jess system with WEE1 (1:200 diluted, the final concentration is 1 µg/ml) and β-actin (1:100 dilution, the final concentration is 5 µg/ml) antibody detection. Use the area under the curve (AUC) from the resulting electropherograms for each protein peak at the concentration tested to use the equation % degradation = 100 - [100*(WEE1/β-actin)/(WEE1 _DMSO /β-actin _DMSO )] , to calculate the degradation percentage of WEE1. For illustrative purposes, electropherograms were exported as virtual ink dots using Compass (ProteinSimple) for SW v 6.0. WEE-1 antibody (sc-5285) was purchased from Santa Cruz Biotechnology, and β-actin (MAB8929) was purchased from R&D Systems. Table 2 provides the percentage of WEE1 remaining after 5 hours of treatment in MOLT-4 cells at the concentrations tested. A "hook effect" was observed at higher concentrations, however, these results indicate that many of the exemplified compounds are potent degraders of WEE1. Table 2 The remaining percentage of WEE1 in MOLT-4 cells after 5 hours Instance# 0.01 µM 0.1 µM 1 µM 10 µM 1 20 17 49 46 2 40 28 51 59 3 59 27 19 73 4 88 32 30 114 5 79 twenty one 41 65 6 8 5 14 58 7 7 8 twenty three 30 8 28 14 32 36 9 40 twenty three 48 119 10 16 11 33 81 11 18 5 20 35 12 73 twenty two 15 19 13 39 15 12 14 14 ND ND ND ND 15 ND ND ND ND 16 57 15 11 11 17 twenty two 10 13 38 18 ND ND ND ND 19 46 17 twenty one 33 20 ND ND ND ND twenty one ND ND ND ND twenty two ND ND ND ND twenty three ND ND ND ND twenty four 26 19 31 53 25 107 113 116 101 26 ND ND ND ND 27 31 15 twenty one 35 28 16 9 15 18 29 ND ND ND ND 30 111 108 109 103 31 108 105 104 112 32 ND ND ND ND 33 ND ND ND ND 34 ND ND ND ND 35 25 15 25 91 36 ND ND ND ND 37 16 11 12 17 38 18 11 twenty two 60 39 92 90 90 103 46 16 9 10 25 47 17 9 17 65 51 15 14 28 47 52 27 18 26 74 53 33 12 13 82 54 twenty two 9 twenty four 47 55 37 15 19 36

Figure 3 indicates that (A) Examples 1 and 2 induce WEE1 degradation in MOLT-4 cells in a dose-dependent manner; (B) and (C) Examples 6 to 8 and Examples 54 to 55 induce degradation in MOLT in a dose-dependent manner Induction of WEE1 degradation in -4 cells. Example C HiBiT assay for IKZF1 and GSPT1 degradation assessment

5x10 ⁵ JURKAT-IKZF1-HiBiT (Promega CS3023169) or 5x10 ⁵ HEK-293-GSPT1-HiBiT (Promega CS3023105) were inoculated into wells of a white flat-bottom opaque 96-well plate in a volume of 90 µl, and incubated at 37°C and 5% Incubate for 1 hour (IKFZ1) or overnight (GSPT1) under CO2. RPMI-1640 + 10% FBS + 1% Pen/Strep + 200 µg/mL hygromycin (IKZF1) or DMEM + 10% FBS + 1% hygromycin + 200 µg/mL hygromycin (GSPT1) constitute the complete medium . One hour prior to compound treatment, 90 µL of 100x Vivazine substrate (Promega N2581 ) diluted 1:50 in culture medium was added to each well. Starting with a high dose of 10 µM using Pico8, cells were treated with compounds in a 10.5 log serial dilution format, with 0.1% DMSO normalization including all doses. 0.1% DMSO was included as a control. The total volume of each well is 180ul. Cells were incubated at 37°C and 5% CO2 for 16 hours (IKZF1) or 24 hours (GSPT1). After each incubation period, plates were read using a SpectraMax M5e multimode microplate reader following the Cell-Titer Glo luminescence protocol. Data were corrected for background signal and remaining IKZF1 or GSPT1 protein expressed as % relative to DMSO. DC50 and Dmax were determined using GraphPad Prizm software (v9.1).

Table 3 summarizes the DC50 and Dmax of IKZF1 (16 hours) and GSPT1 (24 hours) protein degradation. table 3 Instance# GSPT1 protein degradation (24 h) IKZF1 protein degradation (16h) DC50 (nM) Dmax DC50 (nM) Dmax 1 ND ND 107 19 2 ND ND ND ND 3 >10000 0 >10000 0 6 161 15 >10000 18 7 27 25 >10000 34 8 122 20 >10000 0 9 1905 25 >10000 55 10 421 40 1349 50 11 330 34 11 46 12 229 35 1863 34 13 407 41 >10000 29 16 520 35 75 58 17 45 31 ND ND 19 119 14 347 34 twenty four 49 31 >10000 0 25 1291 47 >10000 49 27 595 53 82 89 28 55 18 169 39 30 >10000 30 1628 51 31 >10000 0 >10000 0 35 76 55 3311 93 37 161 12 227 29 38 40 37 >10000 0 39 291 26 >10000 0 46 46 41 2086 64 47 156 31 68 twenty two 51 37 47 3645 59 52 379 35 >10000 0 53 135 27 160 70 54 36 41 >10000 twenty one 55 116 26 >10000 twenty two

Figure 4 indicates that (4A) Example 6, Example 7, Example 54 and Example 55 induce negligible IKZF1 (16 hours) protein degradation, (4B) Examples 6, Example 7, Example 54 and Example 55 induce no GSPT1 (6 hours) protein degradation.

Furthermore, while the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will appreciate that various modifications can be made without departing from the spirit of the disclosure. Therefore, it should be clearly understood that the forms disclosed herein are for illustration only, and are not intended to limit the scope of the disclosure, but also cover all modifications and alternatives accompanying the true scope and spirit of the disclosure.

[Fig. 1] shows a general synthetic scheme for the preparation of compounds of formula (I). [Fig. 2] shows the general synthetic scheme for the example of the preparation of the compound of formula (I). [Fig. 3 (A)] is a blot diagram showing the activity of the compound of formula (I) in degrading WEE1 in MOLT-4 cells in a dose-related manner. [Fig. 3(B)] is a blot diagram showing the activity of the compound of formula (I) in degrading WEE1 in MOLT-4 cells in a dose-related manner. [Fig. 3(C)] is a graph showing the activity of the compound of formula (I) in degrading WEE1 in MOLT-4 cells in a dose-related manner. [Fig. 4(A)] is a graph showing the activity of the compound of formula (I) in inducing the degradation of IKZF1 protein. [Fig. 4(B)] is a graph showing the activity of the compound of formula (I) in inducing the degradation of GSPT1 protein.

Claims (63)

A compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound has the following structure:

(I) wherein: R ¹ is selected from the group consisting of hydrogen, halogen, and substituted or unsubstituted C ₁ -C ₆ alkyl; ring A is selected from the group consisting of substituted Or unsubstituted phenyl, and substituted or unsubstituted 5 to 6 membered monocyclic heteroaryl; Ring B is selected from the group consisting of: substituted or unsubstituted monocyclic 5 to 7 membered carbocycle and substituted or unsubstituted 5 to 7 membered monocyclic heterocyclic groups; R ² is

; Y is CH or N; m is 0, 1, 2, or 3; R ³ is selected from the group consisting of halogen and substituted or unsubstituted C ₁ -C ₆ alkyl; R ⁴ is not Exists in or is selected from the group consisting of:

, –NH–, –N(unsubstituted C _1-6 alkyl)–, –N(unsubstituted C ₃ - ₆ cycloalkyl)–, –NH(CH ₂ ) _1-6 –, –N( Unsubstituted C _1-6 alkyl) (CH ₂ ) _1-6 – and –N (unsubstituted C ₃ - ₆ cycloalkyl) (CH ₂ ) _1-6 –; wherein: X ¹ and X ² are independently selected from the group consisting of carbon or nitrogen; X ³ is absent, -CH ₂ -, -NH-, -N (unsubstituted C _1-6 alkyl) -, -N (unsubstituted C _{3 -6} cycloalkyl)–, –C(=O)-NH–, –C(=O)N-(unsubstituted C _1-6 alkyl)– or –C(=O)-N (unsubstituted Substituted C ₃ - ₆ cycloalkyl) -; and Het is substituted or unsubstituted 4 to 10 membered heterocyclic group; R ⁵ is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, - (C=O)–, –(C=S)–, –(C=O)-NH–, –(C=O)-(C ₁ -C ₆ alkyl)-O–, –(C=O )-N(C ₁ -C ₆ alkyl)–, –(C=O)-N(C _{3 -C} 6cycloalkyl)–, –(C=O)-O–, –(C=S) -NH–, substituted or unsubstituted (C ₁ -C ₆ alkylene) -O– or substituted or unsubstituted (C ₁ -C ₆ alkylene) -NH–, provided that when X ³ is –C(=O)-NH–, –C(=O)N-(unsubstituted C _1-6 alkyl) _– or –C(=O)-N (unsubstituted C _3-6 cycloalkyl )-, R ⁵ is absent; R ⁶ is absent, substituted or unsubstituted C ₁ -C ₆ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-( C ₆ -C ₁₂ aryl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)–(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)-(C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, or -C ₁ -C ₆ alkylene-O-; R ⁷ is -(CH ₂ CH ₂ -O) _n -, wherein n is 0, 1, 2, 3, 4 or 5; R ⁸ is absent, Substituted or unsubstituted C ₁ -C ₁₀ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene)-O-, substituted or unsubstituted -(C ₁ -C ₆ alkylene Alkyl)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-O-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ - C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene), substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH–, substituted or unsubstituted Substituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH- (C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)- NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –( C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-( C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH -(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene) -NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene) -(C=O)NH-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C _6alkylene )–NH–, substituted or unsubstituted –(C ₁ -C _6alkylene )-(C=O)NH-(C ₁ -C _6alkylene )–O–, substituted Or unsubstituted - (C ₁ -C ₆ alkylene) -NH (C = O) - (C ₁ -C ₆ alkylene) - (C = O) NH -, substituted or unsubstituted - ( C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-(C=O)NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH -(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–; substituted or unsubstituted –(C ₁ -C ₆ alkylene)-C ≡C–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₆ -C ₁₂ aryl)–, substituted or unsubstituted – (C ₁ -C ₆ alkylene) -(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted– (C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, –(C ₆ -C ₁₂ aryl)–, –(C ₃ -C ₁₀ cycloalkyl)–, –(5 to 10 membered heteroaryl), or -(C ₄ -C ₁₀ heterocyclyl) -; provided that at least one of R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ is present; R ⁹ is selected from Freedom to form a group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,and

. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is an unsubstituted C ₁ -C ₆ alkyl group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a substituted C ₁ -C ₆ alkyl group. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of substituted or unsubstituted pyrrole, substituted or unsubstituted furan , substituted or unsubstituted thiophene, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted

azole, substituted or unsubstituted thiazole, substituted or unsubstituted pyridine, substituted or unsubstituted pyridine

, substituted or unsubstituted pyrimidines, and substituted or unsubstituted pyrimidines

. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,and

; wherein each of the aforementioned groups is substituted or unsubstituted. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein ring A is unsubstituted. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted monocyclic 5- to 7-membered carbocyclyl. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted monocyclic 5-membered carbocyclyl. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

,

,and

; wherein each of the aforementioned groups is substituted or unsubstituted. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein ring B is substituted by 1, 2, or 3 substituents, and these substituents are independently selected from the following groups: Groups: halogen, hydroxyl, amino, unsubstituted N-linked amido, unsubstituted C ₁ -C ₆ haloalkyl, and substituted or unsubstituted C ₁ -C ₆ alkyl. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein

substituted or unsubstituted

. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein Y is CH. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein m is 0. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein ^R is

. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein ^X is carbon. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein X ² is nitrogen. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein X ¹ is nitrogen. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein X ² is nitrogen. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein X ² is carbon. The compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, wherein X ³ does not exist. The compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, wherein X ³ is -CH ₂ -, -NH-, -N(unsubstituted C _1-6 alkyl)-, or -N(unsubstituted C ₃ - ₆ cycloalkyl)-. The compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, wherein X ³ is -C(=O)-NH-, -C(=O)N-(unsubstituted C _{1 -6} alkyl)–, or –C(=O)—N(unsubstituted C ₃ - ₆ cycloalkyl)–. The compound according to any one of claims 17 to 22, or a pharmaceutically acceptable salt thereof, wherein Het is a substituted or unsubstituted monocyclic 4-8 membered heterocyclic group. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 4- to 8-membered heterocyclic group is selected from the group consisting of substituted or unsubstituted pyrrolidine, substituted or unsubstituted Substituted piperazine

, substituted or unsubstituted piperidine, and substituted or unsubstituted 1,4-diazepane. Such as the compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein the monocyclic 4- to 8-membered heterocyclic group is selected from the group consisting of: unsubstituted pyrrolidine, unsubstituted piperidine

, unsubstituted piperidine, and unsubstituted 1,4-diazepane. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein ^R is absent, -NH-, -N(unsubstituted C _1-6 alkyl)-, or - N(unsubstituted C _{3 -6} cycloalkyl)–. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -NH(CH ₂ ) _1-6 -, -N(unsubstituted C _1-6 alkyl) (CH ₂ ) _1-6 -, or -N(unsubstituted C ₃ - ₆ cycloalkyl)(CH ₂ ) _1-6 -. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is absent. The compound according to any one of claims 1 to 23 or 26 to 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is a substituted or unsubstituted C ₁ -C ₆ alkylene group. The compound of any one of claims 1 to 23 or 26 to 30, or a pharmaceutically acceptable salt thereof, wherein ^R is -(C=O)-, -(C=S)-, -(C= O)-NH–, –(C=O)-(C ₁ -C ₆ alkyl)-O–, –(C=O)-N(C ₁ -C ₆ alkyl)–, –(C=O )-N(C ₃ -C ₆ cycloalkyl)–, –(C=O)-O–, or –(C=S)-NH–. The compound according to claim 33, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is -(C=O)-. The compound according to any one of claims 1 to 23 or 26 to 30, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is substituted or unsubstituted –(C ₁ -C ₆ alkylene)-O– , or substituted or unsubstituted -(C ₁ -C ₆ alkylene)-NH-. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is absent. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a substituted or unsubstituted C ₁ -C ₆ alkylene group. The compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is an unsubstituted C ₁ -C ₆ alkylene group. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-(C ₆ -C ₁₂ aryl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)–(C ₃ -C ₁₀ cycloalkyl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene Base)-(C ₃ -C ₁₀ heterocyclyl)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, or –C ₁ -C ₆ alkylene-O–. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein n is 0. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, 4, or 5. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein n is 1. The compound according to claim 41, or a pharmaceutically acceptable salt thereof, wherein n is 2. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein ^R is substituted or unsubstituted C ₁ -C ₁₀ alkylene, substituted or unsubstituted -(C ₁ -C ₆ alkylene) -O–, substituted or unsubstituted -(C ₁ -C ₆ alkylene) -NH–, substituted or unsubstituted -(C ₁ -C ₆ alkylene) -O-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)–, or substituted Or unsubstituted -(C ₁ -C ₆ alkylene)-(C=O)NH-. The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is a substituted or unsubstituted C ₁ -C ₁₀ alkylene group. The compound according to claim 45, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is an unsubstituted C ₁ -C ₁₀ alkylene group. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-O-. The compound according to claim 47, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is unsubstituted -(C ₁ -C ₆ alkylene)-O-. The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-NH-. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is unsubstituted -(C ₁ -C ₆ alkylene)-NH-. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-NH-(C ₁ - C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene) -NH(C=O)-(C ₁ -C ₆ alkylene)-O–, or substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)–. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-NH-(C ₁ - C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-O–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH- (C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C =O)NH-(C ₁ -C ₆ alkylene)–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene group) –NH–, substituted or unsubstituted –(C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)–O–, substituted or unsubstituted Substituted – (C ₁ -C ₆ alkylene)-NH(C=O)-(C ₁ -C ₆ alkylene)-(C=O)NH-, substituted or unsubstituted – (C ₁ - C ₆ alkylene)-NH-(C ₁ -C ₆ alkylene)-(C=O)NH-, or substituted or unsubstituted –(C ₁ -C ₆ alkylene)-NH-( C ₁ -C ₆ alkylene)-(C=O)NH-(C ₁ -C ₆ alkylene)-. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is substituted or unsubstituted -(C ₁ -C ₆ alkylene)-C≡C-, Substituted or unsubstituted – (C ₁ -C ₆ alkylene) - (C ₆ -C ₁₂ aryl) –, substituted or unsubstituted – (C ₁ -C ₆ alkylene) - (C ₃ - C ₁₀ cycloalkyl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)–(C ₄ -C ₁₀ heterocyclyl)–, substituted or unsubstituted–(C ₁ -C ₆ alkylene)-(5 to 10 membered heteroaryl)–, –(C ₆ -C ₁₂ aryl)–, –(C ₃ -C ₁₀ cycloalkyl)–, –(5 to 10 membered heteroaryl group), or -(C ₄ -C ₁₀ heterocyclyl)-. The compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein ^R9 is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,and

. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein ^R9 is selected from the group consisting of:

,

,

,

,

,

,

,

,and

. The compound of claim 54, or a pharmaceutically acceptable salt thereof, wherein ^R9 is selected from the group consisting of:

,and

. The compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein ^R9 is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,and

. Such as the compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein ^R9 is

. The compound of claim 1, wherein the compound is selected from the group consisting of:

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

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,

,

,

,

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,

,

,

,

,and

, or a pharmaceutically acceptable salt of any one of the foregoing. A pharmaceutical composition comprising an effective amount of the compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination. Use of an effective amount of a compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 60 in the manufacture of a medicament for improving or treating cancer, wherein The cancer is selected from the group consisting of brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder/cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer Cancer, choriocarcinoma, uterine body cancer, cervical cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms' cancer, skin Carcinoma, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, multiple Myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. An effective amount of the compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 60 in the manufacture of a medicament for inhibiting malignant growth or tumor replication Use, wherein the malignant growth or the tumor is caused by a cancer selected from the group consisting of brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder/cholangiocarcinoma , liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body cancer, cervix cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms Carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, Multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. An effective amount of the compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 60 in the manufacture of a drug for improving or treating malignant growth or tumor Use, wherein the malignant growth or the tumor is caused by a cancer selected from the group consisting of brain cancer, craniocervical cancer, esophageal cancer, thyroid cancer, small cell cancer, non-small cell cancer, breast cancer, lung cancer, gastric cancer, gallbladder/cholangiocarcinoma , liver cancer, pancreatic cancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma, uterine body cancer, cervix cancer, renal pelvis/ureter cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, fetal cancer, Wilms Carcinoma, skin cancer, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's tumor, soft tissue sarcoma, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, polycythemia vera, malignant lymphoma, Multiple myeloma, Hodgkin's lymphoma, and non-Hodgkin's lymphoma.

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