KR102637915B1 - New bifunctional heterocyclic compounds for degrading BTK via ubiquitin proteosome pathway and uses thereof - Google Patents

Abstract

The present invention relates to a novel heterocyclic compound and a composition containing the same for preventing or treating cancer, autoimmune diseases, and inflammatory diseases. The novel heterocyclic compound of the present invention relates to Bruton's tyrosine through the ubiquitin proteosome pathway. It is a bifunctional compound that has a kinase (Bruton's tyrosine kinase; BTK) decomposition effect and can be usefully used as a composition for preventing or treating cancer, autoimmune diseases, and Parkinson's disease.

Description

Novel bifunctional heterocyclic compounds for degrading BTK via ubiquitin proteosome pathway and uses thereof}

The present invention relates to a novel bifunctional compound that has the activity of degrading Bruton's tyrosine kinase (BTK) through the ubiquitin proteasome pathway.

Cancer refers to a life-threatening neoplasm that proliferates in the human body indiscriminately and destroys organs. It is also called a malignant tumor. It has the characteristics of uncontrolled proliferation and invasion, and it leaves the first organ where it occurs and metastasizes to various parts of the body through lymph nodes and blood vessels, especially the liver, lungs, bones, and brain, ultimately threatening life.

Despite the advancement of modern medicine, the cause or origin of cancer has not been fully revealed, but the causes currently thought to be carcinogenic chemicals (approximately 1,500 types), radiation, continuous stimulation and damage, and heredity factors. And it is recognized that it is caused by a virus. It is recognized that approximately 80-90% of cancer occurrence is directly or indirectly related to environmental factors, and more than 90% of exogenous carcinogens are various compounds existing in the natural environment. In addition, cancer is complex because there are many types, different stages for each type, and different treatment methods and principles. The main methods of treating cancer are surgery, radiation therapy, and chemotherapy using chemotherapy agents that inhibit cell proliferation.

Among these, chemotherapy drugs are not targeted treatments that act directly on the target of each cancer, so if chemotherapy treatment is repeated, side effects due to cytotoxicity and drug resistance occur, and the initial damage caused by the anticancer drugs used during chemotherapy can occur. Despite a successful response, if the cancer treatment period is prolonged or the cancer recurs, the treatment will ultimately fail due to side effects due to cytotoxicity and drug resistance. Therefore, in order to overcome the limitations of these chemotherapy agents, the development of targeted therapeutic agents with a clear anticancer action mechanism is continuously needed. Accordingly, much research is being conducted on specific molecular biological factors involved in tumor formation to develop targeted treatments. In particular, molecular biological factors are used in various ways to predict cancer prognosis or determine whether to receive chemotherapy or radiation treatment. It is becoming.

Bruton's tyrosine kinase (BTK) is a member of the Tec family of tyrosine kinases, which affects the development of early B-cells and the activation of mature B-cells, and is a regulatory factor that regulates signal transduction and survival. BTK is activated through B-cell signaling through the B-cell receptor (BCR), and plays a critical role in signaling and development of B cells by regulating various major signaling pathways within cells and inducing signaling essential for cell survival. Do it.

However, when BTK is overexpressed in B cells due to abnormal signaling by BCR, excessive phosphorylation of downstream molecules of the BCR signaling system occurs step by step, causing abnormal B cell proliferation and formation of pathological autoantibodies. Accordingly, it can induce autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, cancer, B-cell malignancies, and inflammatory diseases.

Additionally, BTK is known to be overexpressed in B-lineage malignant lymphoid tumors such as B-cell precursor-acute lymphocytic leukemia, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. When BTK is inhibited in the proliferation of abnormal B cells, signal transduction by the BCR is blocked and B cell-mediated diseases can be blocked, so the use of BTK inhibitors may be a useful approach for treating B-cell mediated diseases. In the past, BTK inhibitors have attracted attention as therapeutic drugs for these diseases because effective effects have been proven through BTK inhibition in experimental animal models for autoimmune diseases or B-cell malignancies.

The PROTAC (Proteolysis-targeting chimaera) technology of the present invention is a small molecule-based new drug development platform technology that consists of an E3 ligase binding module, a connector, and a target protein binding module, and induces in vivo degradation through ubiquitination of disease-causing target proteins. As a result, it can decompose more than 80% of disease-causing proteins that are difficult to target with existing drug development techniques and overcome the resistance problem of existing drugs.

Therefore, proteins related to incurable diseases such as dementia and cancer, which were inaccessible through existing new drug development methods, can be used as drug targets, which is expected to accelerate the development of treatments for diseases that do not currently exist.

Meanwhile, as a prior literature, Korean Patent Publication No. 10-2016-0062103 and Korean Patent No. 2128018 disclose Bruton's tyrosine kinase (BTK) inhibitors, but ubiquitination of disease-causing target proteins This is different from the present invention, which removes by inducing in vivo decomposition through.

In addition, International Patent Publication No. WO 2020-081450 discloses a compound that has a BTK decomposition effect through the ubiquitin proteasome pathway, but its structure and activity are different from the compound of the present invention.

Against this background, the inventors of the present invention discovered that disease-causing target proteins can be selectively and excellently degraded using a new compound such as Formula 1 of the present invention, and this was used to prevent cancer, autoimmune diseases, Parkinson's disease, etc. The present invention was completed by confirming the possibility of developing a pharmaceutical composition for treatment or improvement.

Korean Patent Publication No. 10-2016-0062103, Inhibitor of Bruton's Tyrosine Kinase, published on June 1, 2016. Korean Patent No. 2128018, Pyrazolo pyrimidine derivatives, manufacturing method thereof, and pharmaceutical compositions for preventing or treating cancer, autoimmune diseases, and brain diseases containing the same as active ingredients, registered on June 23, 2020. International Publication Patent No. WO 2020-081450, Bifunctional compounds for degrading BTK via ubiquitin proteosome pathyway, published on April 23, 2020.

Lee Sang-ho, Park Se-jin, Ha Jae-du, and Hwang Jong-yeon, Next-generation drug development platform: targeted protein degradation technology, KEIT PD Issue Report, 18(3), 18-40, 2018.

The purpose of the present invention is to provide a novel bifunctional compound having a BTC decomposition effect through the ubiquitin proteasome pathway and a composition containing the same for preventing or treating cancer, autoimmune diseases, and Parkinson's disease, and more specifically, To provide novel bifunctional compounds that have a BTC decomposition effect through the ubiquitin proteasome pathway, which has an excellent selective decomposition effect on disease-causing target proteins, and compositions containing the same for preventing or treating cancer, autoimmune diseases, and Parkinson's disease. there is.

The present invention relates to a bifunctional drug having the following formula (1) consisting of a targeting ligand-linker (L)-binder (B), or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof. It's about compounds.

[Formula 1]

In the above formula,

W is -NH-, -N(C ₁ -C ₆ alkyl)-, -O-, or -NHC(O)-;

R ₁ is substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, or substituted or unsubstituted heteroaryl,

More specifically, R ₁ is substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, or substituted or unsubstituted 4- to 12-membered heteroaryl,

The substituted phenyl, indanyl, or heteroaryl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, halogen, halo C ₁ - substituted with C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, or substituted or unsubstituted -NHC(O)phenyl;

In the substituted -NHC(O)phenyl, one or more hydrogens in phenyl are independently substituted with C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or halogen;

or R ₁ -W is pyrrolidinyl or piperidinyl;

R ₂ is -H, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, substituted or unsubstituted three-membered group. to 12-membered carbocyclyl, or substituted or unsubstituted heterocyclyl,

More specifically, R ₂ is -H, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, substituted or unsubstituted. It is a substituted 3- to 12-membered carbocyclyl, or a substituted or unsubstituted 3- to 12-membered heterocyclyl,

The substituted carbocyclyl or heterocyclyl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylamine, halogen, -CN, -OH, or -NH ₂ ;

A is substituted or unsubstituted 3- to 12-membered carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted 6- to 12-membered aryl, or substituted or unsubstituted heteroaryl,

More specifically, A is substituted or unsubstituted 3- to 12-membered carbocyclyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, substituted or unsubstituted 6- to 12-membered aryl, or It is a substituted or unsubstituted 4- to 12-membered heteroaryl,

The substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ is substituted with -C ₆ alkoxy, C ₁ -C ₆ alkylamine, halogen, -CN, -OH, or -NH ₂ ;

In addition, L is of the following formula 2,

[Formula 2]

In the above formula,

D is each independently a direct bond, -C(O)-, -O-, -NH-, -CH(OH)-, -C(O)NH-, -NHC(O)-, -NHC(O) CH ₂ O-, -NHC(O)CH ₂ NH-, -C(O)CH ₂ NH-, -C(=S)-, or -C(CN)=CH-;

E is each independently a direct bond, substituted or unsubstituted 3- to 12-membered carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted 6- to 12-membered aryl, or substituted or unsubstituted It is a heteroaryl,

More specifically, E is each independently directly bonded, substituted or unsubstituted 3- to 12-membered carbocyclyl, substituted or unsubstituted 3- to 12-membered heterocyclyl, or substituted or unsubstituted 3- to 12-membered heterocyclyl. It is a 12-membered aryl, or a substituted or unsubstituted 4- to 12-membered heteroaryl,

The substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo substituted with C ₁ -C ₆ alkoxy, -CN, -OH, or -NH ₂ ;

m is each independently an integer selected from 0 to 12;

In addition, B is selected from the following formulas 3 to 7,

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

In the above formula,

Z is -C(R ^A ) ₂ -, -C(O)-, -C(R ^A ) ₂ -C(R ^A ) ₂ -, -C(R ^A )=C(R ^A )-, -C (R ^A )=N-, -N=C(R ^A )-, or -N=N-;

Y is a direct bond, -C(R ^A ) ₂ -, -N(R ^A )-, -C(O)NH-, -SO ₂ NH-, or -O-;

X is each independently C, CH or N;

R ^A is each independently -H, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or halo C ₁ -C ₆ alkoxy;

R is each independently -H, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, -CN, -OH, or -NH ₂ and; and

q is an integer selected from 0 to 3;

In addition, the present invention in Formula 1,

W, R ₁ , R ₂ and A are Izac, which is the formula 1, or its enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, characterized in that defined as follows. soluble compounds;

In the above formula,

W is -NH-;

R ₁ is substituted or unsubstituted phenyl or substituted or unsubstituted indanyl,

As for the substituted phenyl or indanyl, one or more hydrogens in the ring are independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ - C ₆ alkoxy, or substituted or unsubstituted -NHC(O)phenyl,

In the substituted -NHC(O)phenyl, one or more hydrogens in the phenyl are independently substituted with halo C ₁ -C ₆ alkyl;

R ₂ is H or C ₁ -C ₆ alkyl;

A is the formula 8 or 9 below,

[Formula 8]

[Formula 9]

In the above formula,

X is each independently CH or N;

R ^A is each independently -H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylamine; and

p is an integer each independently selected from 0 to 2.

In addition, the present invention in Formula 1,

L is a bifunctional compound of Formula 1, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof, which is defined as follows with respect to Formula 2;

In the above formula,

D is each independently a direct bond, -C(O)-, -O-, -NH-, -CH(OH)-, -C(O)NH-, -NHC(O)-, -NHC(O) CH ₂ O-, -NHC(O)CH ₂ NH-, -C(O)CH ₂ NH-, -C(=S)-, or -C(CN)=CH-;

m is each independently an integer selected from 0 to 12;

E is each independently a direct bond, phenyl, cyclopropyl, cyclohexyl, triazolyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, 1,2,3,6-tetrahydropyridinyl, selected from Formula 10 or 11 below,

In the substituted piperazinyl or piperidinyl or azetidinyl, one or more hydrogens in the ring may be independently substituted with a substituent selected from the group consisting of hydroxy, halogen, or C ₁ -C ₆ alkyl,

[Formula 10]

[Formula 11]

In the above formula,

p is each independently an integer selected from 0 to 2; and

r is an integer each independently selected from 1 to 2.

In addition, the present invention in Formula 1,

B is Formula 1, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug, or pharmaceutically acceptable substance thereof, wherein B is selected from the following Formula 3, Formula 4, Formula 6, or Formula 7: Bifunctional compounds that are possible salts;

[Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

In the above formula,

X is each independently C, CH or N;

Y is a direct bond, -C(R ^A ) ₂ -, -N(R ^A )-, -C(O)NH-, or -SO ₂ NH-;

Z is -C(R ^A ) ₂ -, -C(O)-, or -N=N-;

R ^A is each independently -H or halo C ₁ -C ₆ alkoxy;

Each R is independently -H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; and

q is an integer selected from 0 to 3;

In addition, the present invention relates to a bifunctional compound having the following formula (1), or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof;

[Formula 1]

In the above formula,

W is -NH-;

R ₁ is substituted or unsubstituted phenyl or substituted or unsubstituted indanyl,

As for the substituted phenyl or indanyl, one or more hydrogens in the ring are independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ - C ₆ alkoxy, or substituted or unsubstituted -NHC(O)phenyl,

In the substituted -NHC(O)phenyl, one or more hydrogens in the phenyl are independently substituted with halo C ₁ -C ₆ alkyl;

R ₂ is H or C ₁ -C ₆ alkyl;

A is the formula 8 or 9 below,

[Formula 8]

[Formula 9]

In the above formula,

X is each independently -CH= or -N=;

R ^A is each independently -H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ alkylamine;

p is each independently an integer selected from 0 to 2;

L is the formula 2 below,

[Formula 2]

In the above formula,

D is each independently a direct bond, -C(O)-, -O-, -NH-, -CH(OH)-, -C(O)NH-, -NHC(O)-, -NHC(O) CH ₂ O-, -NHC(O)CH ₂ NH-, -C(O)CH ₂ NH-, -C(=S)-, or -C(CN)=CH-;

m is each independently an integer selected from 0 to 12;

E is each independently a direct bond, phenyl, cyclopropyl, cyclohexyl, triazolyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, 1,2,3,6-tetrahydropyridinyl, selected from Formula 10 or 11 below,

In the substituted piperazinyl or piperidinyl or azetidinyl, one or more hydrogens in the ring may be independently substituted with a substituent selected from the group consisting of hydroxy, halogen, or C ₁ -C ₆ alkyl,

[Formula 10]

[Formula 11]

In the above formula,

p is each independently an integer selected from 0 to 2;

r is each independently an integer selected from 1 to 2;

B is selected from Formula 3, Formula 4, Formula 6, or Formula 7,

[Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

In the above formula,

X is each independently C, CH or N;

Y is a direct bond, -C(R ^A ) ₂ -, -N(R ^A )-, -C(O)NH-, or -SO ₂ NH-;

Z is -C(R ^A ) ₂ -, -C(O)-, or -N=N-;

R ^A is each independently -H or halo C ₁ -C ₆ alkoxy;

Each R is independently -H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; and

q is an integer selected from 0 to 3;

The manufacturing method and reaction conditions for “BTK targeting ligand-L (linker)-B (E3 ligase binder)” having various structures of Formula 1, which is the final compound of the present invention, are as follows.

To prepare the compound of Formula 1 of the present invention, “BTK targeting ligand” was prepared using the pyrazolo pyrimidine production method known in Korean Patent No. 2128018 invented by the present inventor.

<BTK targeting ligand>

The targeting ligand-linker (L)-binder (B) compound of the present invention was prepared as shown in Schemes 1 to 4 below.

[Scheme 1]

BTK inhibitor S1 is reacted with an electrophile whose primary or secondary amine is protected to synthesize S1-1, and the protecting group is removed to obtain primary or secondary amine S1-2. Protac P1-1 is synthesized by amide reaction between S1-2 and a CRBN binder containing a carboxylic acid-linker. Protac P1-2 is synthesized by reacting S1-2 with a CRBN binder having an electrophile-linker. Protac P1-3 is synthesized by reacting S1-2 with a fluorine-containing CRBN binder and S _N Ar (nucleophilic aromatic substitution).

[Scheme 2]

Protac P2-1 is synthesized by amide reaction of the BTK inhibitor S1 with a CRBN binder having a carboxylic acid-linker. Protac P2-2 is synthesized by reductive alkylation of S1 with a CRBN binder having an aldehyde-linker. Protac P2-3 is synthesized through reductive alkylation by reacting S1 with a CRBN binder containing a cyclic ketone. Protac P2-4 is synthesized by reacting S1 with a CRBN binder containing an isocyanate-linker.

[Scheme 3]

S3-1 is synthesized by reacting the BTK inhibitor S1 with a linker having carboxylic acid. Protac P3-1 is synthesized by amide reaction of S3-1 with a CRBN binder having a primary or secondary amine-linker. Protac P3-2 is synthesized by amide reaction of S3-1 with a CRBN binder containing a primary amine. S3-2 is synthesized by reacting with a linker containing a halogen in S1. Protac P3-3 is synthesized by reacting S3-2 with a CRBN binder having a primary amine-linker.

[Scheme 4]

In Scheme 4, starting material 1 (Korean Patent No. 10-2128018) is reacted with amine 2 protected with an appropriate protecting group (P) in the presence of an acid, a reaction in the presence of a base, or a metal catalyst reaction to obtain intermediate 3 , which Intermediate 4 can be obtained by deprotection. Intermediate 4 is subjected to a reductive amination or N-alkylation reaction with Intermediate 5 (WO2018/140809, WO2019/149922), in which a heterocyclyl is linked to a CRBN ligand and an aldehyde or leaving group (LG) is introduced, to efficiently produce final compound 6 . It can be synthesized.

Meanwhile, intermediate 4 is subjected to a reductive amination or N-alkylation reaction with compound 7 , which has an aldehyde or leaving group (LG) in the heterocyclyl protected with an appropriate protecting group (P), to obtain intermediate 8 , and then deprotected to obtain intermediate 8. After obtaining 9 , the final compound 6 can be synthesized by reacting at high temperature with compound 10 (WO2017/197051, WO2018/140809) in which halogen (Hal) is substituted in the CRBN ligand.

In addition, in the present invention, the compound represented by Formula 1 is a compound selected from the group of compounds below, or its enantiomer, diastereomer, or stereoisomer, hydrate, solvate, prodrug, or pharmaceutical agent thereof. This relates to allowable salts.

4-((6-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 1),

5-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 2),

4-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 3),

N-(2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 4),

N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 5),

N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )Ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-4-(7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl)amino)-1- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutane Amide (Compound 6),

4-((12-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (compound 7),

5-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 8),

N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (Compound 9),

N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (Compound 10),

tert- Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12, 15-Tetraoxa-3-azaheptadecane-17-oate (Compound 11),

N-(2-(2-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl )-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide (Compound 12),

4-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d])pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (compound 13),

tert- Butyl 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy ) Acetate (Compound 14),

5-((15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 15),

N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (Compound 16),

N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (Compound 17),

N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-(4-(2-(2,6-dioxopy) Peridin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 18),

N-(2-(2-(2-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy )Ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (Compound 19),

N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 20),

N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-5-yl)piperidine-4-carboxamide (Compound 21),

N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide (Compound 22),

2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)acetamide (Compound 23),

N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-4-yl)piperidine-4-carboxamide (Compound 24),

N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)acetamide (Compound 25),

5-(4-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 26),

N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-5-yl)azetidine-3-carboxamide (Compound 27),

5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl) Isoindoline-1,3-dione (Compound 28),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dione (Compound 29),

5-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 30),

5-(4-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 31),

5-(4-(2-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 32),

5-(4-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 33),

5-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperi Din-3-yl)isoindoline-1,3-dione (Compound 34),

5-((2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 35),

5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 36),

3-(6-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 37),

1-(5-(4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H )-dione (compound 38),

5-(4-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 39),

5-(4-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 40),

5-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Benzyl) amino) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 41),

5-(4-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)benzyl)amino)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 42),

5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione (Compound 43),

5-(4-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidin-1-yl) -2-oxoethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 44),

5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 45),

3-(6-((4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)-4-oxobenzo[d][1,2,3]triazine -3(4H)-yl)piperidine-2,6-dione (Compound 46),

5-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (compound 47),

3-(6-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][1, 2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 48),

5-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione (Compound 49),

5-(3-((4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperi Din-3-yl)isoindoline-1,3-dione (Compound 50),

5-((2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 51),

3-(6-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 52),

3-(7-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H )-yl)piperidine-2,6-dione (Compound 53),

5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 54),

3-(6-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][1,2 ,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 55),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 56),

3-(6-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d])pyrimidine- 6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 57),

3-(6-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H) -1) Piperidine-2,6-dione (Compound 58),

3-(5-(4-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H )-yl)piperidine-2,6-dione (Compound 59),

3-(7-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- I) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidine-1-carbonyl) piperidin-1-yl) -4-oxobenzo [d] [1 ,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 60),

3-(7-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 61),

3-(5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 62),

3-(7-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 63),

3-(4-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)p Peridine-2,6-dione (Compound 64),

3-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 65),

5-(3-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 66),

5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (compound 67),

3-(7-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][1 ,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 68),

3-(7-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H) -1) Piperidine-2,6-dione (Compound 69),

5-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 70),

3-(7-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione ( Compound 71),

5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 72),

5-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)iso indolin-2-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 73),

3-(7-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)isoindolin-2-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidin-2 ,6-dione (Compound 74),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 75),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl) amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine- 1-yl) isoindoline-1,3-dione (compound 76),

5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-2'-(2,6 -dioxopiperidin-3-yl)-[2,5'-biisoindoline]-1',3'-dione (Compound 77),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 78),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 79),

3-(5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxoisoindoline-2- 1) Piperidine-2,6-dione (Compound 80),

3-(5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 81 ),

5-(4-((7-((3-((2,6-dichlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 82),

5-(4-((7-((3-((2,4-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 83),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((1-methyl-3-(o-tolylamino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Compound 84 ),

5-(4-((7-((3-((2-chloro-6-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 85),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 86),

5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 87),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Compound 88),

5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Compound 89),

2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)acetamide (Compound 90),

2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoi Soindolin-5-yl)acetamide (Compound 91),

4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -dihydroisoquinolin-2(1H)-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine- 1-Carboxamide (Compound 92),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 93),

2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (Compound 94),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 95),

7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(2-(2 ,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 96),

2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-N-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p Peridin-4-yl)acetamide (Compound 97),

3-(5-(((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 98),

7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 99),

N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide (Compound 100),

N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine-4- Carboxamide (Compound 101),

N4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-N1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1,4-dicarboxamide (Compound 102),

3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 103),

3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione (Compound 104),

3-(5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 105),

3-(5-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (Compound 106),

(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl pivalate (Compound 107),

2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 108),

5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 109),

5-((2-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 110),

1-(5-(4-(2-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2, 4(1H,3H)-dione (Compound 111),

1-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2, 4(1H,3H)-dione (Compound 112),

N-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamide (Compound 113),

N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine-4- Carboxamide (Compound 114),

3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 115 ),

3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (compound 116),

3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)p Peridine-2,6-dione (Compound 117),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-methoxy-2-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 118),

5-(4-((7-((3-((2,3-dihydro-1H-inden-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) Isoindoline-1,3-dione (Compound 119),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((2-fluoro-4-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 120),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 121),

N-(4-((6-((2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperi din-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl )Amino)-3-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 122),

5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-Dihydroisoquinolin-2(1H)-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 123) ,

5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 124),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione (compound 125),

5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione (compound 126),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 127),

5-(4-(((1r,4r)-4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexyl)oxy)piperidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 128),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 129),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 130),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 131),

3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)piperidine-2,6-dione (Compound 132),

3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo [3,4-b]pyridin-6-yl)piperidine-2,6-dione (Compound 133),

5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 134),

5-(4-((1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 135),

5-(4-((4-(3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 136 ),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-Dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 137) ,

5-(3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 138),

5-(4-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 139),

5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 140),

5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 141),

5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 142),

5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 143),

5-((R)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 144),

5-((S)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 145),

5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 146),

5-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 147),

5-((1R,5S,6S)-6-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 148),

5-(4-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 149),

5-((R)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 150),

5-((S)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 151),

5-(3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- 1) Isoindoline-1,3-dione (Compound 152),

5-((1R,5S,6S)-6-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- 1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 153),

5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 154),

5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 155),

5-(4-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Pyridin-2-yl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 156),

5-(4-(2-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) pyridin-2-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 157),

5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 158 ),

5-(3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperazin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 159),

5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 160),

5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 161),

5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-3-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 162),

5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 163 ),

5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 164),

5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (compound 165),

5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 166),

5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 167),

5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) -[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 168),

5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 169 ),

3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-yl)piperidine-2,6-dione (Compound 170),

5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyrimidin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 171),

5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 172),

5-((R)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 173),

5-((S)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 174),

5-(4-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) azetidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 175 ),

5-((R)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 176),

5-((S)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 177),

5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Compound 178),

5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl) amino) phenyl) piperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 179),

5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl) amino) phenyl) piperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- dione (compound 180),

5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 181) ,

5-(3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) azetidin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 182) ,

5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 183),

5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 184),

5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 185),

5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 186),

3-(2-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- 1) Piperidine-2,6-dione (Compound 187),

3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6 -yl)piperidine-2,6-dione (Compound 188),

2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(3-(N-(2,6-dioxopiperidin-3-yl)sulfa Moyl)-4-methylphenyl)acetamide (Compound 189),

7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(3-(N -(2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 190),

3-(3-((3-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrole -1-yl)piperidine-2,6-dione (Compound 192),

3-(3-((3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)amino)-2,5 -dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (Compound 193),

5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 194),

5-(4-((7-((3-((2-bromo-6-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 195),

5-(4-(((1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)amino)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (compound 199),

3-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrole-1- 1) Piperidine-2,6-dione (Compound 201),

N-(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclopropyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperidine-4-carboxamide (Compound 204),

N-(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoine Dolin-5-yl)oxy)acetamide (Compound 205),

(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl piperidine-4-carboxylate bistrifluoroacetic acid (Compound 206),

(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl 4-methylpentanoate (Compound 207),

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione (compound 208),

3-(5-(1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidin-2,6- Dione (Compound 209),

5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione (Compound 210),

5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione (Compound 211),

5-(4-((7-((3-((2,6-dibromophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 217),

5-(4-((7-((3-((2-bromo-6-chlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 218),

5-(4-((7-((3-((2-chloro-6-iodophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 219),

3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (compound 220),

2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2,6-dimethylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Dolin-1,3-dione (Compound 221),

5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidin-1-yl) -2-oxoethyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1 ,3-dione (compound 222),

5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidin-1-yl) -2-oxoethyl) piperazin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 225),

5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Compound 226),

5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 227),

5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino ) Phenyl) piperidin-1-carbonyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 228),

5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-2-fluorophenyl)piperidine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 229),

5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 230),

5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3-fluorophenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 231),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 232),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione (compound 233),

5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 234),

5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 235),

5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 236),

3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( Compound 237),

5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 238),

5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 239),

(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl) piperidine-4-carbonyl) piperidin-4-yl) acrylonitrile (Compound 240),

(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)acrylonitrile (Compound 241),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 243),

5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- Fluoroisoindoline-1,3-dione (Compound 244),

3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( Compound 245),

5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carbonyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 246),

5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 247),

5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxophyll) Peridin-3-yl)isoindoline-1,3-dione (Compound 248),

5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- 1) Isoindoline-1,3-dione (Compound 250),

5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )phenyl)piperidin-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 253),

5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )phenyl)piperidin-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-dione (Compound 254),

3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione (compound 255),

3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 256),

3-(5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Phenyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 257),

3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 258),

(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- Carbonyl)piperidin-4-yl)acrylonitrile (Compound 259),

(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoine Dolin-5-yl)glycyl)piperidin-4-yl)acrylonitrile (Compound 260),

(E)-2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidine-1-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) Glycyl) piperidin-4-yl) acrylonitrile (Compound 261),

3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidine-1-carbonyl) piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1- 1) Piperidine-2,6-dione (Compound 262),

5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 263),

3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d] Imidazol-1-yl)piperidine-2,6-dione (Compound 264),

5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridazin-3-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 268), and

3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2,6-dione (Compound 272).

Additionally, the following terms in the present invention have the following meanings unless otherwise indicated. Any undefined terms have meanings understood in the art.

The term “alkyl” refers to a single-bonded, straight-chain or branched-chain hydrocarbon group having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n- These include butyl, isobutyl, tert- butyl, 1-methylpropyl, pentyl and hexyl.

The term “alkenyl” refers to a straight or branched hydrocarbon group having 2 to 16 carbon atoms and preferably 2 to 8 carbon atoms and at least one double bond between carbon atoms.

The term “alkynyl” refers to a straight or branched hydrocarbon group having 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, and having at least one triple bond between carbon atoms.

The term “alkoxy” refers to an oxygen group to which a single bonded straight-chain or branched-chain saturated hydrocarbon having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms is bonded, and includes methoxy, ethoxy, propoxy, n-butoxy, tert -butoxy, 1-methylpropoxy, etc.

The term “alkoxyalkoxy” refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group are replaced by another alkoxy group, and the alkoxy group is as disclosed above.

The terms “halo” and “halogen” are used in their conventional sense to refer to fluoro, chloro, bromo or iodo substituents.

The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by a halo group, and the alkyl and halo groups are as disclosed above.

The term “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group are replaced by a halo group, and halo and alkoxy are as disclosed above.

The terms “cycle” and “ring” refer to a substituted or aromatic group that may or may not be substituted and/or may or may not contain heteroatoms and may be a monocycle, bicycle, polycycle, or spirocycle. It refers to a flag.

The term “carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which may contain fused or bridged ring systems having 3 to 10 carbon atoms. In certain embodiments, carbocyclyl contains 3 to 12 carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyls can be saturated (i.e., contain only a single C-C bond) or unsaturated (i.e., contain one or more double or triple bonds). Fully saturated carbocyclyl radicals are also called “cycloalkyl”. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also called “cycloalkenyls.” Examples of monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, but are not limited to, indanyl, adamantyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like.

The term “heterocyclyl” refers to a stable 3- to 12-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise within the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical in question is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom in the ring(s).

Examples of such heterocyclyl radicals include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, 1,2,3,6-tetrahydropyridinyl, isoindolinyl, tetra Hydroisoindolinyl, 2-azaspiro[3.4]octanyl, 6-azaspiro[3.4]octanyl, azaspirodecanyl, 2-azabicyclo[2.1.0]fentanyl, octahydro-1H-cyclopenta[c ]Includes pyridinyl, 7-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.2.0]octanyl, etc.

The term “aryl” refers to an aromatic substituent having at least one ring with a shared pi electron system, and includes phenyl, benzyl, naphthyl, anthryl, indanyl, biphenyl, triphenyl, etc.

The term “heteroaryl” refers to a monocyclic, bicyclic or tricyclic aromatic ring compound containing one or more heteroatoms such as N, O, or S, and the number and type of heteroatoms contained in the ring, and depending on the number of carbon atoms, including, but not limited to, pyrazolopyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, triazolyl, pyridyl, pyrrolyl, pyrrolidinyl, furanyl, quinolidinyl, indolyl, Imidazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl, dibenzofuranyl, dibenzoselenophenyl, benzofuranyl, benzothiophenyl, Benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridylindolyl, pyrrolodipyridinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl , thiadiazolyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, oxadiazinyl, benzimidazolyl, indazolyl, indoxazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, Isoquinolinyl, cynolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuro These include pyridinyl, furodipyridinyl, benzothienopyridinyl, thienodipyridinyl, benzoselenophenopyridinyl, and selenophenodipyridinyl.

Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

In the present invention, the pharmaceutically acceptable salt refers to a salt or complex of Formula 1 that possesses desirable biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid. , benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, particularly chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl salt. Rates (e.g. benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate and Diphenylacetate). The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

The acid addition salt according to the present invention can be prepared by conventional methods, for example, the precipitate produced by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and adding an organic acid or inorganic acid. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically appropriate to prepare sodium, potassium, or calcium salts as metal salts. Additionally, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The cancer refers to solid cancer or blood cancer, and the solid cancer includes brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, Oropharyngeal cancer, nasal cavity cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, Gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer, anal cancer, bladder cancer, kidney cancer, male genital cancer, penile cancer, prostate cancer, female genital cancer, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer. , female external genital cancer, female urethra cancer, or skin cancer, but is not particularly limited thereto. Additionally, the blood cancer may be selected from the group consisting of leukemia, malignant lymphoma, multiple myeloma, or aplastic anemia, but is not particularly limited thereto.

In addition, the above autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barre syndrome, and acute industrial accidents. Encephalomyelitis, Addison's disease, myoclonus-myoclonus syndrome, ankylosing myelitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive disorder, Goodpasture syndrome, idiopathic thrombocytopenia purpura, optic neuritis, scleroderma , primary biliary cirrhosis, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma, and It may be selected from the group consisting of vulvodynia, but is not particularly limited thereto.

The pharmaceutical composition according to the present invention can be formulated in a suitable form with a commonly used pharmaceutically acceptable carrier. “Pharmaceutically acceptable” refers to a composition that is physiologically acceptable and does not typically cause allergic reactions such as gastrointestinal upset, dizziness, or similar reactions when administered to humans. In addition, the composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to conventional methods.

Carriers, excipients, and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, and methyl. It may include, but is not limited to, cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, syrups, etc. In addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. . Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, tween 61, cacao, laurel, glycerol, gelatin, etc. can be used. In order to formulate a formulation for parenteral administration, the pyrimidine derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized or mixed with auxiliaries such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts or buffers for adjusting osmotic pressure, and It can be mixed with water with other therapeutically useful substances to prepare a solution or suspension, which can be prepared in ampoule or vial unit dosage form.

The pharmaceutical composition containing the compound of Formula 1 disclosed in the present invention as an active ingredient can be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, for example, oral, rectal or by intravenous, intramuscular, subcutaneous, intrathecal or intracerebrovascular injection. The dosage is determined by the age, gender, and weight of the subject to be treated, the specific disease or pathological state to be treated, the severity of the disease or pathological state, administration time, route of administration, absorption, distribution and excretion rate of the drug, types of other drugs used, and the prescriber's It will vary depending on judgment, etc. Dosage determinations based on these factors are within the level of one skilled in the art, and dosages generally range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The above dosage does not limit the scope of the present invention in any way.

Additionally, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response regulators for the prevention or treatment of cancer, autoimmune disease, and Parkinson's disease.

The present invention relates to a novel bifunctional compound and a composition containing the same for preventing or treating cancer, autoimmune diseases, and Parkinson's disease, wherein the novel bifunctional compound inhibits Bruton's tyrosine kinase (BTK). Because it has selective and excellent effects, it can be usefully used as a composition for preventing or treating cancer, autoimmune diseases, and Parkinson's disease.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.

<Example 1. Compound synthesis and confirmation of physicochemical properties>

The synthesis process of compounds 1 to 272 of the present invention is as follows.

Compound 1. 4-((6-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dion

EDCI (20.1 mg, 0.105 mmol), HOBt (14.1 mg, 0.105 mmol), and Compound 1-2 were added to a solution of Compound 1-1 (Korean Patent No. 2128018) (10 mg, 0.021 mmol) dissolved in DMF (1 mL). (WO2020/200291) (10.0 mg, 0.021 mmol) and DIPEA (21.7 mg, 0.168 mmol) were added and heated to 40°C for 16 hours. Cold water was added to the reaction mixture and extracted with 5% MeOH/dichloromethane. The organic layer was washed with cold water and brine, and the organic layer was concentrated under reduced pressure to obtain 31 mg of crude mixture. The crude product was purified by preparative TLC to obtain 6 mg of compound 1 as a brown oil.

Compound 2. 5-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy) Acetate (Compound 2-3) synthesis

Compound 2-2 (Angene, AG01C1H7) ( tert- butyl 2-(2-(2-aminoethoxy)ethoxy)acetate; 83.3 mg, 0.380 mmol) was dissolved in 1.0 mL DMSO and DIPEA (187.6 mg, 1.488 mmol) was added and stirred for 10 minutes, then compound 2-1 (Combi-Blocks, HD-3240) (5-fluorothalidomide; 100 mg, 0.362 mmol) was added to the reaction mixture, heated to 90°C, and when the reaction was completed. It was stirred until. Cold water was added to the reaction mixture, extraction was performed with EtOAc, the organic layer was washed with water and brine, the organic layer was concentrated under reduced pressure, and the crude material was purified by preparative TLC to obtain 26 mg of compound 2-3 as a brown oil.

Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy ) Acetic acid (compound 2-4) synthesis

Compound 2-3 (25 mg, 0.05 mmol) was dissolved in 5.0 mL dichloromethane, TFA (30.0 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The organic solvent was concentrated under reduced pressure, and the resulting crude material was neutralized using saturated sodium bicarbonate solution, extracted with EtOAc, and the organic layer was concentrated under reduced pressure to obtain 15.0 mg of Compound 2-4.

Step 3: 5-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperi Synthesis of din-3-yl)isoindoline-1,3-dione (compound 2)

Dissolve Compound 2-4 (10.0 mg, 0.02 mmol) in 0.5 mL DMF, add HATU (30.4 mg, 0.08 mmol) and TEA (16.1 mg, 0.16 mmol), stir for 10 minutes, and then add Compound 2-5 (Korea Registered). Patent No. 2128018) (9.25 mg, 0.02 mmol) was added and stirred at 40°C for 16 hours. The reaction product was quenched with ice water and the solid formed was filtered, the solid was dissolved in 10 mL of ethyl acetate, and the organic layer was washed with water and brine solution. The organic layer was concentrated under reduced pressure, and the crude material was purified by MPLC to obtain 6.0 mg of Compound 2 as a brown solid.

Compound 3. 4-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)acetate (Compound 3-3) Synthesis

Compound 3-2 (Angene, AG01C1H7) (41.6 mg, 0.190 mmol) was dissolved in 1.0 mL DMSO, DIPEA (93.8 mg, 0.721 mmol) was added, stirred for 10 minutes, and compound 3-1 (Axis Pharm, AP12129) (4-fluorothalidomide; 50.0 mg, 0.181 mmol) was added, heated to 90°C, and stirred for 16 hours. Cold water was added to the reaction mixture, extraction was performed with EtOAc, the organic layer was washed with water and brine, the organic layer was concentrated under reduced pressure, and the crude material was purified by preparative TLC to obtain compound 3-3 (40.0 mg, 0.08 mmol) as a brown oil. did.

Step 2: 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy ) Acetic acid (compound 3-4) synthesis

To a solution of compound 3-3 (25 mg, 0.084 mmol) in 5.0 mL DCM was added TFA (48 mg, 0.42 mmol) and stirred at room temperature for 16 hours, then the solvent was evaporated under vacuum to give 46 mg of compound 3-4 as a brown color. Obtained from oil.

Step 3: 4-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperi Synthesis of din-3-yl)isoindoline-1,3-dione (compound 3)

HATU (144.0 mg, 0.378 mmol) and TEA (76.1 mg, 0.752 mmol) were added to a solution of Compound 3-4 (45.0 mg, 0.0946 mmol) in 2 mL DMF, stirred for 10 minutes, and then Compound 3-5 ( Korean Patent No. 2128018) (37.5 mg, 0.0946 mmol) was added and stirred at 40°C until the reaction was complete. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material was purified by MPLC to obtain 26 mg of Compound 3 as yellow. Obtained as a solid.

Compound 4. N-(2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)-1-(2-(2,6-dioxopiperi) din-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide

Step 1: tert- Butyl 2-(2-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-car Synthesis of Paxamido)ethoxy)ethoxy)acetate (Compound 4-3)

Compound 4-1 (WO 2020/162725) (50.0 mg, 0.129 mmol) was dissolved in 1 mL of DMF, EDCI (38.5 mg, 0.285 mmol), HOBt·H ₂ O (49.4 mg, 0.285 mmol), and Compound 4- 2 (Angene, AG01C1H7) (28.5 mg, 0.129 mmol), and DIPEA (66.8 mg, 0.516 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 7 hours. The reaction was quenched with water, extracted with EtOAc, the organic layer was concentrated under reduced pressure, and the crude material was purified by column chromatography to obtain 44 mg of compound 4-3 as a yellow solid.

Step 2: 2-(2-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4 -Carboxamido)ethoxy)ethoxy)acetic acid (Compound 4-4) synthesis

TFA (38 mg, 0.33 mmol) was added to a solution of compound 4-3 (39 mg, 0.066 mmol) in 1 mL of DCM at room temperature and stirred for 12 hours. The volatiles were evaporated under vacuum and the residual solvent was removed with a high vacuum pump to yield 34 mg of compound 4-4 as a yellow solid.

Step 3: N-(2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)-1-(2-(2,6-dioxopiperi) Din-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 4) synthesis

HATU (42 mg, 0.11 mmol) and TEA (33 mg, 0.11 mmol) were added to a solution of Compound 4-4 (15 mg, 0.028 mmol) in 2 mL DMF, stirred for 10 minutes, and then Compound 4-5 ( Korean Patent No. 2128018) (11.3 mg, 0.0280 mmol) was added and stirred at 40°C for 16 hours. The reaction mixture was quenched with ice water, the solid formed was filtered, the solid was dissolved in 10 mL of ethyl acetate, the organic layer was washed with water and brine solution, the organic layer was concentrated under reduced pressure, and the crude material was purified by MPLC to obtain compound 4 10. mg was obtained as an orange solid.

Compound 5. N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-1-(2-(2,6-dioxopiperi din-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide

Step 1: tert- Butyl 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)-1-oxo- Synthesis of 5,8,11,14-tetraoxa-2-azahexadecane-16-oate (Compound 5-3)

In a solution of compound 5-1 (WO 2020/162725) (50.0 mg, 0.129 mmol) in DMF (1 mL) was added EDCI (38.5 mg, 0.285 mmol), HOBt·H ₂ O (49.4 mg, 0.285 mmol), compound 5- 2 (Combi-Blocks, HD-3240) (40.0 mg, 0.129 mmol) and DIPEA (66.8 mg, 0.516 mmol) were added at room temperature and stirred at room temperature for 4 hours. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 21 mg of compound 5-3 as a yellow oil.

Step 2: 1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)-1- Synthesis of oxo-5,8,11,14-tetraoxa-2-azahexadecane-16-oxic acid (Compound 5-4)

TFA (17 mg, 0.14 mmol) was added to a solution of compound 5-3 (20 mg, 0.029 mmol) in 1 mL of DCM at room temperature and stirred for 16 hours. The volatiles were evaporated under vacuum and the residual solvent was removed with a high vacuum pump to obtain 17 mg of compound 5-4 as a dark brown oil.

Step 3: N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-1-(2-(2,6-dioxopiperi Synthesis of din-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 5)

HATU (24 mg, 0.064 mmol) and TEA (13 mg, 0.13 mmol) were added to a solution of compound 5-4 (10 mg, 0.016 mmol) in 2 mL DMF, stirred for 10 minutes, and compound 5-5 (Korea registration) was added. Patent No. 2128018) (6.3 mg, 0.016 mmol) was added and stirred at 40°C for 16 hours. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 8.0 mg of Compound 5. Obtained as a yellow solid.

Compound 6. N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-4-(7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl)amino) -1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-4 -Oxobutanamide

Step 1: 4-(7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] Synthesis of pyrimidin-6-yl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutanoic acid (Compound 6-3)

Compound 6-2 (TCI, S0107) (100 mg, 0.997 mmol) as succinic anhydride was added to a stirred solution of compound 6-1 (Korean Patent No. 2128018) (100 mg, 0.199 mmol) in dry THF at 0°C. Added for 1 hour. Later, the temperature was raised to 40°C and 2 drops of TEA were added to dissolve the reaction and stirred for 26 hours. TLC showed completion of the reaction, THF was removed by evaporation under reduced pressure and the residue was dissolved in DCM and washed with water. The DCM layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The resulting crude mixture was purified on a silica gel column using 5% MeOH:DCM as an eluent to obtain compound 6-3 (98 mg, 0.163 mmol, 90%) as a brown solid.

Step 2: N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-4-(7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl)amino) -1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-4 -Synthesis of oxobutanamide (compound 6)

HATU (25 mg, 0.064 mmol) and TEA (13 mg, 0.13 mmol) were added to a solution of compound 6-3 (10.0 mg, 0.016 mmol) in 2 mL DMF and stirred for 10 minutes, then compound 6-4 (WO 2019 /148055) (9.0 mg, 0.016 mmol) was added and stirred at 40°C for 16 hours. The reaction product was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 10 mg of Compound 6. Obtained as an orange solid.

Compound 7. 4-((12-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

Step 1: Synthesis of 12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoic acid (Compound 7-3)

To a solution of compound 7-2 (Combi-Blocks, QB-6982) (12-aminododecanoic acid; 4.7 mg, 0.021 mmol) in 0.5 mL DMSO was added DIPEA (14 mg, 0.11 mmol) and stirred for 10 minutes. Compound 7-1 (Axis Pharm, AP12129) (4-pomalidomide; 5.0 mg, 0.018 mmol) was added to the reaction mixture, heated to 90°C, and stirred for 16 hours. Cold water was added to the reaction mixture, extracted with EtOAc, and the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 7 mg of compound 7-3 as a green solid.

Step 2: 4-((12-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 7) synthesis

HATU (21.2 mg, 0.0561 mmol) and TEA (11.3 mg, 0.112 mmol) were added to a solution of compound 7-3 (7.0 mg, 0.014 mmol) dissolved in 0.5 mL DMF, stirred for 10 minutes, and compound 7-4 ( Korean Patent No. 2128018) (5.9 mg, 0.014 mmol) was added and stirred at 40°C for 16 hours. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 7.1 mg of Compound 7. Obtained as an orange solid.

Compound 8. 5-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy) Acetate (Compound 8-3) synthesis

To a solution of Compound 8-1 (Combi-Blocks, HD-3240) (5-fluoro pomalidomide; 50 mg, 0.18 mmol) in 1.0 mL DMSO was added DIPEA (188 mg, 1.45 mmol) and stirred for 10 minutes. . Compound 8-2 (BLDpharm, BD00927562) (58 mg, 0.19 mmol) was added to the reaction mixture, heated to 90°C, and stirred for 24 hours. The reaction mixture was diluted with ice and water, extracted with EtOAc, washed with water and brine solution, and then concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 18 mg of compound 8-3 as a green oil.

Step 2: 14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-3,6,9,12-tetraoxa Tetradecanoic acid (compound 8-4) synthesis

To a solution of compound 8-3 (18 mg, 0.031 mmol) in DCM (0.2 mL) was added TFA (0.2 mL) at room temperature and stirred for 16 hours. The volatile material was evaporated under vacuum and the residual solvent was concentrated under reduced pressure to obtain 13 mg of compound 8-4 as a dark brown oil.

Step 3: 5-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperi Synthesis of din-3-yl)isoindoline-1,3-dione (compound 8)

HATU (38.2 mg, 0.100 mmol) and TEA (20.2 mg, 0.200 mmol) were added to a solution of compound 8-4 (13.0 mg, 0.0250 mmol) in 0.5 mL DMF, stirred for 10 minutes, and compound 8-5 (Korea registration) was added. Patent No. 2128018) (10.3 mg, 0.0250 mmol) was added and stirred at 40°C for 6 hours. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 8.0 mg of Compound 8. Obtained as a light brown solid.

Compound 9. N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopy Peridin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide

Step 1: tert- Butyl-1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-2-oxo-6,9,12,15 -Synthesis of tetraoxa-3-azaheptadecane-17-oate (Compound 9-3)

In a solution of compound 9-1 (WO 2020/160198) (30 mg, 0.0903 mmol) in DMF (1 mL) was added EDCI (24.2 mg, 0.180 mmol), HOBt·H ₂ O (34.5 mg, 0.180 mmol), compound 9- 2 (BLDpharm, BD00927562) (30.5 mg, 0.993 mmol) and DIPEA (46.6 mg, 0.360 mmol) were added at room temperature and stirred at room temperature for 4 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The crude material obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 22 mg of compound 9-3 as a clear oil.

Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)-2-oxo-6,9,12, Synthesis of 15-tetraoxa-3-azaheptadecane-17-oic acid (Compound 9-4)

To a solution of compound 9-3 (22 mg, 0.038 mmol) in DCM (2 mL) was added TFA (1 mL) at room temperature and stirred for 16 hours. The volatile material was concentrated under reduced pressure to obtain 19 mg of compound 9-4 as an off-white oil.

Step 3: N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopy Synthesis of peridin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (Compound 9)

HATU (40.3 mg, 0.106 mmol) and TEA (85.8 mg, 0.850 mmol) were added to a solution of compound 9-4 (14.0 mg, 0.0247 mmol) in 0.5 mL DMF, stirred for 10 minutes, and compound 9-5 (Korea registration) was added. Patent No. 2128018) (10.0 mg, 0.0247 mmol) was added and stirred at 40°C for 6 hours. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 7.0 mg of Compound 9. Obtained as a light brown solid.

Compound 10. N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopy Peridin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide

Step 1: tert- Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15- Synthesis of tetraoxa-3-azaheptadecane-17-oate (compound 10-3)

In a solution of compound 10-1 (WO 2020/162725) (30 mg, 0.090 mmol) in DMF (1 mL) at room temperature EDCI (24.5 mg, 0.180 mmol), HOBt·H ₂ O (34.7 mg, 0.181 mmol), compound 10-2 (BLDpharm, BD00927562) (30.6 mg, 0.996 mmol) and DIPEA (47.0 mg, 0.362 mmol) were added and stirred at room temperature for 4 hours. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 26 mg of compound 10-3 as a yellow oil.

Step 2: 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12, Synthesis of 15-tetraoxa-3-azaheptadecane-17-oic acid (compound 10-4)

To a suspension of compound 10-3 (26 mg, 0.041 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature and stirred for 16 hours. The volatile material was evaporated under vacuum and the residual solvent was removed with a high vacuum pump to obtain 22 mg of compound 10-4 as a yellow solid.

Step 3: N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopy Synthesis of peridin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (Compound 10)

HATU (40.3 mg, 0.106 mmol) and TEA (85.8 mg, 0.850 mmol) were added to a solution of compound 10-4 (15.0 mg, 0.0246 mmol) in 0.5 mL DMF, stirred for 10 minutes, and then compound 10-5 (Korea registration) Patent No. 2128018) (10.6 mg, 0.0265 mmol) was added and stirred at room temperature until the reaction was complete. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in 10 mL of ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain Compound 10 14. mg was obtained as a light brown solid.

Compound 11. tert- Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15- tetraoxa-3-azaheptadecane-17-oate

Step 1: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(pro-2-pin-1-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3, 6-diamine (Compound 11-1) synthesis

Compound 11-1-B (TCI, P1272) (propargyl bromide; 7.1 mg, 0.060) was added to a solution of compound 11-1-A (Korean Patent No. 2128018) (20 mg, 0.050 mmol) dissolved in DMF (0.5 mL). mmol) and cesium carbonate (20 mg, 0.060 mmol) were added at room temperature. It was stirred at room temperature for 4 hours. TLC indicated consumption of starting material. Water was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3 x 15 mL) and the combined organic layers were washed with water and brine solution (3 x 10 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated under pressure to obtain compound 11-1 (15 mg, 0.034 mmol, 71%) as an off-white solid.

Step 2: N ⁶ -(2-((1-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)-1,2,3 ,4-tetrahydroisoquinoline-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 11-3) synthesis

Compound 11-2 (BroadPharm, BP-20692) (azido-PEG2-amine; 2.4 mg, 0.013 mmol) in a suspension of Compound 11-1 (5.0 mg, 0.011 mmol) in water/t-BuOH (1:1) , sodium ascorbate (0.87 mg, 0.0044 mmol, 3 eq.) and copper sulfate (0.35 mg, 0.0022 mmol, 1 eq.) were added. The reaction was heated to 70° C. and stirred for 3 hours under nitrogen. The volatile substances were evaporated under vacuum, DCM was added to the residue, the DCM layer was washed with water, and the organic layer was concentrated under reduced pressure to obtain 11 mg (crude) of Compound 11-3 as a dark brown oil.

Step 3: tert- Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12,15- Synthesis of tetraoxa-3-azaheptadecane-17-oate (Compound 11)

EDCI (4.8 mg, 35.8 mmol), HOBt·H ₂ O (6.86 mg, 35.8 mmol), and Compound 11 were added to a solution of Compound 11-4 (WO 2020/162725) (5.30 mg, 16.1 mmol) dissolved in DMF (1 mL). -3 (11.0 mg, 17.9 mmol) and DIPEA (9.20 mg, 71.6 mmol) were added at room temperature and stirred at 40°C for 4 hours. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 3.0 mg of Compound 11 as a brown solid.

Compound 12. N-(2-(2-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy) Toxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide

Step 1: N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Synthesis of dioxoisoindolin-5-yl)amino)acetamide (Compound 12-3)

EDCI (24.48 mg, 181.2 mmol), HOBt·H ₂ O (34.73 mg, 181.2 mmol), and Compound 12 were added to a solution of Compound 12-1 (WO 2020/162725) (30.0 mg, 90.6 mmol) dissolved in DMF (1 mL). -2 (BroadPharm, BP-20692) (azido-2PEG-amine; 17.3 mg, 99.6 mmol) and DIPEA (46.93 mg, 962.2 mmol) were added at room temperature and stirred at 40°C for 4 hours. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 20 mg of compound 12-3 as a brown oil.

Step 2: N-(2-(2-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy) Toxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide (Compound 12) synthesis

Compound 12-3 (11.8 mg, 24.0 mmol) and sodium ascorbate (13.0 mmol) were added to a suspension of compound 12-4 (same as compound 11-1) (10 mg, 22.0 mmol) dissolved in water/t-BuOH (1:1). mg, 66.0 mmol) and copper sulfate (3.70 mg, 22.0 mmol) were added. The reaction was stirred at 70° C. under nitrogen for 14 hours. The volatiles were evaporated under vacuum, DCM was added to the residue, the organic layer was washed with water, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 4.0 mg of Compound 12 as a brown solid.

Compound 13. 4-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d])pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopy peridin-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl-2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy) Acetate (Compound 13-3) synthesis

DIPEA (111 mg, 0.860 mmol) was added to a solution of compound 13-1 (Axis Pharm, AP12129) (4-fluoropomalidomide; 30 mg, 0.10 mmol) in 1.0 mL DMSO and stirred for 10 minutes. Compound 13-2 (BLDpharm, BD00927562) (58 mg, 0.19 mmol) was added to the reaction mixture, heated to 90°C, and stirred for 12 hours. Ice was added to the reaction mixture, diluted with water, and extracted with EtOAc. The organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 17 mg of compound 13-3 as a brown oil.

Step 2: tert- Butyl (15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (Compound 13-4)

Compound 13-3 (17 mg, 0.030) was dissolved in 40% TFA/DCM (2 mL) and stirred at room temperature for 2 hours. The solvent was evaporated under vacuum to give compound 13-4 (15 mg, 0.029, 98%) as a brown oil.

Step 3: 4-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperi Synthesis of din-3-yl)isoindoline-1,3-dione (Compound 13)

HATU (44 mg, 0.12 mmol) and TEA (23 mg, 0.23 mmol) were added to a solution of compound 13-4 (15 mg, 0.029 mmol) dissolved in DMF (0.5 mL), stirred for 10 minutes, and then compound 13-5. (Korean Patent No. 2128018) (12 mg, 0.030 mmol) was added and stirred at 40°C for 14 hours. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 6 mg of Compound 13. Obtained as a yellow solid.

Compound 14. tert- Butyl 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)acetate

Step 1: Synthesis of 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azychoic acid-20-oic acid (Compound 14-2)

TEA (91.4 mg, 0.904 mmol) and (Boc) ₂ O (197 mg, 0.904 mmol) was added and stirred at room temperature for 6 hours. DCM was added to the residue obtained by concentrating the organic solvent, washed with 0.5 N-HCl, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 230 mg of compound 14-2 as a clear oil.

Step 2: tert- Butyl (15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)carbamate (Compound 14-4)

To a solution of compound 14-2 (151 mg, 0.413 mmol) in DMF (5 mL) was added HATU (428.0 mg, 1.12 mmol) and TEA (190 mg, 1.87 mmol) and stirred for 10 minutes, then compound 14-3 ( Korean Patent No. 2128018) (150 mg, 0.375 mmol) was added and stirred at 40°C overnight. The reaction mixture was washed with ice water, the formed solid was filtered, the solid was dissolved in ethyl acetate, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain compound 14-4 190. mg was obtained as an orange solid.

Step 3: 1-Amino-15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-3,6,9,12-tetraoxapentadecan-15-one hydrochloride (Compound 14-5) synthesis

To a solution of compound 14-4 (180 mg, 0.241 mmol) in DCM (5 mL) was added HCl/dioxane (1.5 equiv) at 0°C and stirred at room temperature for 4 hours. The solvent was evaporated under vacuum to obtain 161 mg of compound 14-5 as a brown solid.

Step 4: tert- Butyl 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy)acetate (Compound 14) synthesis

DIPEA (32 mg, 0.24 mmol) was added to a solution of compound 14-5 (20 mg, 0.031 mmol) in 1.0 mL DMSO and stirred for 10 minutes. Compound 14-6 (Axis Pharm, AP12129) (10.3 mg, 0.0371 mmol) was added to the reaction mixture, heated to 90°C, and stirred for 12 hours. Ice was added to the reaction mixture, diluted with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 7.4 mg of compound 14 as a yellow oil.

Compound 15. 5-((15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

DIPEA (32 mg, 0.24 mmol) was added to a solution of Compound 15-1 (same as Compound 14-5) (20 mg, 0.031 mmol) in 1.0 mL DMSO and stirred for 10 minutes. Compound 15-2 (Combi-Blocks, HD-3240) (10.3 mg, 0.0371 mmol) was added to the reaction mixture, heated to 90°C, and stirred for 12 hours. Water and ice were added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 7 mg of compound 15 as a yellow oil.

Compound 16. N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopy Peridin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide

In a solution of compound 16-2 (WO 2020/160198) (9.0 mg, 0.027 mmol) in DMF (0.5 mL) at room temperature EDCI (11 mg, 0.058 mmol), HOBt·H ₂ O (7.8 mg, 0.058 mmol), compound 16-1 (same as compound 14-5) (20 mg, 0.029 mmol) and DIPEA (18 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water and then extracted with EtOAc. The crude mixture obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 14 mg of Compound 16 as an off-white solid.

Compound 17. N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopy Peridin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide

In a solution of Compound 17-2 (WO 2020/263935) (9.0 mg, 0.027 mmol) in DMF (0.5 mL) at room temperature EDCI (11 mg, 0.058 mmol), HOBt·H ₂ O (7.8 mg, 0.058 mmol), Compound 17-1 (same as compound 14-5) (20 mg, 0.029 mmol) and DIPEA (18 mg, 0.14 mmol) were added. The resulting mixture was stirred at 40°C for 4 hours. The reaction was quenched with water and then extracted with EtOAc. The crude mixture obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 16 mg of Compound 17 as an off-white solid.

Compound 18. N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-(4-(2-(2,6 -dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide

EDCI (8.0 mg, 0.042 mmol), HOBt·H ₂ O (5.6 mg, 0.042 mmol), and a solution of Compound 18-2 (WO 2020/160193) (8.0 mg, 0.020 mmol) dissolved in DMF (0.5 mL) at room temperature. Compound 18-1 (same as compound 14-5) (15 mg, 0.021 mmol) and DIPEA (13.6 mg, 0.105 mmol) were added. The resulting mixture was stirred at 40°C for 4 hours. The reaction was quenched with water and then extracted with EtOAc. The crude material obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 10 mg of Compound 18 as an off-white solid.

Compound 19. N-(2-(2-(2-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)ethoxy )Ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide

Step 1: N-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Synthesis of dioxoisoindolin-5-yl)amino)acetamide (Compound 19-1)

A solution of compound 19-1-A (WO 2020/162725) (50.0 mg, 0.151 mmol) in DMF (1 mL) was added at room temperature to EDCI (57.9 mg, 0.302 mmol), HOBt·H ₂ O (40.8 mg, 0.302 mmol). , compound 19-1-B (BROADPHARM, BP-20580) (azido-2PEG amine; 36.2 mg, 0.166 mmol) and DIPEA (78.2 mg, 0.604 mmol) were added. The resulting mixture was stirred at 40°C for 4 hours. The reaction was quenched and extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The crude mixture was purified by silica gel column chromatography using 10% MeOH/DCM as an eluent to obtain compound 19-1 (34 mg, 0.064 mmol) as a yellow oil.

Step 2: 1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)prop-2-pin-1-one (Compound 19-2) synthesis

To a solution of compound 19-2-B (TCI, P0497) (propiolic acid; 21 mg, 0.30 mmol) in DMF (2 mL) was added HATU (380 mg, 1.00 mmol) and TEA (156 mg, 0.400 mmol) and 10 After stirring for several minutes, compound 19-2-A (Korean Patent No. 2128018) (20 mg, 0.050 mmol) was added and stirred at room temperature for 4 hours. TLC indicated consumption of starting material. The reaction mixture was quenched with ice water and the formed solid was filtered. The solid was dissolved in 10 mL of ethyl acetate and the organic layer was washed with water and brine solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified by MPLC using 10% MeOH/DCM as eluent to yield compound 19-2 (91 mg, 0.20 mmol, 80%) as an orange solid.

Step 3: N-(2-(2-(2-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)ethoxy )Ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (compound 19) Synthesis

To a suspension of compound 19-1 (10 mg, 22.0 mmol) in t-BuOH (1 mL) was added compound 19-2 (11.8 mg, 24.0 mmol), sodium ascorbate (13.0 mg, 66.0 mmol), copper sulfate (3.70 mg, 22.0 mmol) and TEA (2.9 mg, 0.018 mmol) were added. The reaction was heated to 70° C. and stirred under argon for 14 hours. TLC indicated consumption of starting material. The volatiles were evaporated under vacuum, DCM was added to the residue and the DCM layer was washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 10% MeOH/DCM as an eluent to obtain compound 19 (4.0 mg, 0.0040 mmol, 22%) as a brown solid.

Compound 20. N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindoline-5-yl)piperazine-1-yl)acetamide

Step 1: 2-(2-(( tert- Butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (Compound 20-2) synthesis

A stirred solution of compound 20-2-A (BROADPHARM, BP-23275) ( tert- butyl (2-(2-hydroxyethoxy)ethyl)carbamate; 1.0 g, 4.8 mmol) in DCM (20 mL) Cooled to 0°C and charged with TEA (0.97 g, 9.6 mmol) and DMAP (0.29 g, 2.4 mmol) and slowly charged p-toluene sulfonyl chloride (1.4 g, 7.3 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction was diluted with 20 mL of DCM and washed with water. The aqueous layer was extracted with DCM (25 mL×2) and the combined organic layers were washed with 10% NaOH and brine solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified on a silica gel column and eluted with a 50% EA:HEX solvent mixture to obtain compound 20-2 (1.1 g, 3.0 mmol, 62%) in the form of a clear oil.

Step 2: tert- Butyl (2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Synthesis of -3,4-dihydroisoquinoline-2(1H)-yl)ethoxy)ethyl)carbamate (Compound 20-3)

Compound 20-1 (Korean Patent No. 2128018) (30 mg, 0.051 mmol) and potassium carbonate (14 mg, 0.10 mmol) were added to a solution of Compound 20-2 (20 mg, 0.056 mmol) in DMF (0.5 mL) at room temperature. was added and stirred at 70°C for 16 hours. After the reaction was completed, water was added to the mixture, the white precipitate formed was filtered, and the solid was dissolved in DCM. The crude material obtained by concentrating the organic layer under reduced pressure was separated by MPLC to obtain 23 mg of compound 20-3 as a white solid.

Step 3: N ⁶ -(2-(2-(2-aminoethoxy)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride (Compound 20-4) synthesis

4 N-HCl/dioxane (0.23 mL, 0.058 mmol) was added to a solution of compound 20-3 (23 mg, 0.039 mmol) in 1 mL of DCM, the temperature was raised from 0°C to room temperature, and the mixture was stirred for 1 hour. The volatiles were evaporated, the yellow solid formed was washed with diethyl ether, and the volatiles were distilled under steam to obtain 18 mg of compound 20-4 as a yellow solid.

Step 4: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 20)

In a solution of compound 20-5 (WO 2020/160193) (7.2 mg, 0.018 mmol) in DMF (0.5 mL) at room temperature EDCI (6.9 mg, 0.036 mmol), HOBt·H ₂ O (4.8 mg, 0.036 mmol), compound 20-4 (10 mg, 0.018 mmol) and DIPEA (12 mg, 0.090 mmol) were added and stirred at 40°C for 16 hours. The reaction product was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 4 mg of Compound 20 as a yellow solid.

Compound 21. N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperidine-4-carboxamide

Step 1: 2-(2-(( tert- Butoxycarbonyl)amino)ethoxy)ethyl 4-methylbenzenesulfonate (Compound 21-1-B2) synthesis

Stirred solution of compound 21-1-B1 ( tert- butyl (2-(2-hydroxyethoxy)ethyl)carbamate) (Sigma-Aldrich, 749648) (1.0 g, 4.8 mmol) in DCM (20 mL) Cooled to 0°C, added TEA (0.97 g, 9.6 mmol), DMAP (0.29 g, 2.4 mmol) and slowly charged p-toluene sulfonyl chloride (1.4 g, 7.3 mmol) and stirred at room temperature for 16 hours. did. After completion of the reaction, the reaction was diluted with 20 mL of DCM and washed with water. The aqueous layer was extracted with 25 mL×2 DCM and the combined organic layers were washed with 10% NaOH and brine solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified on a silica gel column and eluted with a 50% EA:HEX solvent mixture to obtain compound 21-1-B2 (1.1 g, 3.0 mmol, 62%) as a clear oil.

Step 2: tert- Butyl (2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-Dihydroisoquinoline-2(1H)-yl)ethoxy)ethyl)carbamate (Compound 21-1-C) synthesis

Compound 21-1-A (Korean Patent No. 2128018) and potassium carbonate (14 mg, 0.10 mmol) were added to a solution of compound 21-1-B2 (20 mg, 0.056 mmol) in DMF (0.5 mL) at room temperature. . The reaction was stirred at 70°C for 16 hours. TLC indicated consumption of starting material. Water was added to the reaction mixture, the white precipitate formed was filtered and the solid was washed three times with water and dissolved in DCM. The organic layer was dried over sodium sulfate and the solvent was evaporated under pressure. The crude material was purified using 5% MeOH:DCM as an eluent to obtain compound 21-1-C (23 mg, 0.039 mmol, 47%) as a white solid.

Step 3: N ⁶ -(2-(2-(2-aminoethoxy)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride (Compound 21-1) synthesis

To a solution of compound 21-1-C (23 mg, 0.039 mmol) in 1 mL of DCM was added 4 N HCl/dioxane (0.23 mL, 0.058 mmol), the temperature was raised from 0°C to room temperature, and the mixture was stirred for 1 hour. The volatiles were evaporated, the yellow solid formed was washed with diethyl ether, and the volatiles were distilled under steam to obtain compound 21-1 (18 mg, 0.037 mmol, 94%) as a yellow solid.

Step 4: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperidine-4-carboxamide (Compound 21) synthesis

In a solution of compound 21-2 (WO 2020/162725) (8.8 mg, 0.022 mmol) in DMF (0.5 mL) at room temperature EDCI (8.4 mg, 0.044 mmol), HOBt·H ₂ O (5.9 mg, 0.044 mmol), compound 21-1 (12 mg, 0.022 mmol) and DIPEA (14 mg, 0.11 mmol) were added and stirred at 40°C for 16 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The crude material obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 4 mg of Compound 21 as a yellow solid.

Compound 22. N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopy Peridin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide

In a solution of compound 22-2 (WO 2020/162725) (4.6 mg, 0.014 mmol) in DMF (0.5 mL) at room temperature EDCI (5.3 mg, 0.028 mmol), HOBt·H ₂ O (3.7 mg, 0.028 mmol), compound 22-1 (same as compound 14-5) (10 mg, 0.014 mmol) and DIPEA (9.0 mg, 0.070 mmol) were added. The resulting mixture was stirred at 40°C for 4 hours. The reaction mixture was quenched with water, extracted with EtOAc, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by silica gel column chromatography to obtain 10 mg of Compound 22 as an off-white solid.

Compound 23. 2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)acetamide

Step 1: tert- Butyl 2-(2-(2-iodoethoxy)ethoxy)acetate (Compound 23-1-B) synthesis

Imidazole (22.46 mg, 0.33 mmol) was added to a solution of triphenylphosphine (70.8 mg, 0.27 mmol) in 3 mL of anhydrous DCM at 0°C and stirred until dissolved. Iodine (68.5 mg, 0.33 mmol) was added and the solution turned yellow. A solution of Compound 23-1-A (BLDpharm, MFCD25959245) ( tert- butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate; 50 mg, 0.22 mmol) in 2 mL DCM was added and the reaction was allowed to proceed at 23 Stirred at ℃ for 16 hours. TLC analysis indicated completion of the reaction and the reaction was diluted with DCM and washed with 1N HCl. The DCM layer was dried over sodium sulfate and the solvent was concentrated in vacuo. The crude product was purified by silica gel flash chromatography using a 1:1 EA:HEX elution system to obtain compound 23-1-B (44 mg, 0.13 mmol) as a white liquid.

Step 2: Synthesis of 2-(2-(2-iodoethoxy)ethoxy)acetic acid (Compound 23-1)

TFA (5 mL) was added to a solution of compound 23-1-B (500 mg, 1.51 mmol) dissolved in DCM (5 mL) and stirred at room temperature until the reaction was complete. After completion of the reaction, the solvent was evaporated to obtain compound 23-1 (410 mg, 1.49 mmol, 98%) in the form of a brown oil.

Step 3: N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-(2-(2-iodoethoxy) Synthesis of ethoxy)acetamide (compound 23-3)

To a solution of compound 23-1 (250 mg, 0.0366 mmol) in anhydrous THF (10 mL) was added thionyl chloride (342 mg, 2.86 mmol) at 0°C and stirred at 60°C for 2 hours until hydrochloric acid was formed. . After formation of hydrochloric acid, the solvent and excess thionyl chloride were evaporated together with the solvent under reduced pressure. The residue was dissolved in THF, compound 23-2 (WO 2019/148055) (100 mg, 0.366 mmol) was added to the solution, and the resulting mixture was heated at 80° C. for 4 hours until the reaction was completed. THF was evaporated under vacuum, the residue was dissolved in ethyl acetate, washed with sodium bicarbonate solution, the organic layer was concentrated under reduced pressure, and the resulting crude material was purified by MPLC to obtain 112 mg of compound 23-3 as a white solid.

Step 4: 2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1, Synthesis of 3-dioxoisoindolin-5-yl)acetamide (Compound 23)

In a solution of Compound 23-4 (Korean Patent No. 2128018) (15 mg, 0.037 mmol) in DMF (0.5 mL), Compound 23-3 (20 mg, 0.037 mmol) and TEA (15 mg, 0.11 mmol) were added at 50°C. ) was added and stirred at 50°C for 16 hours. Water was added to the reaction mixture, the white precipitate formed was filtered, the solid was dissolved in DCM, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 9 mg of Compound 23 as a yellow solid.

Compound 24. N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-4-yl)piperidine-4-carboxamide

Step 1: tert- Butyl (2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Synthesis of -3,4-dihydroisoquinoline-2(1H)-yl)ethoxy)ethyl)carbamate (Compound 24-3)

To a solution of compound 24-2 (same as compound 20-2) (99.0 mg, 0.275 mmol) in DMF (0.5 mL) was added compound 24-1 (Korean Patent No. 2128018) (100 mg, 0.250 mmol) and potassium carbonate 39.1 mg, 0.500 mmol) was added at room temperature and stirred at 70°C for 16 hours. After completing the reaction, water was added to the reaction mixture, the white precipitate formed was filtered, the solid was dissolved in DCM, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 89 mg of compound 24-3 as an off-white solid. .

Step 2: N ⁶ -(2-(2-(2-aminoethoxy)ethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride (Compound 24-4) synthesis

4 N-hydrochloric acid/dioxane (0.050 mL, 0.20 mmol) was added to a solution of compound 24-3 (23 mg, 0.039 mmol) in 1 mL of DCM, the temperature was raised from 0° C. to room temperature, and the mixture was stirred for 1 hour. The volatiles were evaporated and the yellow solid formed was washed with diethyl ether and the volatiles were distilled off under vacuum to obtain 80 mg of compound 24-4 as a yellow solid.

Step 3: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 24) synthesis

To a solution of compound 24-5 (WO 2020/162725) (6.2 mg, 0.028 mmol) in DMF (0.5 mL) was added EDCI (11 mg, 0.056 mmol), HOBt·H ₂ O (7.5 mg, 0.056 mmol), at room temperature. Compound 24-4 (15 mg, 0.028 mmol) and DIPEA (18 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was cooled in ice, the formed precipitate was washed with water, and the formed precipitate was dissolved in DCM. The crude material obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 10 mg of Compound 24 as a yellow solid.

Compound 25. N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1, 3-dioxoisoindolin-5-yl)oxy)acetamide

In a solution of compound 25-2 (WO 2020/160198) (6.0 mg, 0.018 mmol) in DMF (0.5 mL) at room temperature EDCI (7.2 mg, 0.038 mmol), HOBt·H ₂ O (5.1 mg, 0.038 mmol), compound 25-1 (same as compound 21-1) (10 mg, 0.019 mmol) and DIPEA (12 mg, 0.095 mmol) were added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water and then extracted with EtOAc. The crude material obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography to obtain 4.0 mg of Compound 25 as an off-white solid.

Compound 26. 5-(4-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyrrolidin-1-carbonyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 26-3)

A solution of compound 26-2 (Sigma aldrich, 483818) (26 mg, 0.12 mmol) in DMF (0.5 mL) was added at room temperature to EDCI (47 mg, 0.24 mmol), HOBt·H ₂ O (33 mg, 0.24 mmol), compound. 26-1 (Korean Patent No. 2128018) (50 mg, 0.12 mmol) and DIPEA (78 mg, 0.60 mmol) were added. The resulting mixture was stirred at 40°C for 16 hours. The reaction was quenched with water, and the precipitate formed was filtered and washed four times with water. The precipitate was dissolved in DCM, the organic layer was concentrated under reduced pressure, and the crude material obtained was purified by silica gel column chromatography to obtain 70 mg of compound 26-3 as a yellow solid.

Step 2: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide hydrochloride (Compound 26-4)

4 N-hydrochloric acid/dioxane (0.050 mL, 0.20 mmol) was added to a solution of compound 26-3 (23 mg, 0.039 mmol) in 1 mL of DCM and stirred at room temperature for 1 hour. The volatiles were evaporated, the yellow solid formed was washed with diethyl ether, and the volatiles were distilled to obtain 50 mg of compound 26-4 as a yellow solid.

Step 3: 5-(4-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyrrolidin-1-carbonyl) piperidin-1-yl) -2- (2, Synthesis of 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 26)

In a solution of Compound 26-5 (WO 2020/162725) (4 mg, 0.009 mmol) in DMF (0.5 mL) at room temperature was added 50% T3P/EA (17 mg, 0.027 mmol), Compound 26-4 (10 mg, 0.018 mmol) and TEA (4.5 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the reaction mixture, extracted with MC, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The resulting crude material was purified by MPLC to obtain 1 mg of Compound 26 as an off-white solid.

Compound 27. N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)azetidine-3-carboxamide

In a solution of Compound 27-2 (WO 2020/038415) (6.7 mg, 0.019 mmol) in DMF (0.5 mL) at room temperature, 50% T3P/EA (36 mg, 0.057 mmol), Compound 27-1 (Compound 21-1 and same) (10 mg, 0.019 mmol) and TEA (12 mg, 0.095 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, extracted with MC, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 1.7 mg of Compound 27 as a green solid.

Compound 28. 5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)methyl)piperidine-1-carboxylate (Compound 28-3)

Compound 28-1 (Korean Patent No. 2128018) in a solution of Compound 28-2 (TCI, B3873) (1-Boc-piperidine-4-carboxaldehyde; 120 mg, 0.56 mmol) in MeOH (4.0 mL) (200 mg, 0.52 mmol) was added and stirred at room temperature for 1 hour using AcOH (0.5 mL) as a catalyst. Sodium cyanoborohydride (48 mg, 0.76 mmol) was added and stirred at room temperature for 1 hour until the reaction was complete, and then MeOH was evaporated. The reaction was quenched by adding water and EA. The aqueous layer was extracted with EA, and the organic layer was concentrated under reduced pressure. The crude material was purified on a silica gel column to obtain 175.8 mg of compound 28-3 as a green solid.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6 -Synthesis of diamine hydrochloride (compound 28-4)

To a solution of compound 28-3 (159 mg, 0.27 mmol) in DCM (10.0 mL) was added 4 N-HCl/dioxane (0.13 mL, 0.054 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain 137.6 mg of Compound 28-4 as a yellow solid compound.

Step 3: 5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioc Synthesis of sopiperidin-3-yl)isoindoline-1,3-dione (Compound 28)

To a solution of Compound 28-5 (WO 2020/162725) (7.0 mg, 0.018 mmol) in DMF (0.5 mL) was added HATU (21 mg, 0.056 mmol), Compound 28-4 (10 mg, 0.018 mmol) and TEA ( 10 mg, 0.090 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with EA and washed with water and brine solutions. The crude material obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 3.5 mg of compound 28 as an off-white solid.

Compound 29. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

Compound 29-1 (same as Compound 28-4) (300 mg, 0.604 mmol) in a solution of Compound 29-2 (Combi-Blocks, HD-3240) (167 mg, 0.604 mmol) in DMSO (5 mL) at room temperature. and DIPEA (234 mg, 1.18 mmol) were added. The resulting mixture was stirred at 90°C for 6 hours. Water was added to the reaction mixture, extracted with EA, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 304 mg of Compound 29 as a fluorescent green solid.

Compound 30. 5-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

HATU (21 mg, 0.056 mmol), Compound 30-1 (same as Compound 29-1) (10 mg) in a solution of Compound 30-2 (WO 2020/160198) (6.0 mg, 0.018 mmol) dissolved in DMF (0.5 mL) , 0.018 mmol), and TEA (10 mg, 0.090 mol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (15 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to obtain compound 30 (3.5 mg, 0.0040 mmol, 22%) as a white solid.

Compound 31. 5-(4-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 31-2 (WO 2020/160193) (2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- dissolved in 0.5 mL DMF HATU (28.8 mg, 0.076 mmol) and TEA (16.1 mg, 0.16 mmol) were added to the (1) piperazin-1-yl) acetic acid (8.4 mg, 0.021 mmol) solution and stirred for 10 minutes, and finally compound 31-1. (Same as Compound 29-1) (10 mg, 0.019 mmol) was added and stirred at 40°C for 16 hours. After completion of the reaction, it was diluted with DCM and washed with water. The organic layer was washed with a brine solution, and then concentrated under reduced pressure. The crude material obtained was purified on a silica gel column to obtain 4.0 mg of Compound 31 as a yellow solid.

Compound 32. 5-(4-(2-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

50% T3P/EA (34 mg, 0.034 mmol), Compound 32-1 (same as Compound 26-4) in a solution of Compound 32-2 (WO 2020/160193) (11 mg, 0.028 mmol) in DMF (0.5 mL) (10 mg, 0.018 mmol) and TEA (14 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature until the reaction was complete. TLC showed the formation of product, water was added to the reaction mixture, extracted with MC (15 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 32 (2.0 mg, 0.002 mmol, 12%) as an off-white solid.

Compound 33. 5-(4-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 33-3)

A solution of compound 33-2 (TCI, B1188) (26 mg, 0.12 mmol) in DMF (0.5 mL) was added at room temperature to EDCI (47 mg, 0.24 mmol), HOBt·H ₂ O (33 mg, 0.24 mmol), compound 33. -1 (Korean Patent No. 2128018) (50 mg, 0.12 mmol) and DIPEA (78 mg, 0.60 mmol) were added. The resulting mixture was stirred at 40°C for 2 hours. The reaction mixture was quenched with water, and the precipitate formed was filtered and washed four times with water. The precipitate was dissolved in DCM, the organic layer was concentrated under reduced pressure, and the crude mixture obtained was purified by silica gel column chromatography to obtain 70 mg of compound 33-3 as a yellow solid.

Step 2: N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide hydrochloride (Compound 33-4)

To a solution of compound 33-3 (60 mg, 0.10 mmol) in 1 mL of DCM was added 4 N-HCl/dioxane (0.050 mL, 0.20 mmol) and stirred at room temperature for 3 hours. The volatiles were evaporated, the yellow solid formed was washed with diethyl ether, and the volatiles were distilled under steam to obtain 44 mg of compound 33-4 as a yellow solid.

Step 3: 5-(4-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 33) synthesis

A solution of Compound 33-5 (WO 2020/160193) (6.9 mg, 0.018 mmol) in DMF (0.5 mL) at room temperature with 50% T3P/EA (34 mg, 0.034 mmol), Compound 33-4 (10 mg, 0.018 mmol) ) and TEA (14 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the reaction mixture, extracted with MC and washed with water and brine solutions. The crude mixture obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 5.4 mg of Compound 33 as an off-white solid.

Compound 34. 5-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethoxy)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

In a solution of Compound 34-2 (WO 2020/160198) (6.0 mg, 0.018 mmol) in DMF (0.5 mL) was added 50% T3P/EA (34 mg, 0.034 mmol), Compound 34-1 (Compound 33-4) at room temperature. (same as) (10 mg, 0.018 mmol) and TEA (14 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the mixture, extracted with MC and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 2 mg of compound 34 as an off-white solid.

Compound 35. 5-((2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl) amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyrrolidin-1-yl)-2-oxoethyl) amino)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

In a solution of Compound 35-2 (WO 2020/162725) (6.0 mg, 0.018 mmol) in DMF (0.5 mL) was added 50% T3P/EA (34 mg, 0.034 mmol), Compound 35-1 (Compound 33-4) at room temperature. (same as) (10 mg, 0.018 mmol) and TEA (14 mg, 0.14 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the reaction mixture, extracted with MC and washed with water and brine solutions. The organic layer was concentrated under reduced pressure, and the crude product was purified by MPLC to obtain 4.4 mg of Compound 35 as an off-white solid.

Compound 36. 5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione

In a solution of Compound 36-2 (WO 2020/162725) (6.0 mg, 0.018 mmol) in DMF (0.5 mL), 50% T3P/EA (35 mg, 0.056 mmol), Compound 36-1 (Compound 28-4 and same) (10 mg, 0.018 mmol) and TEA (10 mg, 0.090 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the reaction mixture, extracted with MC and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 2 mg of compound 36 as an off-white solid.

Compound 37. 3-(6-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

In a solution of Compound 37-2 (WO 2020/162725) (6.5 mg, 0.018 mmol) in DMF (0.5 mL) at room temperature, 50% T3P/EA (35 mg, 0.056 mmol), Compound 37-1 (Compound 28-4 and same) (10 mg, 0.018 mmol) and TEA (10 mg, 0.090 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours until the reaction was complete. Water was added to the reaction mixture, extracted with MC and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 6 mg of Compound 37 as an off-white solid.

Compound 38. 1-(5-(4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4( 1H,3H)-dione

Step 1: Synthesis of 3-((2-carboxyethyl)amino)-4-methoxybenzoic acid (Compound 38-3)

A suspension of compound 38-1 (TCI, A1955) (3-amino-4-methoxybenzoic acid, 5.0 g, 29 mmol) in compound 38-2 (TCI, A0141) (acrylic acid, 8.05 mL, 117 mmol) was added to 100% It was heated to °C and stirred for 10 minutes. After 10 minutes, stirring was slowed to 150 rpm and the reaction was maintained at 100°C for 3 hours. After 3 hours TLC showed completion of the reaction and the reaction was cooled to give a gray suspension which was run for the next step.

Step 2: Synthesis of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (Compound 38-4)

Acetic acid (35 mL) and urea (11.3 g, 188 mmol) were added to the residue of compound 38-3 and heated to 100°C for 12 hours. TLC showed the reaction was complete. The reaction was cooled and 150 mL of 1 N-HCl and 50 mL of water were added to the reaction. The reaction mass was kept at 5°C overnight. The reaction mass was brought to room temperature and the solid was filtered. The filter cake was digested with 50 mL 0.05 N-HCl and then washed with water. The solid was dried to obtain 3.0 g of compound 38-4 in the form of a purple solid.

Step 3: 1-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H) ,3H)-Dione (Compound 38) synthesis

To a solution of Compound 38-4 (4.7 mg, 0.018 mmol) in DMF (0.5 mL) was added HATU (21 mg, 0.056 mmol), Compound 38-5 (same as Compound 28-4) (10 mg, 0.018 mmol) and TEA (10 mg, 0.090 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with EA and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 2.5 mg of compound 38 as an off-white solid.

Compound 39. 5-(4-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)methyl)azetidine-1-carboxylate (Compound 39-3)

Compound 39-1 (Korean Patent No. 2128018) (200 mg, 0.500 mmol) and acetic acid (6 mg, 0.10 mmol) in a solution of Compound 39-2 (TCI, B5160) (102 mg, 0.550 mmol) in 25 mL of MeOH. was added and stirred for 1 hour. NaCNBH ₃ (47.2 mg, 0.750 mmol) was added to the reaction and stirred at room temperature for 4 hours. TLC showed that after the reaction was completed, the solvent was completely evaporated, and the remaining residue was dissolved in MC and washed with water. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 160 mg of compound 39-3 as a yellow solid.

Step 2: N ⁶ -(2-(azetidin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride (Compound 39-4) synthesis

To a solution of compound 39-3 (150 mg, 0.263 mmol) in 10 mL of DCM was added 4 N-HCl/dioxane (0.131 mL, 0.527 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the remaining dioxane was extracted with 20 mL CHCl ₃ . The solid was dried under vacuum to obtain 140 mg of compound 39-4 as a yellow solid.

Step 3: 5-(4-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2- Synthesis of (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 39)

HATU (20.0 mg, 0.052 mmol), Compound 39-4 (10 mg, 0.017 mmol) and TEA in a solution of Compound 39-5 (WO 2020/160193) (6.8 mg, 0.017 mmol) in DMF (0.5 mL) at room temperature. (8.6 mg, 0.085 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with DCM and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 3.0 mg of compound 39 as a green solid.

Compound 40. 5-(4-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopy) peridin-3-yl)isoindoline-1,3-dione

T3P (38 mg, 0.0.059 mmol), Compound 40-1 (same as Compound 39-4) in a solution of Compound 40-2 (WO 2020/162725) (7.3 mg, 0.019 mmol) in DMF (0.5 mL) at room temperature. (10 mg, 0.019 mmol) and TEA (9.3 mg, 0.095 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with EA and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 4.0 mg of compound 40 as a brown solid.

Compound 41. 5-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)benzyl)amino)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: N ⁶ -(3-(aminomethyl)phenyl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 41-3) synthesis

p-TSA·H ₂ O in a suspension of compound 41-1 (Korean Patent No. 2128018) (100 mg, 0.347 mmol) and compound 41-2 (TCI, A2718) (84.8 mg, 0.347 mmol) in 25 mL of IPA. (72.6 g, 0.381 mmol) was added and the reaction was heated to 90°C and stirred for 12 hours. The solid obtained from the reaction mixture was filtered and washed with ethanol (50 mL) to obtain the pTSA salt of the title compound as a yellow solid, which was later neutralized with sodium carbonate solution to obtain 95.0 mg of compound 41-3 as an off-white solid.

Step 2: tert- Butyl 3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)methyl)azetidine-1-carboxylate (Compound 41-5)

Compound 41-3 (100 mg, 0.267 mmol) and acetic acid (3.2 mg, 0.053 mmol) in a solution of Compound 41-4 (TCI, B3873) (Boc-piperidinaldehyde; 63.0 mg, 0.894 mmol) in 25 mL of MeOH. Added and stirred for 3 hours (imine generation). NaBH ₃ CN (25.2 mg, 0.400 mmol) was added to the reaction and stirred at room temperature for 1 hour. It was confirmed that the reaction was complete and the solvent was completely evaporated. The residue was dissolved in MC and washed with water. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 80.2 mg of compound 41-5 as a yellow solid.

Step 3: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(3-(((piperidin-4-ylmethyl)amino)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride (Compound 41-6) synthesis

To a solution of compound 41-5 (70 mg, 0.123 mmol) in 2 mL DCM was added 4 N-HCl/dioxane (0.123 mL, 0.246 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and the remaining dioxane was extracted with 20 mL CHCl ₃ . The solid was dried under vacuum to obtain 50 mg of compound 41-6 as a yellow solid.

Step 4: 5-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)benzyl)amino)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 41) synthesis

Compound 41-6 (10 mg, 0.019 mmol) and DIPEA (12.3 mg, 0.0950 mmol) were added to a solution of compound 41-7 (Combi-Blocks, HD-3240) (5.5 mg, 0.019 mmol) dissolved in DMSO (0.5 mL). Added at room temperature. The resulting mixture was stirred at 90°C for 16 hours. The resulting mixture was stirred at room temperature until the reaction was complete. Water was added to the reaction mixture, extracted with MC and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 3.0 mg of compound 41 as a yellow solid.

Compound 42. 5-(4-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)benzyl)amino)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

HATU (22 mg, 0.057 mmol), compound 42-1 (same as compound 41-6) (same as compound 41-6) ( 10 mg, 0.019 mmol) and TEA (10 mg, 0.095 mmol) were added. The resulting mixture was stirred at 35°C for 4 hours. Water was added to the reaction mixture, extracted with DCM and washed with water and brine solutions. The crude product obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 3.6 mg of compound 42 as a yellow solid.

Compound 43. 5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine -3-day) Isoindoline-1,3-dione

Step 1: tert- Butyl 4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)piperidine-1-carboxylate (Compound 43-3) synthesis

HATU (148.2 mg, 0.39 mmol) in a solution of compound 43-2 (BLDPharm, BD00948389) (1-( tert -butoxycarbonyl)piperidine-4-carboxylic acid; 32.8 mg, 0.14 mmol) in 1 mL DMF. and TEA (52.6 mg, 0.52 mmol) were added and stirred for 10 minutes. Finally, compound 43-1 (Korean Patent No. 2128018) (50 mg, 0.13 mmol) was added and stirred at 30°C for 12 hours. The reaction was quenched by adding 10 mL water and ice. After the reaction was quenched, the compound was filtered and washed with water. The compound was extracted using DCM, the organic layer was concentrated under reduced pressure, and the crude product was purified on a silica gel column to obtain 74.4 mg of compound 43-3 as a brown solid.

Step 2: (7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Dihydroisoquinoline-2(1H)-yl)(piperidin-4-yl)methanone hydrochloride (Compound 43-4) synthesis

To a solution of compound 43-3 (60 mg, 0.10 mmol) in DCM (3.0 mL) was added 4 N-HCl/dioxane (0.05 mL, 0.20 mmol). The reaction was stirred at room temperature for 3 hours. No starting material was observed in the TLC results. The solvent was evaporated under vacuum to obtain 46 mg of Compound 43-4 as a yellow solid.

Step 3: 5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine -3-day) Synthesis of isoindoline-1,3-dione (Compound 43)

To a solution of compound 43-5 (WO 2020/160198) (6.9 mg, 0.021 mmol) in 2 mL DMF was added HATU (28.8 mg, 0.076 mmol) and TEA (16.1 mg, 0.16 mmol) and stirred for 10 min and finally Compound 43-4 (10 mg, 0.018 mmol) was added and stirred at 35°C for 12 hours. After completion of the reaction, it was dissolved in water and ice. The compound gave a yellow solid in solution. The compound was diluted with DCM, the organic layer was concentrated under reduced pressure, and the crude material obtained was purified on a silica gel column to obtain 9.2 mg of compound 43 in the form of a light yellow solid.

Compound 44. 5-(4-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of compound 44-2 (WO 2020/160193) (8.4 mg, 0.021 mmol) in 2 mL DMF was added HATU (28.8 mg, 0.076 mmol) and TEA (16.1 mg, 0.16 mmol) and stirred for 10 min and finally Compound 44-1 (same as compound 43-4) (10 mg, 0.018 mmol) was added and stirred at 35°C for 12 hours. After completion of the reaction, the reaction was quenched with water and ice. The compound gave a yellow solid in solution. The compound was filtered and washed with water and brine solution. The compound was extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material obtained was purified on a silica gel column to obtain 4.8 mg of compound 44 in the form of a light yellow solid.

Compound 45. 5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopy) peridin-3-yl)isoindoline-1,3-dione

To a solution of compound 45-2 (WO 2020/162725) (6.9 mg, 0.021 mmol) in 2 mL DMF was added HATU (28.8 mg, 0.0757 mmol) and TEA (16.1 mg, 0.160 mmol) and stirred for 10 min and finally Compound 45-1 (same as compound 43-4) (10 mg, 0.018 mmol) was added and stirred at 35°C for 12 hours. After completion of the reaction, the reaction was quenched with water and ice. The compound gave a yellow solid in solution. The compound was filtered and washed with water and brine solution. The compound was extracted with DCM, the organic layer was concentrated under reduced pressure, and the crude material obtained was purified on a silica gel column to obtain 3.8 mg of compound 45 in the form of a light yellow solid.

Compound 46. 3-(6-((4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)-4-oxobenzo[d][1,2,3 ]triazine-3(4H)-yl)piperidine-2,6-dione

Compound 46-1 (same as compound 28-4) (10 mg, 0.018 mmol) and DIPEA (9.3 mg) in a solution of compound 46-2 (WO 2020/162725) (10 mg, 0.020 mmol) in DMSO (1.0 mL) , 0.072 mmol) was added and stirred at 90°C for 13 hours until the reaction was complete. After quenching the reaction by adding water and ice to the reaction mixture, extraction was performed with EA, the combined organic layer was washed with water and brine solution, and the crude material obtained by concentrating the organic layer under reduced pressure was purified on a silica gel column to obtain compound 46 4.6. mg was obtained in the form of a brown solid.

Compound 47. 5-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1 ,3-dione

To a solution of Compound 47-2 (Combi-Blocks, HD-3240) (8.6 mg, 0.031 mmol) in DMSO (2.0 mL) was added Compound 47-1 (same as Compound 40-1) (15 mg, 0.031 mmol) and DIPEA ( 13.4 mg, 0.104 mmol) was added and stirred at 90°C for 12 hours until the reaction was complete. The reaction was quenched by adding water and ice to the reaction mixture, extracted with DCM, the combined organic layer was washed with water and brine solution, and the crude material obtained by concentrating the organic layer under reduced pressure was purified on a silica gel column to obtain 3.5 mg of compound 47. Obtained in the form of a brown solid.

Compound 48. 3-(6-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d] [1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

To a solution of compound 48-2 (WO 2020/162725) (6.9 mg, 0.021 mmol) in 1 mL DMF was added T3P (36.3 mg, 0.0570 mmol) and TEA (16.1 mg, 0.160 mmol) and stirred for 10 min and finally. Compound 48-1 (same as compound 29-1) (10 mg, 0.019 mmol) was added and stirred at 35°C for 12 hours. After completion of the reaction, the mixture was quenched with water. The aqueous layer was extracted with DCM and the organic layer was washed with water and brine solution. The crude material obtained by concentrating the organic layer under reduced pressure was purified on a silica gel column to obtain 3.8 mg of Compound 48 in the form of a green solid.

Compound 49. 5-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine -3-day) Isoindoline-1,3-dione

To a solution of compound 49-2 (WO 2020/160198) (6.3 mg, 0.019 mmol) in 1 mL of DMF was added T3P (38 mg, 0.059 mmol) and TEA (9.6 mg, 0.095 mmol) and stirred for 10 min and finally Compound 49-1 (same as compound 40-1) (10 mg, 0.019 mmol) was added and stirred at 30°C overnight. After completion of the reaction, the reaction mixture was quenched with water. The aqueous layer was extracted with DCM, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified on a silica gel column to obtain 2.9 mg of compound 49 as a white solid.

Compound 50. 5-(3-((4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 3-((4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)methyl)azetidine-1-carboxylate (Compound 50-3) synthesis

Compound 50-1 ( Compound 29-1 (same as compound 29-1) (47.1 mg, 0.0948 mmol) was added and stirred at room temperature for 3 hours using AcOH (0.1 mL) as a catalyst (imine generation). Sodium cyanoborohydride (8.9 mg, 0.14 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water and MeOH was evaporated. The aqueous layer was extracted with EA and evaporated. The crude material was purified on a silica gel column to obtain 28.5 mg of compound 50-3 in the form of a green solid.

Step 2: N ⁶ -(2-((1-(azetidin-3-ylmethyl)piperidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 50-4) synthesis

To a solution of compound 50-3 (20 mg, 0.030 mmol) in DCM (5.0 mL) was added 4 N-HCl/dioxane (0.02 mL, 0.060 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated under vacuum to obtain 15 mg of a yellow solid compound. The compound was neutralized with NaHCO ₃ , the aqueous layer was extracted with MC, and the organic layer was concentrated under reduced pressure to obtain 16.0 mg of compound 50-4 as a white solid.

Step 3: 5-(3-((4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6- Synthesis of dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 50)

To a solution of Compound 50-5 (Combi-Blocks, HD-3240) (5.9 mg, 0.021 mmol) in DMSO (2.0 mL) was added Compound 50-4 (10 mg, 0.018 mmol) and DIPEA (7.0 mg, 0.54 mmol). did. It was stirred at 90°C for 12 hours until the reaction was complete. The reaction was quenched by adding water and ice to the reaction mixture, extracted with DCM, the organic layer was washed with water and brine solution (25 mL×3), and the organic layer was concentrated under reduced pressure. The crude material obtained was purified on a silica gel column. Thus, 6.4 mg of Compound 50 in the form of a green solid was obtained.

Compound 51. 5-((2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopy) peridin-3-yl)isoindoline-1,3-dione

T3P (32.4 mg, 0.0510 mmol) and TEA (8.6 mg, 0.085 mmol) were added to a solution of compound 51-2 (WO 2020/162725) (5.6 mg, 0.017 mmol) dissolved in 1 mL DMF, stirred for 10 minutes, and finally Compound 51-1 (same as compound 40-1) (10 mg, 0.017 mmol) was added and stirred at 30°C overnight. After completion of the reaction, the reaction was quenched with water, the aqueous layer was extracted with DCM, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified on a silica gel column to obtain 3.5 mg of Compound 51 in the form of a yellow solid.

Compound 52. 3-(6-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

To a solution of compound 52-2 (WO 2020/162725) (7.3 mg, 0.022 mmol) in 1 mL DMF was added HATU (30.4 mg, 0.0805 mmol) and TEA (16.2 mg, 0.161 mmol) and stirred for 10 min and finally. Compound 52-1 (same as compound 29-1) (10 mg, 0.020 mmol) was added and stirred at 35°C for 12 hours. After completion of the reaction, the reaction was quenched with water, extracted with DCM, and the organic layer was washed with water and brine solution. The crude material obtained by concentrating the organic layer under reduced pressure was purified on a silica gel column to obtain 6.4 mg of compound 52 in the form of an orange solid.

Compound 53. 3-(7-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine- 3(4H)-yl)piperidine-2,6-dione

Step 1: Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)-4-fluorobenzamide (Compound 53-2-C)

Compound 53-2-A (BLDpharm, MFCD00075553) (2-amino-4-fluorobenzoic acid; 12.5 g, 80.5 mmol) dissolved in DMF (150 mL) and Compound 53-2-B dissolved in DCM (50 mL) (3-aminopiperidine-2,6-dione hydrochloride; 19.9 g, 120.8 mmol) solution, EDCI·HCl (30.8 g, 161 mmol), HOBt (24.6 g, 161 mmol), DIPEA (31.3 g, 241.5 mmol) mmol) was added at room temperature and the reaction mixture was stirred for 12 hours. The reaction mixture was concentrated to remove DCM, water was added and extracted with EtOAc (2 x 450 mL) and the organic layer was washed with brine solution (2 x 250 mL), dried over sodium sulfate and concentrated under reduced pressure to give the crude product. . The crude mixture was crystallized and purified using MC and hexane (1:9) to give compound 53-2-C (18 g, 67.86 mmol, 84%) as a white solid.

Step 2: 3-(7-Fluoro-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidine-2,6-dione (Compound 53-2) synthesis

To a solution of compound 53-2-C (18 g, 67.86 mmol) in glacial acetic acid (300 mL) was added sodium nitrite (9.36 g, 135.7 mmol) and stirred at room temperature for 2 hours. The reaction was quenched and extracted with EtOAc (2×250 mL). The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The crude mixture was crystallized and purified using MC and hexane (1:9) to give compound 53-2 (16.5 g, 59.7 mmol, 88%) as a white solid.

Step 3: 3-(7-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine- Synthesis of 3(4H)-yl)piperidine-2,6-dione (Compound 53)

Compound 53-1 (same as Compound 29-1) (12 mg, 0.024 mmol) and DIPEA (9.3 mg, 0.72 mmol) were added to a solution of Compound 53-2 (8.0 mg, 0.029 mmol) dissolved in DMSO (2.0 mL). and stirred at 90°C for 4 hours until the reaction was complete. The reaction was quenched by adding water to the reaction mixture, extracted with DCM, the organic layer was washed with water and brine solution, and the crude material obtained by concentrating the organic layer under reduced pressure was purified on a silica gel column to yield 9.7 mg of Compound 53 as a bright green solid. obtained in the form

Compound 54. 5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidine-1-carbonyl) piperidin-1-yl) -2- (2,6-dioxophyll) peridin-3-yl)isoindoline-1,3-dione

HATU (22 mg, 0.057 mmol), compound 54-1 (same as compound 43-4) (10 mg) in a solution of compound 54-2 (WO 2020/162725) (8.0 mg, 0.021 mmol) in DMF (1 mL) , 0.019 mmol) and TEA (6.0 mg, 0.057 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extracted with EA, washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 6.0 mg of compound 54 as a brown solid.

Compound 55. 3-(6-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

Step 1: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-hydroxy-2-nitrobenzamide (Compound 55-2-C)

Compound 55-2-B (BLDPharm, BD170886) (glutaric acid) was added to a solution of compound 55-2-A (BLDPharm, BD21759) (5-hydroxy-2-nitrobenzoic acid; 200 mg, 1.08 mmol) in DMF (5 mL). Mead salt; 178 mg, 1.08 mmol), EDCI·HCl (228 mg, 1.18 mmol), HOBt·H ₂ O (182 mg, 1.18 mmol), and DIPEA (0.564 mL, 3.24 mmol) were added and stirred at room temperature overnight. . The reaction mixture was concentrated under vacuum and filtered twice with methanol. Afterwards, the filtrate was concentrated under vacuum to obtain an oil. The crude mixture was purified by silica gel column chromatography using 7% DCM/MeOH to yield compound 55-2-C (380 mg, mixture) as a yellow oil.

Step 2: Synthesis of 2-amino-N-(2,6-dioxopiperidin-3-yl)-5-hydroxybenzamide (Compound 55-2-D)

To a solution of compound 55-2-C (380 mg, 1.08 mmol) in MeOH (4 mL) was added 10% Pd/C (38 mg) and stirred at room temperature overnight under hydrogen gas environment. The solution was filtered through a pad of Celite and removed under vacuum to give an oil. The crude mixture was purified by silica gel column chromatography using 7% DCM/MeOH to obtain compound 55-2-D (105 mg, 0.399 mmol, 37%) as a yellow solid.

Step 3: tert- Butyl 2-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-6-yl) Oxy)acetate (compound 55-2-F) synthesis

To a solution of Compound 55-2-D (48 mg, 0.175 mmol) in DMF (1 mL) was added Compound 55-2-E (TCI, B1473) ( tert- butyl bromoacetate; 0.026 mL, 0.175 mmol), potassium carbonate ( 36 mg, 0.262 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was quenched with H ₂ O and then extracted with EtOAc. The combined organic layers were dried over MgSO ₄ and the solvent was removed under vacuum. The crude mixture was purified by silica gel column chromatography (MPLC, Hex/EtOAc 55%) to obtain compound 55-2-F (33 mg, 0.085 mmol, 48%) as a white solid.

Step 4: 2-((3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazine-6- 1) Oxy) acetic acid (compound 55-2) synthesis

A solution of compound 55-2-F (30 mg, 0.077 mmol) in 40% TFA/DCM (0.7 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to obtain compound 55-2 (33 mg, crude) as a white solid.

Step 5: 3-(6-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][ Synthesis of 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 55)

To a solution of compound 55-2 (6.6 mg, 0.021 mmol) in DMF (1 mL) was added HATU (22 mg, 0.057 mmol), compound 55-1 (same as compound 43-4) (10 mg, 0.019 mmol) and TEA ( 6.0 mg, 0.057 mmol) was added at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 5.0 mg of Compound 55 as a brown solid.

Compound 56. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

Compound 56-1 (same as compound 43-4) (10 mg, 0.019 mmol) and DIPEA (12 mg, 0.095 mmol) was added at room temperature. The resulting mixture was stirred at 90°C for 3 hours. Water was added to the reaction mixture, extracted with EA and washed with water and brine solutions. The crude material obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 6.0 mg of compound 56 as a yellow solid.

Compound 57. 3-(6-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]) pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

To a solution of Compound 57-2 (WO 2020/162725) (6.9 mg, 0.021 mmol) in DMF (1 mL) was added HATU (22 mg, 0.057 mmol), Compound 57-1 (same as Compound 43-4) (10 mg, 0.019 mmol) and TEA (6.0 mg, 0.057 mmol) were added at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 5.0 mg of Compound 57 as a brown solid.

Compound 58. 3-(6-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3 (4H)-yl)piperidine-2,6-dione

Compound 58-1 (same as compound 43-4) (10 mg, 0.019 mmol) and DIPEA (7.4 mg, 0.057 mmol) was added at room temperature. The reaction mixture was stirred at 90°C for 12 hours. Water was added to the reaction mixture, extracted with EA, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 6.0 mg of compound 58 as an off-white solid.

Compound 59. 3-(5-(4-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine- 3(4H)-yl)piperidine-2,6-dione

Compound 59-1 (same as compound 43-4) (10 mg, 0.019 mmol) and DIPEA (7.4 mg, 0.057 mmol) was added at room temperature and the resulting mixture was stirred at 90°C for 12 hours. Water was added to the reaction mixture, extracted with EA, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 12 mg of compound 59 as a yellow solid.

Compound 60. 3-(7-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidine-1-carbonyl) piperidin-1-yl) -4-oxobenzo[d ][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

Step 1: tert- Butyl 1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)p Synthesis of peridine-4-carboxylate (compound 60-1)

Compound 60-1-B (TCI, B3873) ( tert- butyl piperidine-4-) in a solution of Compound 60-1-A (same as Compound 53-2) (1.0 g, 3.62 mmol) in DMSO (10 mL) Carboxylate; 1.06 g, 5.43 mmol) and DIPEA (1.9 mL, 10.8 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was quenched with water, extracted with DCM (25 ml×2) and the organic layer was washed with saturated brine solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH/DCM to obtain compound 60-1 (1.1 g, 2.49 mmol, 69%) as a yellow solid.

Step 2: 1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazine-7-yl ) Piperidine-4-carboxylic acid (compound 60-2) synthesis

TFA (0.25 mL) was added to a solution of compound 60-1 (100 mg, 0.226 mmol) in 1 mL of DCM and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated to obtain 80.0 mg of free base compound 60-2 as a yellow fluffy solid.

Step 3: 3-(7-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidine-1-carbonyl) piperidin-1-yl) -4-oxobenzo[d ][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 60) synthesis

Compound 60-3 (same as compound 43-4) (10 mg, 0.019 mmol), HATU (23 mg, 0.060 mmol) and TEA were added to a solution of compound 60-2 (8.5 mg, 0.022 mmol) in DMF (1 mL). (6.0 mg, 0.060 mmol) was added at 30°C. The resulting mixture was stirred at 30°C for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (20 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 60 (6.0 mg, 0.015 mmol, 40%) as a yellow solid.

Compound 61. 3-(7-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

Compound 61-1 (same as Compound 29-1) (10 mg, 0.019 mmol), HATU (23) in a solution of Compound 61-2 (same as Compound 60-2) (8.5 mg, 0.022 mmol) in DMF (1 mL) mg, 0.060 mmol) and TEA (6.0 mg, 0.060 mmol) were added at 30°C and the resulting mixture was stirred at 30°C for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (20 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 61 (7.0 mg, 0.015 mmol, 42%) as a yellow solid.

Compound 62. 3-(5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

Step 1: tert- Butyl 1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-5-yl)p Synthesis of Peridine-4-carboxylate (Compound 62-2-C)

To a solution of compound 62-2-A (WO 2020/162725) (1.0 g, 3.62 mmol) in DMSO (10 mL) was added compound 62-2-B (TCI, B3873) ( tert- butylpiperidine-4-car). Boxylate; 1.06 g, 5.43 mmol) and DIPEA (1.9 mL, 10.8 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was quenched with water, extracted with DCM (25 mL×2), and the organic layer was washed with saturated brine solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH/DCM to obtain compound 62-2-C (1.1 g, 2.49 mmol, 69%) as a yellow solid.

Step 2: 1-(3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazine-5-yl ) Piperidine-4-carboxylic acid (compound 62-2) synthesis

To a solution of compound 62-2-C (100 mg, 0.226 mmol) in 1 mL of DCM was added 4 N HCl/1,4-dioxane (1.0 mL) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, neutralized with NaHCO ₃ (aq), and extracted with DCM to obtain 80.0 mg of compound 62-2 as a yellow solid.

Step 3: 3-(5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 62) synthesis

To a solution of compound 62-2 (8.4 mg, 0.022 mmol) in DMF (1 mL) was added HATU (22 mg, 0.057 mmol), compound 62-1 (same as compound 29-1) (10 mg, 0.020 mmol) and TEA ( 6.0 mg, 0.057 mmol) was added at 30°C and the resulting mixture was stirred at 30°C for 12 hours. Water was added to the reaction mixture, extracted with DCM, the organic layer was washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 5.0 mg of Compound 62 as an off-white solid.

Compound 63. 3-(7-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

Step 1: tert- Butyl (3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)glycinate (Compound 63-1) synthesis

Compound 63-1-B (BLDPharm, BD22001) ( tert- butyl glycinate; 64) in a solution of Compound 63-1-A (same as Compound 53-2) (90 mg, 0.325 mmol) in DMSO (2 mL) mg, 0.487 mmol) and DIPEA (0.17 mL, 0.975 mmol) were added. The reaction mixture was stirred at 90° C. for 2 hours. The reaction mixture was quenched with water, extracted with DCM (25 mL×2) and the organic layer was washed with saturated brine solution. The combined organic layers were concentrated under reduced pressure to obtain a crude mixture, which was purified by column chromatography using MeOH/DCM to obtain compound 63-1 (90 mg, 0.232 mmol, 71%) as a yellow solid.

Step 2: (3-(2,6-dioxopiperidin-3-yl)-4-oxo-3,4-dihydrobenzo[d][1,2,3]triazin-7-yl)glycine (Compound 63-2) synthesis

TFA/DCM (0.5 mL) was added to a solution of compound 63-1 (50 mg, 120 mmol) in 10 mL of DCM and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated, and the residue was extracted and concentrated with CHCl ₃ to obtain 38.0 mg of compound 63-2 as a yellow fluffy solid.

Step 3: 3-(7-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[ d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 63) synthesis

HATU (22 mg, 0.057 mmol), compound 63-3 (same as compound 29-1) (10 mg, 0.019 mmol) and TEA were added to a solution of compound 63-2 (7.2 mg, 0.022 mmol) in DMF (1 mL). (6.0 mg, 0.057 mmol) was added at 30°C and the resulting mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extracted with DCM, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 3.5 mg of compound 63 as a brown solid.

Compound 64. 3-(4-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-3-oxopropyl)-1-oxoisoindoline-2- 1) Piperidine-2,6-dione

HATU (23.0 mg, 0.060 mmol), Compound 64-2 (WO 2020/051235) (6.3 mg, 0.020 mmol) and TEA (11.0 mg, 0.080 mmol) were added and the resulting mixture was stirred at room temperature for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with MC (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 64 (7.0 mg, 0.0088 mmol, 44%) as a brown solid.

Compound 65. 3-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

HATU (33 mg, 0.87 mmol), Compound 65-1 (Korean Patent No. 2128018) (10 mg, 0.029 mmol) and TEA (12 mg, 0.12 mmol) were added and the resulting mixture was stirred at room temperature for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 65 (9.0 mg, 0.012 mmol, 44%) as a brown solid.

Compound 66. 5-(3-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

To a solution of Compound 66-2 (Combi-Blocks, HD-3240) (7.73 mg, 0.028 mmol) in DMSO (1 mL) was added Compound 66-1 (same as Compound 67-4) (15.0 mg, 0.028 mmol) and DIPEA ( 14.5 mg, 0.11 mmol) was added and the resulting mixture was stirred at 90°C for 6 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (50 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 66 (4.0 mg, 0.053 mmol, 18%) as a yellow solid.

Compound 67. 5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyrrolidine-1-carbonyl) piperidin-1-yl) -2- (2,6-dioxophyll) peridin-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,2 ,3,4-Tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carboxylate (Compound 67-3) synthesis

To a solution of compound 67-2 (Sigma aldrich, 706590) (1-( tert -butoxycarbonyl)pyrrolidine-3-carboxylic acid; 30.0 mg, 0.137 mmol) in DMF (1 mL) was added HATU (143 mg). , 0.375 mmol), Compound 67-1 (Korean Patent No. 2128018) (50.0 mg, 0.125 mmol) and TEA (50.5 mg, 0.500 mmol) were added, and the resulting mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extracted with EA, washed with water and brine solutions, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 71 mg of compound 67-3 as a brown solid.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6 -Synthesis of diamine hydrochloride (compound 67-4)

To a solution of compound 67-3 (60.0 mg, 0.100 mmol) in 1.0 mL of DCM was added 4 N-HCl/dioxane (0.5 mL) and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was evaporated and residual dioxane was extracted with CHCl ₃ . The reaction product was neutralized with aqueous sodium bicarbonate solution, extracted with DCM, and the organic layer was concentrated under reduced pressure to obtain 45 mg of compound 67-4 as a yellow fluffy solid.

Step 3: 5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyrrolidine-1-carbonyl) piperidin-1-yl) -2- (2,6-dioxophyll) Synthesis of peridin-3-yl)isoindoline-1,3-dione (compound 67)

A solution of Compound 67-4 (10.7 mg, 0.0281 mmol) in DMF (1 mL) was added with HATU (31.9 mg, 0.0843 mmol), Compound 67-5 (WO 2020/162725) (15.0 mg, 0.0281 mmol) and TEA (14.5 mg). , 0.112 mmol) was added and the resulting mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 6.0 mg of Compound 67 as a white solid.

Compound 68. 3-(7-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d ][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione

HATU (22 mg, 0.057 mmol), compound 68-1 (same as compound 43-4) (10 mg, 0.019 mmol) and TEA (6.0 mg, 0.057 mmol) were added at room temperature and the resulting mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 10.8 mg of Compound 68 as a yellow solid.

Compound 69. 3-(7-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3 (4H)-yl)piperidine-2,6-dione

Compound 69-1 (same as Compound 43-4) (10 mg, 0.019 mmol) and DIPEA (12) in a solution of Compound 69-2 (same as Compound 53-2) (5.8 mg, 0.019 mmol) in DMSO (1 mL) mg, 0.095 mmol) was added at room temperature and the resulting mixture was stirred at 90°C for 3 hours. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 4.5 mg of compound 69 as a yellow solid.

Compound 70. 5-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 70-1 (Korean Patent No. 2128018) (20.0 mg, 0.0402 mmol) and DIPEA ( 16.0 mg, 0.120 mmol) was added at room temperature and the resulting mixture was stirred at 90°C for 6 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (10 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified on MPLC using 5% MeOH/MC (eluting at 4%) to give compound 70 (20.0 mg, 0.0305 mmol, 75%) as a fluorescent green solid.

Compound 71. 3-(7-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6 -Dion

Compound 71-1 (Korean Patent No. 2128018) (20.0 mg, 0.0402 mmol) and DIPEA (16.0 mg, 0.0402 mmol) were added to a solution of Compound 71-2 (same as Compound 53-2) (11.1 mg, 0.0402 mmol) in DMSO (0.5 mL). mg, 0.120 mmol) was added at room temperature and the resulting mixture was stirred at 90°C for 6 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (10 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 5% MeOH/MC to obtain compound 71 (18.0 mg, 0.0274 mmol, 68%) as a fluorescent green solid.

Compound 72. 5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dion

HATU (23.0 mg, 0.060 mmol), compound 72-2 (WO 2020/162725) (6.3 mg, 0.020 mmol) and TEA (11.0 mg, 0.080 mmol) were added and the resulting mixture was stirred at room temperature for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with MC (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC to give compound 72 (30 mg, 0.042 mmol, 84%) as a neon green solid.

Compound 73. 5-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) isoindolin-2-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione

Step 1: tert- Butyl 4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)isoindoline -2-yl)methyl)piperidine-1-carboxylate (Compound 73-1-C) synthesis

Compound 73-1-B (TCI, B3873) (Boc-piperidine aldehyde; 56.0 mg) in a solution of compound 73-1-A (Korean Patent No. 2128018) (92.0 mg, 0.0239 mmol) in MeOH (1 mL) , 0.263 mmol) and acetic acid (2.73 ㎕, 0.2 mmol) were added and stirred for 2 hours. NaCNBH ₃ (22.5 mg, 0.195 mmol) was added to the reaction mixture and stirred for 3 hours. TLC showed the reaction was complete and the solvent was completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified under MPLC using 5% MeOH in DCM to give compound 73-1-C (70.0 mg, 0.120 mmol, 70%) as a black solid.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(Piperidin-4-ylmethyl)isoindolin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-3,6-diamine (Compound 73-1) synthesis

To a solution of compound 73-1-C (60 mg, 0.103 mmol) in DCM (5 mL) was added 4 N HCl/1,4-dioxane (360 μl, 0.360 mmol) and stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, neutralized with NaHCO ₃ (aq.), and extracted with DCM (20 mL×3). The organic layer was evaporated under vacuum to obtain compound 73-1 (26 mg, 0.140 mmol, 53%) as a brown solid.

Step 3: 5-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) isoindolin-2-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 73) synthesis

Compound 73-1 (10.0 mg, 0.020 mmol) and DIPEA (8.0 mg, 0.062 mmol) in a solution of Compound 73-2 (Combi-Blocks, HD-3240) (5.5 mg, 0.020 mmol) in DMSO (5 mL). It was added at room temperature and the resulting mixture was stirred at 90°C for 3 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (50 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified on MPLC using 10% MeOH/MC (eluting at 4%) to give compound 73 (9.0 mg, 0.012399 mmol, 58%) as a yellow solid.

Compound 74. 3-(7-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)isoindolin-2-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperi Din-2,6-dione

Compound 74-1 (same as Compound 73-1) (12.0 mg, 0.024 mmol) and DIPEA (0.072 mmol) in a solution of Compound 74-2 (same as Compound 53-2) (6.8 mg, 0.024 mmol) in DMSO (0.5 mL) mg, 9.32 mmol) was added at room temperature and the resulting mixture was stirred at 90°C for 3 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (10 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified on MPLC using 10% MeOH/MC (eluting at 4%) to give compound 74 (1.6 mg, 0.0021 mmol, 10%) as a yellow solid.

Compound 75. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-(hydroxymethyl)piperidin-1-yl)isoindoline-1,3-dione (Compound 75 -3) Synthesis

Compound 75-2 (TCI, P1653) (200 mg, 1.73 mmol) and DIPEA ( 372 mg, 519 mmol) was added and the resulting mixture was stirred at 90°C for 1 hour. Water was added to the reaction mixture, extraction was performed with EA, the organic layer was washed with water and brine solution, and the organic layer was concentrated under reduced pressure. The crude material obtained was purified by MPLC to obtain 440 mg of compound 75-3 as a yellow solid.

Step 2: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (Compound 75-4 ) synthesis

To a solution of oxalyl chloride (256 mg, 0.673 mmol) in DCM (25 mL) at -78°C, DMSO (315 mg, 4.03 mmol) dissolved in DCM was added dropwise. To this mixture, compound 75-3 (250 mg, 0.673 mmol) dissolved in DCM (5 mL) was added dropwise and stirred for 10 minutes, and TEA (612 mg, 6.05 mmol) was added thereto until the reaction was completed. It was stirred at room temperature for 1 hour. The reaction mixture was washed with water, the aqueous solution was extracted with EA, the organic layer was washed with water and brine solution, and the crude material obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 110 mg of compound 75-4 as a yellow solid. .

Step 3: 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Synthesis of isoindoline-1,3-dione (compound 75)

Compound 75-5 (Korean Patent No. 2128018) (20 mg, 0.048 mmol) and acetic acid were added to a solution of Compound 75-4 (20 mg, 0.053 mmol) in 0.5 mL of MeOH, stirred for 1 hour, and NaCNBH ₃ (4.5 mg, 0.072 mmol) was added and stirred at room temperature for 12 hours. The solvent in the reaction mixture was completely evaporated, and the residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The crude material obtained by concentrating the organic layer under reduced pressure was purified by MPLC to obtain 3.5 mg of compound 75 as a yellow solid.

Compound 76. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-(2-methoxyethoxy)-2,6- dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)p peridin-1-yl)isoindoline-1,3-dione

To a solution of Compound 76-2 (WO 2020/162725) (8.5 mg, 0.23 mmol) in 0.5 mL of MeOH, Compound 76-1 (Korean Patent No. 2128018) (10 mg, 0.021 mmol) and drops of acetic acid were added and incubated for 1 hour. It was stirred for a while. NaCNBH ₃ (2.0 mg, 0.031 mmol) was added to the reaction and stirred for 12 hours. TLC showed the reaction was complete and the solvent was completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by MPLC using 5% MeOH/MC to give compound 76 (3.5 mg, 0.0012 mmol, 20%) as a yellow solid.

Compound 77. 5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-2'-( 2,6-dioxopiperidin-3-yl)-[2,5'-biisoindoline]-1',3'-dione

Compound 77-2 (Combi-Blocks, HD-3240) (14.3 mg, 0.0519 mmol) and DIPEA in a solution of Compound 77-1 (Korean Patent No. 2128018) (20.0 mg, 0.0519 mmol) dissolved in DMSO (0.5 mL) (26.9 μL, 0.156 mmol) was added at room temperature and the resulting mixture was stirred at 90°C. After 2 hours, the reaction mixture was extracted with water and DCM (80 mL×3) and then washed with brine (50 mL×2). Compound 77 (9.9 mg, 0.0154 mmol, 30%) was obtained as a yellow solid using MPLC (5% MeOH in MC, gradient).

Compound 78. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl )Isoindoline-1,3-dione

Add compound 78-1 (Korean Patent No. 2128018) (10 mg, 0.022 mmol) and drops of acetic acid to a solution of compound 78-2 (WO 2020/051564) (9.0 mg, 0.024 mmol) in 10 mL of MeOH and leave for 1 hour. It was stirred for a while. NaCNBH ₃ (2.0 mg, 0.033 mmol) was added to the reaction and stirred at room temperature for 12 hours. The residue from which the solvent of the reaction mixture was completely removed was dissolved in MC, washed with water and saturated sodium bicarbonate solution, and the organic layer was concentrated under a steam pressure. The crude material obtained was purified by MPLC to obtain 7.0 mg of compound 78 as a yellow solid.

Compound 79. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

To a solution of compound 79-1 (same as compound 29) (25 mg, 0.0332 mmol) in DMF (1 mL) was added iodomethane (4.24 mg, 0.0298 mmol) followed by cesium carbonate (21.6 mg, 0.0664 mmol). did. The reaction mixture was stirred at room temperature for 12 hours. TLC showed that a new spot was formed, the reaction was quenched with water and the aqueous layer was extracted with EtOAc (25 mL×2), the combined organic layers were washed with water and brine solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to yield compound 79 (20.0 mg, 0.0260 mmol, 78%) as a yellow crystalline solid.

Compound 80. 3-(5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxoisoindoline -2-yl)piperidine-2,6-dione

To a solution of compound 80-2 (WO 2020/162725) (14.0 mg, 0.044 mmol) in DMF (2 mL) was added HATU (45.6 mg, 0.120 mmol), compound 80-1 (same as compound 29-1) (20.0 mg, 0.0402 mmol) and TEA (20.3 mg, 0.201 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours until the reaction was complete. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 5% MeOH/MC to obtain compound 80 (6.0 mg, 0.040 mmol, 19%) as an off-white solid.

Compound 81. 3-(5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

HATU (57.0 mg, 0.150 mmol), compound 81-1 (Korean Patent No. 2128018) (20 mg) in a solution of compound 81-2 (WO 2020/162725) (17.5 mg, 0.0550 mmol) in DMF (2 mL) , 0.0500 mmol) and TEA (25.2 mg, 0.250 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours until the reaction was complete. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 5% MeOH/MC to give compound 81 (11 mg, 0.0157 mmol, 31%) as an off-white solid.

Compound 82. 5-(4-((7-((3-((2,6-dichlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

Compound 82-2 (WO 2020/051564) (18.5 mg, 0.0499 mmol) was added to a solution of Compound 82-1 (Korean Patent No. 2128018) (20.0 mg, 0.0454 mmol) dissolved in MeOH (1 mL) with acetic acid (0.519 ㎕). , 0.00908 mmol) and stirred for 1 hour. NaCNBH ₃ (4.28 mg, 0.0681 mmol) was added to the reaction and stirred at room temperature for 2 days. Water was added to the reaction mixture and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using 5% MeOH in DCM to give compound 82 (18.9 mg, 0.0455 mmol, 88%) as a yellow solid.

Compound 83. 5-(4-((7-((3-((2,4-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

Compound 83-2 (WO 2020/051564) (23.4 mg, 0.0499 mmol) was added to a solution of compound 83-1 (Korean Patent No. 2128018) (23.0 mg, 0.0576 mmol) in MeOH (1 mL) with acetic acid (0.658 μl, 0.0115 mmol) and stirred for 12 hours. NaCNBH ₃ (5.43 mg, 0.0864 mmol) was added to the reaction and stirred at room temperature for 2 hours. Water was added to the reaction mixture and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using 80% EA in hex to give compound 83 (11.2 mg, 0.0149 mmol, 26%) as a yellow solid.

Compound 84. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((1-methyl-3-(o-tolylamino)-1H-pyrazolo[3 ,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

Compound 84-2 (WO 2020/051564) (21.1 mg, 0.0571 mmol) was added to a solution of Compound 84-1 (Korean Patent No. 2128018) (20.0 mg, 0.0518 mmol) dissolved in MeOH (1 mL) with acetic acid (0.593 ㎕). , 0.0104 mmol) and stirred for 12 hours. NaCNBH ₃ (4.89 mg, 0.0778 mmol) was added to the reaction and stirred at room temperature for 6 hours. Water was added to the reaction mixture and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using 80% EA in hexane to give compound 84 (33.6 mg, 0.0455 mmol, 88%) as a yellow solid.

Compound 85. 5-(4-((7-((3-((2-chloro-6-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione

Compound 85-2 (WO 2020/051564) (10.6 mg, 0.0288 mmol) was added to a solution of Compound 85-1 (Korean Patent No. 2128018) (11.0 mg, 0.0262 mmol) dissolved in MeOH (1 mL) with acetic acid (0.299 ㎕). , 0.0104 mmol) and stirred for 2 hours. NaCNBH ₃ (4.89 mg, 0.0393 mmol) was added to the reaction and stirred at room temperature for 6 hours. Water was added to the reaction mixture and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using 5% MeOH in DCM to give compound 85 (4.10 mg, 0.00530 mmol, 20%) as a yellow solid.

Compound 86. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione

Compound 86-2 (WO 2020/051564) (23.4 mg, 0.0499 mmol) was added to a solution of compound 86-1 (Korean Patent No. 2128018) (23.0 mg, 0.0576 mmol) in MeOH (1 mL) with acetic acid (0.658 μl, 0.0115 mmol) and stirred for 12 hours. NaCNBH ₃ (5.43 mg, 0.0864 mmol) was added to the reaction and stirred at room temperature for 2 hours. Water was added to the reaction mixture and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by silica gel column chromatography using 5% MeOH in DCM to give compound 86 (2.00 mg, 0.00256 mmol, 10%) as a yellow solid.

Compound 87. 5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dion

Step 1: Synthesis of 2,2,2-trifluoroacetaldehyde compound with azetidin-3-one (compound 87-2)

Compound 87-1 (TCI, B3988) (1-( tert- butoxycarbonyl)-3-azetidinone; 200 mg, 1.168 mmol) was added to 40% TFA/DCM (6/9 mL) and incubated at room temperature. Stirred for 2 hours. After the reaction was over, the reaction mixture solvent was evaporated under vacuum, and the white precipitate was collected by filtration and washed with ether. If impurities were not removed, the crude mixture was purified by MPLC using 70% EA/HEX to give compound 87-2 (196 mg, 1.166 mmol, 99%) as an ivory oil.

Step 2: 2-(2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) synthesis

Compound 87-3 (Combi-Blocks, HD-3240) (2-(2,6-dioxopiperidine-3) dissolved in DMSO in a solution of Compound 87-2 (196 mg, 1.166 mmol) in DMSO (2 mL) -yl)-5-fluoroisoindoline-1,3-dione; 258 mg, 0.934 mmol) was added. Then DIPEA (0.8 mL, 4.664 mmol) was added. The reaction mixture was stirred at 90° C. for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×30 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 60% EA/HEX to give compound 87-4 (91 mg, 0.278 mmol, 44%) as a yellow solid.

Step 3: 5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Synthesis of dione (compound 87)

Compound 87-5 (Korean Patent No. 2128018) (30 mg, 0.0764 mmol) and AcOH (4.0 μl, 0.0764 mmol) were added to a solution of compound 87-4 (25 mg, 0.0764 mmol) in DMF (1 mL). And the reaction mixture was stirred at room temperature for 12 hours. Afterwards, sodium triacetoxyborohydride (24 mg, 0.113 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and NaHCO ₃ , a brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated under vacuum and purified on MPLC using 5% MeOH/MC to give compound 87 (15 mg, 0.0021 mmol, 28%) as an off-white solid.

Compound 88. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dion

Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3-dione (Compound 88-3) synthesis

Compound 88-1 (Combi-Blocks, HD-3240) (2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO (5 mL) ; 300 mg, 1.09 mmol) Compound 88-2 (Sigma aldrich, 841672) (4-piperidone monohydrate hydrochloride; 167 mg, 1.09 mmol) and DIPEA (0.8 mL, 4.344 mmol) were added to the solution at room temperature. The reaction mixture was stirred at 90° C. for 12 hours, quenched with water, extracted with EtOAc (3×50 mL) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered and evaporated under vacuum. The crude mixture was purified on MPLC using 5% MeOH/EtOAc to give compound 88-3 (155 mg, 0.436 mmol, 40%) as a yellow solid.

Step 2: 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Synthesis of dione (compound 88)

To a solution of compound 88-3 (50 mg, 0.141 mmol) in DMF (1 mL) was added a solution of compound 88-4 (Korean Patent No. 2128018) (56 mg, 0.141 mmol) in DMF (141 μl, 0.141 mmol) at room temperature. 1 M AcOH was added. The reaction mixture was stirred at room temperature for 12 hours and then sodium triacetoxyborohydride (45 mg, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, quenched with water and NaHCO ₃ (aq), and extracted with EtOAc (3×15 mL). The combined organic layer was washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The cured mixture was purified on MPLC using 5% MeOH/MC to yield compound 88 (25.0 mg, 0.0338 mmol, 24%) as a yellow solid.

Compound 89. 5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dion

Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-(3-oxopyrrolidin-1-yl)isoindoline-1,3-dione (Compound 89-3) synthesis

Compound 89-1 (Combi-Blocks, HD-3240) (2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione in DMSO (2 mL); To a solution of 127 mg, 0.461 mmol) was added compound 89-2 (Combi blocks, OS-1284) (pyrrolidin-3-one HCl salt; 70 mg, 0.576 mmol). Then DIPEA (0.4 mL, 2.304 mmol) was added. The reaction mixture was stirred at 90° C. for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×50 mL), and then washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated under vacuum and purified on MPLC using 5% MeOH/EA to give compound 89-3 (40 mg, crude) as a yellow solid.

Step 2: 5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Synthesis of dione (compound 89)

Compound 89-3 (18 mg, 0.053 mmol) and AcOH (2.0 μl, 0.035 mmol) were added to a solution of compound 89-4 (Korean Patent No. 2128018) (14 mg, 0.035 mmol) in DMF (1 mL). did. The reaction mixture was stirred at room temperature for 12 hours, then sodium triacetoxyborohydride (11 mg, 0.053 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and after the reaction was completed, it was quenched with water, extracted with EA (3×15 mL), and washed with water (3×) and NaHCO ₃ , a brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 89 (9.6 mg, 0.0132 mmol, 24%) as a yellow solid.

Compound 90. 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)acetamide

Step 1: Synthesis of 2-chloro-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)acetamide (Compound 90-3)

To a suspension of compound 90-1 (WO 2019/148055) (100 mg, 0.367 mmol) in THF (2 mL) was added compound 90-2 (Sigma, 104493) (chloroacetylchloride; 124 mg, 1.10 mmol). The reaction mixture was stirred at 70° C. for 12 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with EA (25 mL×2), the combined organic layers were dried over sodium sulfate, and the solvent was evaporated under vacuum to obtain compound 90-3 (61.0 mg, 0.175 mmol, 48%) as slightly impure. Obtained as a bright green solid.

Step 2: 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-5-yl)acetamide (Compound 90)

To a solution of compound 90-4 (same as compound 29-1) (20.0 mg, 0.040 mmol) in DMF (1 mL) was added compound 90-3 (12.6 mg, 0.360 mmol) and DIPEA (15.6 mg, 0.121 mmol). did. The reaction mixture was stirred at 80° C. for 12 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), the combined organic layers were washed with water (15 mL×2) and brine (15 mL×3) and the crude mixture was washed with 5% MeOH. Purified under MPLC. Compound 90 (11.0 mg, 0.014 mmol, 34%) was obtained as a brown solid using DCM as a solvent mixture.

Compound 91. 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)acetamide

Step 1: tert- Butyl 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Synthesis of -3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)acetate (Compound 91-3)

Compound 91-2 (TCI, B1473) ( tert- butyl bromoacetate; 38.7 mg, 0.201 mmol) in a solution of Compound 91-1 (same as Compound 29-1) (50.0 mg 0.100 mmol) in DCM (2 mL) and 37% NaOH (2 mL) was added followed by TBAB (32.3 mg, 0.100 mmol) and the reaction mixture was stirred at room temperature for 5 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2). The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give compound 91-3 (39 mg, 0.0640 mmol, 63%) as a brown solid.

Step 2: 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Synthesis of amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)acetic acid (Compound 91-4)

Compound 91-3 (35.0 mg, 0.057 mmol) was dissolved in 40% TFA/DCM (1 mL) and stirred for 12 hours. TLC showed that the reaction was complete, and the solvent was completely evaporated to give compound 91-4 (18.0 mg, 0.032 mmol, 57%) as a brown solid. The crude material was taken without further purification.

Step 3: 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1-oxoisoindolin-5-yl)acetamide (Compound 91)

HATU (20.5 mg, 0.0540 mmol), Compound 91-5 (WO 2019/148055) (7.01 mg, 0.0270 mmol) and TEA (10.9 mg) in a solution of Compound 91-4 (15.0 mg, 0.0270 mmol) in DMF (2 mL) , 0.108 mmol) was added at room temperature and stirred at room temperature for 12 hours. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), the combined organic layers were washed with water (15 mL×2) and brine (15 mL×3) and the crude mixture was washed with 5% MeOH/DCM. Compound 91 (9.1 mg, 0.011 mmol, 42.3%) was obtained as a brown solid using a solvent mixture.

Compound 92. 4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p Peridine-1-carboxamide

To a suspension of compound 92-1 (WO 2019/148055) (20.0 mg, 0.0771 mmol) in DCM (5 mL) was added triphosgene (115 mg, 0.385 mmol) and TEA (39.0 mg, 0.385 mmol) and incubated at room temperature for 6 days. Stirred for an hour. The solvent was completely evaporated under vacuum to obtain isocyanate intermediate compound 92-2. THF (5 mL) was added to intermediate compound 92-2, and compound 92-3 (same as compound 29-1) (38.2 mg, 0.0771 mmol) and TEA (15.5 mg, 0.0154 mmol) were added to this solution, and 40 Stirred at °C for 1 hour. TLC showed the reaction was complete, the reaction was quenched with water and extracted with EA (25 mL×3), the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The crude mixture was purified on MPLC using 10% MeOH:MC to give compound 92 (17.0 mg, 0021 mmol 28%) as a white solid.

Compound 93. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl )Isoindoline-1,3-dione

HATU (38.0 mg, 0.100 mmol), compound 93-2 (WO 2020/160193) (20.0 mg, 0.0501 mmol) and TEA (10.9 mg, 0.108 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), the combined organic layers were washed with water (15 mL×2) and brine (15 mL×3) and the crude mixture was washed with 5% MeOH/DCM. Compound 93 (17.0 mg, 0.011 mmol, 42.3%) was obtained as a brown solid using a solvent mixture.

Compound 94. 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acet amides

Step 1: tert- Butyl 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Synthesis of dihydroisoquinoline-2(1H)-yl)acetate (Compound 94-3)

Compound 94-2 (TCI, B1473) ( tert- butyl bromoacetate; 53.7 mg) in a solution of compound 94-1 (Korean Patent No. 2128018) (100 mg, 0.250 mmol) dissolved in THF (10 mL) at 0°C. , 0.275 mmol) was added, followed by TEA (50.6 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 4 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2). The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to give a mixture of compound 94-3 (100 mg, 0.275 mmol, 78%) as a brown solid.

Step 2: 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 , Synthesis of 4-dihydroisoquinoline-2(1H)-yl)acetic acid (Compound 94-4)

Compound 94-3 (95.0 mg, 0.184 mmol) was added to a 7 mL vial, 40% TFA/DCM (5 mL) was added and stirred for 16 hours, and TLC showed that the reaction was complete. The solvent was completely evaporated under vacuum and the residue was washed with diethyl ether to obtain compound 94-4 (78.0 mg, 0.170 mmol, 67%) as a yellow solid.

Step 3: 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acet Synthesis of amide (compound 94)

HATU (24.9 mg, 0.100 mmol), Compound 94-5 (WO 2019/136016) (12.1 mg, 0.0330 mmol) and TEA (13.2) were added to a solution of Compound 94-4 (15.0 mg, 0.0330 mmol) in DMF (2 mL). mg, 0.131 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC showed that the reaction did not proceed and a new spot was formed. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), and the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to give compound 94 (7.0 mg, 0.00982 mmol, 30%) as a white solid.

Compound 95. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione

HATU (24.9 mg, 0.0660 mmol), compound 95-2 (WO 2020/160192) (11.2 mg) in a solution of compound 95-1 (same as compound 103-4) (15.0 mg, 0.0330 mmol) in DMF (2 mL) , 0.0330 mmol) and TEA (13.2 mg, 0.131 mmol) were added at room temperature and stirred at room temperature for 12 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL×2), the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2), and the combined organic layers were dried over sodium sulfate and placed under vacuum. The solvent was evaporated. The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to give compound 95 (7.0 mg, 0.00982 mmol, 30%) as a white solid.

Compound 96. 7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(2 -(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

To a suspension of compound 96-1 (WO 2020/012337) (20.0 mg, 0.0771 mmol) in DCM (5 mL) was added triphosgene (115 mg, 0.385 mmol) and TEA (15.5 mg, 0.0154 mmol) and incubated at room temperature for 6 days. Stirred for an hour. The solvent was completely evaporated under vacuum to obtain isocyanate intermediate compound 96-2. THF (5 mL) was added to intermediate compound 96-2, and compound 96-3 (Korean Patent No. 2128018) (30.8 mg, 0.0771 mmol) and TEA (15.5 mg, 0.0154 mmol) were added to this solution, and 40 Stirred at °C for 1 hour. TLC showed the reaction was complete, the reaction was quenched with water and extracted with EA (25 mL×3), the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 10% MeOH/MC and later recrystallized using MC and diethyl ether as a solvent mixture to obtain compound 96 (16 mg, 0.0233 mmol, 30%) as a white solid. .

Compound 97. 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-N-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- 1) Piperidine-4-1) Acetamide

HATU (16.6 mg, 0.0442 mmol), Compound 97-2 (WO 2021/058017) (7.79 mg) in a solution of Compound 97-1 (same as Compound 103-4) (10.0 mg, 0.0221 mmol) in DMF (2 mL) , 0.0221 mmol) and TEA (8.84 mg, 0.0870 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours and TLC showed that new spots were formed. The reaction was quenched with 10 mL of water and extracted with DCm (15 mL×2), the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2), the combined organic layers were dried over sodium sulfate, and the solvent was removed. Evaporate under vacuum. The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to yield compound 97 (11.0 mg, 0.0142 mmol, 63%) as a green solid.

Compound 98. 3-(5-(((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2, 6-Dion

Step 1: 2-Chloro-1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Synthesis of amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 98-3)

Compound 98-2 (Sigma, 104493) (chloroacetyl chloride; 53.7 mg, 0.0826 mmol) was added to a solution of compound 98-1 (Korean Patent No. 2128018) (30.0 mg, 0.0751 mmol) dissolved in THF (5 mL) at room temperature. was added and the reaction mixture was stirred at room temperature for 4 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2). The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to give a mixture of compound 98-3 (24.0 mg, 0.0505 mmol, 67%) as a yellow solid.

Step 2: 3-(5-(((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2, Synthesis of 6-dione (Compound 98)

A solution of Compound 98-3 (10.0 mg, 0.0210 mmol) in ACN (2 mL) was added with Sodium Carbonate (5.80 mg, 0.0420 mmol), Compound 98-4 (WO 2019/136016) (7.80 mg, 0.0210 mmol) and KI (0.697). mg, 0.00420 mmol) was added at room temperature. The resulting mixture was stirred at 80°C for 4 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL×2), the combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH/DCM as solvent mixture to give compound 98 (7.0 mg, 0.0142 mmol, 63%) as a white solid.

Compound 99. 7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(( 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide

To a suspension of compound 99-1 (WO 2019/136016) (15.0 mg, 00410 mmol) in 2 mL of DMF was added TEA (8.21 mg, 0.0820 mmol), CDI (6.58 mg, 0.0490 mmol) and stirred at room temperature for 4 hours. did. Later, compound 99-2 (Korean Patent No. 2128018) (10.0 mg, 0.490 mmol) was added and stirred at 80°C for 12 hours. TLC showed that a new spot was formed, and the reaction was quenched with water and extracted with EA (25 mL×2). The combined organic layers were washed with water (20 mL×3) and brine solution (20 mL×3), dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 9:1 MC:MeOH as solvent mixture to give compound 99 (11.0 mg, 0.0410 mmol, 39%) as an off-white solid.

Compound 100. N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide

Step 1: tert- Synthesis of butyl 4-((4-nitrophenethyl)carbamoyl)piperidine-1-carboxylate (Compound 100-3)

To a suspension of compound 100-1 (Combi-blocks, OR-2197) (2-(4-nitrophenyl)ethane-1-amine hydrochloride; 500.0 mg, 2.46 mmol) in DMF (5 mL) was added TEA (995.0 mg, 9.48 mmol) was added followed by HATU (1.87 g, 4.92 mmol) at room temperature and the reaction mixture was stirred for 15 minutes. Compound 100-2 (BLDPharm, BD00948389) (1-( tert -butoxycarbonyl)piperidine-4-carboxylic acid; 565.0 mg, 2.46 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. did. The crude reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (2 x 10 mL), dried over MgSO ₄ and concentrated under vacuum to give the crude mixture, which was purified by column chromatography using EA/Hex 50% to give the compound. 100-3 (565 mg, 1.49 mmol, 60%) was obtained as a purple solid.

Step 2: tert- Synthesis of butyl 4-((4-aminophenethyl)carbamoyl)piperidine-1-carboxylate (Compound 100-4)

To a solution of compound 100-3 (200 mg, 0.529 mmol) in EtOAc (5 mL) was added 10% Pd/C (20 mg). The resulting mixture was shaken in a Parr reactor under conditions of room temperature, 35 psi, H ₂ (g) for 12 hours. TLC indicated completion of the reaction, Pd/C was removed using a Celite filter and the combined filtrate was concentrated to give compound 100-4 (160 mg, 0.460 mmol, 87%) as a white solid.

Step 3: N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl ) Synthesis of piperidine-4-carboxamide (compound 100-6)

Compound 100-5 (Korean Patent No. 2128018) (82.3 mg, 287 mmol) and PTSA·H ₂ O (60.0 mg, 0.315 mmol) was added and the reaction was heated to 90°C and stirred for 12 hours. TLC showed completion of the reaction. The solvent was evaporated and the residue was diluted with water, acidified with 1 N HCl and washed with DCM, the aqueous layer was basified with saturated NaHCO ₃ (aq) and the aqueous layer was extracted with DCM (50 mL×2). The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the product 100-6 (80.0 mg, 0.160 mmol, 55%) as a yellow solid.

Step 4: N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide (Compound 100) Synthesis

Compound 100-7 (Combi-Blocks, HD-3240) (11.0 mg, 0.040 mmol) and DIPEA (15.5 mg, 0.120 mmol) were added to a suspension of compound 100-6 (20.0 mg, 0.040 mmol) in DMSO (1 mL). The reaction was heated to 90°C and stirred for 14 hours. TLC showed completion of the reaction. The reaction solvent was diluted with water and the aqueous layer was extracted with EA (20 mL×3), the combined organic layers were dried over sodium sulfate, filtered, the solvent was evaporated under reduced pressure and the crude mixture was subjected to column chromatography using DCM/MeOH 5%. By purification, compound 100 (4.02 mg, 0.005 mmol, 13%) was obtained as a yellow solid.

Compound 101. N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl )-1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine -4-carboxamide

Compound 101-2 (WO 2020/038415) (10.50 mg, 0.030 mmol) and DIPEA (11.6 mg) in a suspension of Compound 101-1 (same as Compound 100-6) (15.0 mg, 0.030 mmol) in DMSO (1 mL) , 0.090 mmol) was added and the reaction was heated to 90°C and stirred for 16 hours. TLC showed completion of the reaction. The reaction was washed with water, the aqueous layer was extracted with EA (20 mL×3), the combined organic layers were dried over sodium sulfate, filtered, the solvent was evaporated under reduced pressure, and the crude mixture was subjected to column chromatography using DCM/MeOH 5%. Purification gave compound 101 (14.0 mg, 0.0172 mmol, 57%) as a purple solid.

Compound 102.N ⁴ -(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-N1- (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1,4-dicarboxamide

A suspension of compound 102-1 (WO 2020/01233) (15.0 mg, 0.057 mmol) in DCM (5 mL) was charged with triphosgene (85.74 mg, 0.289 mmol) and TEA (29.21 mg, 0.289 mmol) and the reaction was incubated at room temperature. It was stirred for 6 hours. TLC showed completion of the reaction. The intermediate compound 102-2 obtained by evaporating the reaction solvent was dissolved in THF, and a solution of compound 102-3 (same as compound 100-6) (28.42 mg, 0.057 mmol) dissolved in THF and TEA (11.52 mg, 0.114 mmol) were added to rb. and the reaction was stirred at 40°C for 1 hour. TLC showed completion of the reaction. The reaction solvent was diluted with water and the aqueous layer was extracted with EA (20 mL×3), the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure and the crude mixture was evaporated under reduced pressure and washed with DCM/MeOH 5% The product was purified by column chromatography to obtain Compound 102 (12 mg, 0.015 mmol, 26%) as a yellow solid.

Compound 103. 3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, 6-Dion

Step 1: 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 , Synthesis of 4-dihydroisoquinoline-2(1H)-yl)acetic acid (Compound 103-4)

Step 1-1. tert- Butyl 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Synthesis of dihydroisoquinoline-2(1H)-yl)acetate (Compound 103-3)

Compound 103-2 (TCI, B1473) ( tert- butyl bromoacetate; 12 μl, 0.083 mmol) was added to a solution of compound 103-1 (Korean Patent No. 2128018) (30 mg, 0.075 mmol) dissolved in THF (1 mL). ) was added, and then TEA (21 μl, 0.150 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was quenched with water, extracted with EA (3×10 mL), and washed with water (3×). The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 103-3 (26 mg, 0.051 mmol, 67%) as a pale yellow oil.

Steps 1-2. 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Synthesis of dihydroisoquinoline-2(1H)-yl)acetic acid (Compound 103-4)

A solution of compound 103-3 (26 mg, 0.051 mmol) was added to 40% TFA/DCM (0.4/0.6 mL) and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was over, the reaction mixture solvent was evaporated under vacuum, and the white precipitate was collected by filtration and washed with ether. The wet product was vacuum dried to yield compound 103-4 (19 mg, 0.034 mmol, 68%) as a pale yellow solid.

Step 2: 3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2, Synthesis of 6-dione (Compound 103)

Step 2-1. Synthesis of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 103-7)

Compound 103-6 (BLDPharm, BD170886) in a solution of Compound 103-5 (TCI, M2941) (methyl 4-bromo-2-(bromomethyl)benzoate; 1 g, 3.25 mmol) in DMF (5 mL) (3-aminopiperidine-2,6-dione hydrochloride; 588 mg, 3.57 mmol) and potassium carbonate (1.3 g, 9.74 mmol) were added at room temperature. The resulting mixture was stirred at 110°C for 3 hours. TLC showed the formation of product, water was added to the reaction mixture and cooled to 0°C. The solid formed was filtered and washed with water. The wet product was vacuum dried to yield compound 103-7 (856 mg, 2.649 mmol, 82%) as a gray solid.

Step 2-2. 3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 103-8) synthesis

To a solution of compound 103-7 (200 mg, 0.62 mmol) in DMF (1 mL) was added SEMCl (0.13 mL, 0.74 mmol) and DBU (0.14 mL, 0.93 mmol). The reaction mixture was stirred at room temperature for 5 hours, and after the reaction was completed, it was quenched with NH ₄ Cl, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 50% EA/HEX to give compound 103-8 (179 mg, 0.39 mmol, 64%) as an ivory solid.

Steps 2-3. tert- Butyl 4-(2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine Synthesis of -1-carboxylate (compound 103-10)

To a solution of Compound 103-8 (100 mg, 0.221 mmol) in dioxane (5 mL) was added Compound 103-9 (TCI, B2415) (1-Boc-piperazine; 49 mg, 0.265 mmol), cesium carbonate (223 mg, 0.684 mmol), RuPhos (21 mg, 0.044 mmol), and RuPhos Pd G2 (34 mg, 0.044 mmol) were added. The reaction mixture was stirred at 100°C for 16 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 50% EA/HEX to give compound 103-10 (56 mg, 0.100 mmol, 45%) as an ivory solid.

Steps 2-4. 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione and 2,2,2-trifluoroacetaldehyde compound (1: 1) Synthesis of (Compound 103-11)

Compound 103-10 (56 mg, 0.100 mmol) was added to 40% TFA/DCM (1.6/2.4 mL). The reaction mixture was stirred at room temperature for 3 hours and after the reaction was over, the reaction mixture solvent was evaporated under vacuum, and the white precipitate was collected by filtration and washed with ether. The wet product was vacuum dried to yield compound 103-11 (32 mg, 0.097 mmol, 97%) as a pale yellow solid.

Steps 2-5. 3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Synthesis of (Compound 103)

To a solution of Compound 103-4 (19 mg, 0.034 mmol) in DMF (1 mL) was added Compound 103-11 (12 mg, 0.038 mmol), EDCl (16 mg, 0.085 mmol), HOBt (7 mg, 0.051 mmol), DIPEA. (24 μl, 0.137 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 103 (6 mg, 0.008 mmol, 23%) as a pale yellow solid.

Compound 104. 3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperi Din-2,6-dione

Step 1: tert- Synthesis of butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetate (Compound 104-3)

Compound 104-2 (TCI, B1473) ( tert- butyl bromoacetate; 13 μl, 0.090 mmol) in a solution of Compound 104-1 (same as Compound 103-11) (27 mg, 0.082 mmol) in THF (1 mL). After addition, TEA (23 μl, 0.164 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was quenched with water, extracted with EA (3×10 mL), and washed with water (3×). The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 104-3 (11 mg, 0.025 mmol, 31%) as an ivory oil.

Step 2: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)acetic acid and 2,2 , Synthesis of 2-trifluoroacetaldehyde compound (1:1) (Compound 104-4)

Compound 104-3 (11 mg, 0.025 mmol) was added to 40% TFA/DCM (0.4/0.6 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was over, the reaction mixture solvent was evaporated under vacuum, and the white precipitate was collected by filtration and washed with ether. The wet product was vacuum dried to give compound 104-4 (10 mg, 0.021 mmol, 83%) as an ivory solid.

Step 3: 3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperi Synthesis of Dean-2,6-dione (Compound 104)

Compound 104-5 (Korean Patent No. 2128018) (8 mg, 0.021 mmol), HATU (16 mg, 0.041 mmol), TEA ( 9 μl, 0.062 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 104 (5 mg, 0.007 mmol, 32%) as an off-white solid.

Compound 105. 3-(5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Step 1: tert- Butyl 2-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-5-yl)oxy ) Synthesis of acetate (compound 105-3)

Compound 105-1 (same as Compound 103-8) (3-(5-bromo-1-oxoisoindolin-2-yl)-1-((2-( Trimethylsilyl) ethoxy) methyl) piperidine-2,6-dione; 100 mg, 0.22 mmol), compound 105-2 (oakwood, 222563) ( tert- butyl 2-hydroxyacetate; 29 mg, 0.22 mmol) , (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (25 mg, 0.022 mmol), NiCl ₂ (glyme) (24 mg, 0.11 mmol), dtbbpy (30 mg, 0.11 mmol). 2,2,6,6-Tetramethylpiperidine (38 μl, 0.22 mmol) was added to the solution and the resulting mixture was stirred vigorously overnight at room temperature under the irradiation of blue LED light. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and then washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 50% EA/HEX to give compound 105-3 (61 mg, 0.121 mmol, 55%) as an off-white solid.

Step 2: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)oxy)acetic acid (Compound 105-4)

Compound 105-3 (60 mg, 0.12 mmol) was added to 40% TFA/DCM (3 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was over, the reaction mixture solvent was evaporated under vacuum, and the white precipitate was collected by filtration and washed with ether. The wet product was vacuum dried to yield compound 105-4 (15 mg, 0.047 mmol, 79%) as an ivory solid.

Step 3: 3-(5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (compound 105) synthesis

Compound 105-4 (20 mg, 0.06 mmol), HATU (48 mg, 0.13 mmol), TEA ( 36 μl, 0.19 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and then washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 105 (7 mg, 0.010 mmol, 17%) as an off-white solid.

Compound 106. 3-(5-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperi Din-2,6-dione

Compound 106-1 (same as compound 116-5) (23 mg, 0.07 mmol) and EDCI (14 mg, 0.07 mmol), HOBt (10 mg, 0.07 mmol), and DIPEA (37 uL, 0.210 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and then washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 10% MeOH/MC to give compound 106 (8 mg, 0.010 mmol, 15%) as an off-white solid.

Compound 107. (3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2, 6-dioxopiperidin-1-yl)methyl pivalate

To a solution of compound 107-1 (same as compound 29) (25 mg, 0.0332 mmol) in DMF (1 mL) was added compound 107-2 (TCI, P1012) (chloromethylpivalate; 4.24 mg, 0.0298 mmol). Cesium carbonate (21.6 mg, 0.0664 mmol) and TBAI (2.45 mg, 0.0664 mmol) were then added. The reaction mixture was stirred at room temperature for 1 hour. TLC showed that a new spot was formed, the reaction was quenched with water and the aqueous layer was extracted with EtOAc (25 mL×2), the combined organic layers were washed with water and brine solution, and the organic layer was dried over sodium sulfate. The solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH/DCM as eluent to yield compound 107 (14.0 mg, 0.0161 mmol, 48%) as a yellow crystalline solid.

Compound 108. 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide

Step 1: tert- Butyl 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Synthesis of dihydroisoquinoline-2(1H)-yl)acetate (Compound 108-3)

Compound 108-2 (TCI, B1473) ( tert- butyl bromoacetate; 26.5 mg, 0.137 mmol) was added followed by TEA (25.2 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 4 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2). The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give a mixture of compound 108-3 as a brown solid.

Step 2: 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 , Synthesis of 4-dihydroisoquinoline-2(1H)-yl)acetic acid (Compound 108-4)

Compound 108-3 (40.0 mg, 0.0779 mmol) was added to 40% TFA/DCM (2 mL) in a 7 mL vial and stirred for 16 hours, and TLC showed that the reaction was complete. The solvent was completely evaporated under vacuum and the residue was washed with diethyl ether to obtain compound 108-4 (28.0 mg, 0.061 mmol, 78%) as a yellow solid.

Step 3: 2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (compound 108) synthesis

To a solution of compound 108-4 (10.0 mg, 0.0218 mmol) in DMF (2 mL) was added HATU (16.5 mg, 0.0436 mmol), compound 108-5 (WO 2020/01233) (5.66 mg, 0.0218 mmol) and TEA at room temperature. added from The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new point has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2), the combined organic layers were dried over sodium sulfate, and the solvent was removed. Evaporate under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give compound 108 (7.0 mg, 0.0100 mmol, 45%) as a white solid.

Compound 109. 5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

Step 1: tert- Butyl 4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)methyl)piperidine-1-carboxylate (Compound 109-3)

Compound 109-1 (Korean Patent No. 2128018) (80.0 g, 0.200 mmol) and acetic acid in a solution of Compound 109-2 (TCI, B3873) (Boc-piperidine aldehyde; 46.9 mg, 0.200 mmol) in 5 mL of MeOH. One drop was added and stirred for 1 hour. NaCNBH ₃ (24.0 mg, 0.400 mmol) was added to the reaction and stirred at room temperature for 12 hours. TLC showed the reaction was complete and the solvent was completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified by MPLC using 10% MeOH/MC to give compound 109-3 (80.0 mg, 0.134 mmol, 67%) as a yellow solid.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6 -Synthesis of diamine (compound 109-4)

To a solution of compound 109-3 (80.0 mg, 0.134 mmol) in 5 mL of DCM, 4 N HCl/dioxane (0.083 mL, 0.335 mmol) was added at room temperature and stirred for 1 hour. TLC indicated completion of the reaction. The solvent was completely evaporated under vacuum. The residue was dissolved in 15 mL of water and washed with DCM (15 mL×2), the aqueous layer was basified with sodium bicarbonate powder and the aqueous layer was extracted with DCM (20 mL×3). The combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum to give compound 109-4 (56.0 mg, 0.112 mmol, 84%) as an off-white solid.

Step 3: 5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- Synthesis of 1,3-dione (Compound 109)

Compound 109-4 (10.0 mg, 0.0201 mmol) and DIPEA (6.09 mg, 1.08 mmol) were added to a solution of Compound 109-5 (Combi-Blocks, HD-3240) (5.56 mg, 0.0201 mmol) in DMSO (1 mL). Added at room temperature. The resulting mixture was stirred at 90°C for 12 hours. TLC showed the formation of new spots, water was added to the reaction mixture, extracted with EA (30 mL×3) and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum to give the crude mixture. The crude mixture was purified by MPLC using 5% MeOH:MC as solvent mixture to give compound 109 (3.0 mg, 0.00398 mmol, 19%) as a brown solid.

Compound 110. 5-((2-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione

HATU (15.3 mg, 0.0402 mmol), compound 110-2 (WO 2020/162725) (5.66 mg) in a solution of compound 110-1 (same as compound 109-4) (10.0 mg, 0.0201 mmol) dissolved in DMF (2 mL) , 0.0218 mmol) and TEA (8.81 mg, 0.0872 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicated that a new spot had been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL×2), the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2), the combined organic layers were dried over sodium sulfate and vacuum. The solvent was evaporated. The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give compound 110 (8.0 mg, 0.00987 mmol, 49%) as a white solid.

Compound 111. 1-(5-(4-(2-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine -2,4(1H,3H)-dione

HATU (19.0 mg, 0.0500 mmol), compound 111-2 (same as compound 112-4) (9.75 mg, 0.0250 mmol) in a solution of compound 111-1 (Korean Patent No. 2128018) (10.0 mg, 0.0250 mmol) in DMF (2 mL) mg, 0.0250 mmol) and TEA (7.58 mg, 0.0750 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicated that a new spot had been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL×2), the combined organic layers were washed with water (20 mL×2) and brine (20 mL×2) and the combined organic layers were dried over sodium. Sulfuric acid and solvent were evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give compound 111 (11.0 mg, 0.00142 mmol, 57%) as a brown solid.

Compound 112. 1-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine -2,4(1H,3H)-dione

Step 1: tert- Butyl 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetate (Compound 112-3) synthesis of

To a solution of compound 112-1 (WO 2019/186358) (300 mg, 1.14 mmol) in 10 mL DMF was added HATU (1.30 g, 3.52 mmol) and DIPEA (590 mg, 4.56 mmol) and stirred for 10 min and finally Compound 112-2 (BLDPharm, BD27827) ( tert- butyl 2-(piperidin-4-yl)acetate; 300 mg, 1.14 mmol) was added and stirred at 30°C for 12 hours. The reaction was quenched by adding 10 mL water and ice. After the reaction was quenched, the compound was extracted with EA and washed with water. The compound was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified on a silica gel column and eluted with a 10% MeOH:DCM solvent mixture to obtain compound 112-3 (71 mg, 0.159 mmol, 14%) as an off-white solid.

Step 2: 2-(1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidin-4-yl)acetic acid (compound Synthesis of 112-4)

A suspension of compound 112-3 (4.41 g, 9.98 mmol) in DCM (24 mL) was stirred with TFA (16 mL) at 40°C for 3 hours. TLC showed completion of the reaction, volatiles were evaporated under vacuum and residual solvent was removed with a high vacuum pump to give compound 112-4 (60 mg, 9.90 mmol, 99%) as a yellow solid.

Step 3: 1-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine Synthesis of -2,4(1H,3H)-dione (Compound 112)

HATU (28.5 mg, 0.0750 mmol) and DIPEA (16.2 mg, 0.125 mmol) were added to a solution of compound 112-5 (Korean Patent No. 2128018) (10 mg, 0.0250 mmol) in 1 mL DMF and stirred for 10 minutes. Finally, compound 112-4 (10.7 mg, 0.0275 mmol) was added at room temperature. After stirring at 40°C for 2 hours, the reaction was quenched by adding 10 mL water and ice. After the reaction was quenched, a white precipitate was observed. The off-white solid was filtered to obtain Compound 112 (17 mg, 0.0221 mmol, 88%) in the form of an off-white solid.

Compound 113. N-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-meth Toxibenzamide

Step 1: tert- Synthesis of butyl (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)glycinate (Compound 113-3)

Compound 113-2 (TCI, G0254) ( tert- butyl glycinate·HCl; 248 mg, 1.89) in a solution of Compound 113-1 (same as Compound 112-1) (500 mg, 1.89 mmol) in DMF (10 mL) mmol), HOBt (384 mg, 2.84 mmol), EDCI (544 mg, 2.84 mmol), DIPEA (1.6 mL, 9.45 mmol), and the reaction mixture was stirred at room temperature for 13 hours. The reaction mixture was quenched with water and then extracted with EA (3×30 mL). The combined organic layer was sat. NaCl (aqueous) solution, dried over Na ₂ SO ₄ and solvent removed in vacuo. The crude mixture was purified by column chromatography using 5% MeOH in DCM to give compound 113-3 (638 mg, 1.69 mmol, 89%) as a white solid.

Step 2: Synthesis of (3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)glycine (Compound 113-4)

To a solution of compound 113-3 (625 mg, 1.66 mmol) in DCM (2 mL) was added 40% TFA/DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated and ether was added to form a solid, which was then purified to obtain compound 113-4 (532 mg, 1.41 mmol, 100%) as a white solid.

Step 3: N-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-meth Synthesis of Toxybenzamide (Compound 113)

Compound 113-5 (Korean Patent No. 2128018) (64.0 mg, 0.156 mmol), HOBt (32.5 mg, 0.240 mmol), EDCI ( 46.0 mg, 0.240 mmol), DIPEA (138 μl, 0.801 mmol), and the reaction mixture was heated from room temperature to 40 degrees and stirred for 17 hours. The reaction mixture was quenched with water and then extracted with EA (3×30 mL). The combined organic layer was sat. NaCl (aqueous) solution, dried over Na ₂ SO ₄ and solvent removed in vacuo. The crude mixture was purified by column chromatography using 5% MeOH in DCM to afford compound 113 (110 mg, 98%) as a white solid.

Compound 114. N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl )-1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine -4-carboxamide

Step 1: tert- Butyl 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-carboxylate (Compound 114-2-C) synthesis

To a suspension of compound 114-2-B (Combi-Blocks, QK-3943) ( tert- butyl piperidine-4-carboxylate; 126 mg, 0.681 mmol) in DMF (5 mL) was added DIPEA (293 mg, 2.26 mg) mmol) followed by the addition of HATU (574 mg, 1.51 mmol) at room temperature and the reaction mixture was stirred for 15 min. Compound 114-2-A (WO 2019/186358) (200 mg, 0.756 mmol) was added and the reaction mixture was allowed to stir at room temperature for 14 hours. Residual solvent was evaporated under vacuum. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give a crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 114-2-C (205 mg, 0.475 mmol, 69%) as a white substance. Obtained as a solid.

Step 2: Synthesis of 1-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoyl)piperidine-4-carboxylic acid (Compound 114-2)

Compound 114-2-C (200 mg, 0.463 mmol) was added to 40% TFA/DCM (10 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction solvent was completely evaporated and the crude material was triturated with ether and dried under vacuum to obtain compound 114-2 (102 mg, 0.271 mmol, 58%) as an ivory solid.

Step 3: N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl )-1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine -4-Carboxamide (Compound 114) synthesis

To a suspension of compound 114-2 (16.0 mg, 0.0413 mmol) in DMF (2 mL) was added DIPEA (15.0 mg, 0.112 mmol) followed by HATU (29.0 mg, 0.0750 mmol) at room temperature and the reaction mixture was stirred for 15 min. give. Compound 114-1 (Korean Patent No. 2128018) (15.0 mg, 0.0375 mmol) was added, and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL of water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 114 (7.70 mg, 0.0101 mmol, 28%) as a beige solid. did.

Compound 115. 3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperazin-1-yl) -1-oxoisoindolin-2-yl) piperidine-2,6-dione

To a solution of compound 115-1 (same as 103-11) (20 mg, 0.047 mmol) in DCM (5 mL) was added triphosgene (70 mg, 0.235 mmol), Et ₃ N (33 μl, 0.235 mmol). . The reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was completely evaporated under vacuum to obtain an isocyanate intermediate. THF (5 mL) was added to the intermediate, and compound 115-2 (Korean Patent No. 2128018) (19 mg, 0.047 mmol) and Et ₃ N (13 μl, 0.094 mmol) were added to this solution. The reaction mixture was stirred at 40° C. for 1 hour. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 115 (3 mg, 0.004 mmol, 9%) as a white solid.

Compound 116. 3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperi Din-2,6-dione

Step 1: 3-(6-Bromo-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (Compound 116- 2) Synthesis of

To a solution of compound 116-1 (WO 2020/160192) (1 g, 3.095 mmol) in DMF (6 mL) was added 2-(trimethylsilyl)ethoxymethylchloride (SEMCl; 1 mL, 5.570 mmol), 1,8- Diazabicyclo(5,4,0)undec-7-ene (DBU; 1 mL, 6.808 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. After the reaction was over, it was quenched with NH ₄ Cl, extracted with EA (3×30 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 50% EA/HEX to give compound 116-2 (556 mg, 1.226 mmol, 40%) as an off-white solid.

Step 2: tert- Butyl 4-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-3-oxoisoindolin-5-yl)oxy ) Synthesis of piperidine-1-carboxylate (compound 116-4)

Compound 116-3 (TCI, B2671) ( tert- butyl 4-hydroxypiperidine-1-carboxylate; 44 mg, 0.221) in a solution of Compound 116-2 (100 mg, 0.221 mmol) in MeCN (3 mL). mmol), (Ir[dF(CF ₃ )ppy] ₂ (dtbpy))PF ₆ (25 mg, 0.022 mmol), NiCl ₂ (glyme) (24 mg, 0.110 mmol), dtbbpy (30 mg, 0.110 mmol), 2,2,6,6-tetramethylpiperidine (38 ㎕, 0.221 mmol) was added and nitrogen gas was purged. The reaction mixture was stirred at room temperature for 16 hours under a blue LED. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate and filtered, the solvent was evaporated under vacuum and purified by MPLC using 50% EA/HEX to give compound 116-4 (44 mg, 0.077 mmol, 35%) as a yellow oil.

Step 3: 3-(1-oxo-6-(piperidin-4-yloxy)isoindolin-2-yl)piperidine-2,6-dione and 2,2,2-trifluoroacet Synthesis of aldehyde compound (1:1) (compound 116-5)

Compound 116-4 (58 mg, 0.101 mmol) was added to 40% TFA/DCM (1.6/2.4 mL). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated and the beige solid formed was washed with diethyl ether and concentrated in vacuo to give compound 116-5 (45 mg, 0.102 mmol, quant.) as a beige solid.

Step 4: 3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperi Synthesis of Din-2,6-dione (Compound 116)

To a solution of Compound 116-5 (10 mg, 0.022 mmol) in DMF (1 mL) was added Compound 116-6 (same as Compound 103-4) (10 mg, 0.022 mmol), HATU (17 mg, 0.044 mmol), Et ₃ N (9 μl, 0.066 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and then washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 116 (9 mg, 0.011 mmol, 53%) as a yellow solid.

Compound 117. 3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)oxy)-1-oxoisoindoline-2- 1) Piperidine-2,6-dione

Step 1: tert- Butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)piperidin-1-yl)acetate (Compound 117- 3) Synthesis of

Compound 117-2 (TCI, B1473) ( tert- butyl bromoacetate; 13 μl, 0.087 mmol) in a solution of Compound 117-1 (same as Compound 116-5) (35 mg, 0.079 mmol) in THF (1 mL) ) was added. Afterwards, Et ₃ N (22 μl, 0.159 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was quenched with water, extracted with EA (3×10 mL), and washed with water (3×). The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 117-3 (8 mg, 0.017 mmol, 22%) as an off-white solid.

Step 2: 2-(4-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)oxy)piperidin-1-yl)acetic acid Synthesis of (Compound 117-4)

Compound 117-3 (8 mg, 0.017 mmol) was added to 40% TFA/DCM (0.4/0.6 mL). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated and the ivory solid formed was washed with diethyl ether and concentrated under vacuum to obtain compound 117-4 (5 mg, 0.012 mmol, 71%) as an ivory solid.

Step 3: 3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)oxy)-1-oxoisoindoline-2- 1) Synthesis of piperidine-2,6-dione (Compound 117)

Compound 117-5 (Korean Patent No. 2128018) (5 mg, 0.012 mmol), HATU (9 mg, 0.025 mmol), and Et ₃ were added to a solution of Compound 117-4 (5 mg, 0.012 mmol) in DMF (1 mL). N (5 μl, 0.037 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was washed with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 117 (7 mg, 0.009 mmol, 72%) as a yellow solid.

Compound 118. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-methoxy-2-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Doline-1,3-dione

Step 1: Synthesis of 6-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (Compound 118-1-C)

Compound 118-1-A (Combi-block, QA-6971) (6-chloro-1H-pyrazolo[3,4-d]pyrimidine; 2 g, 12.94 mmol, 1.0 eq.) in DMF (30 mL) Compound 118-1-B (TCI, I0074) (4.4 g, 19.41 mmol, 1.5 eq.) was added to the solution at room temperature. The mixture was stirred at 80° C. for 3 hours. After cooling to ambient temperature, the solvent was evaporated in vacuo. Water was then added to ethyl acetate, and the solution was washed with saturated ammonium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained solid was filtered, washed with ether and dried to give compound 118-1-C (2.6 g, 72%) as an ivory solid.

Step 2: Synthesis of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (Compound 118-1-D)

To a solution of compound 118-1-C (2.6 g, 9.27 mmol, 1.0 eq.) in DMF (10 mL) was added NaH (449 mg, 11.12 mmol, 1.2 eq.) at 0°C. The reaction mixture was stirred at 0°C for 15 minutes. Methyl iodide (1.15 mL, 18.54 mmol, 2.0 eq.) was added to the reaction mixture at 0°C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 118-1-D (2.5 g, 91%) as an ivory solid.

Step 3: 2,2,2-trifluoro-1-(7-((3-iodo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Synthesis of 3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 118-1)

Compound 118-1-D (1 g, 3.4 mmol, 1.0 eq.) was added to a solution of Compound 118-1-E (Korean Patent No. 2128018) (830 mg, 3.4 mmol, 1.0 eq.) in 0.08 M HCl/ethoxyethanol. .) was added at room temperature. The reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 118-1 (1.05 g, 61%) as an ivory solid.

Step 4: 2,2,2-trifluoro-1-(7-((3-((4-methoxy-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]Synthesis of pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 118-3)

To a solution of compound 118-1 (50 mg, 0.1 mmol, 1.0 eq.) in toluene (2 mL) was added Cs ₂ CO ₃ (326 mg, 1.0 mmol, 10 eq.), Pd ₂ (dba) ₃ (4.6 mg, 0.005 mmol, 0.05 eq.), Xantphos (9.3 mg, 0.016 mmol, 0.16 eq.), Compound 118-2 (TCI, M1474) (4-methoxy-2-methylaniline; 13 μl, 0.1 mmol, 1.0 eq.) was added under nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 118-3 (38 mg, 71%) as a brown solid.

Step 5: N ³ -(4-methoxy-2-methylphenyl)-1-methyl-N ⁶ Synthesis of -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 118-4)

To a solution of compound 118-3 (30 mg, 0.059 mmol, 1 eq) in THF (1 mL)/MeOH (0.5 mL)/H ₂ O (0.5 mL) was added LiOH·H ₂ O (6.2 mg, 0.147 mmol, 2.5 eq). ) was added and stirred at room temperature for 2 hours. After checking TLC, the reaction was quenched with water and extracted with EA. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum to yield compound 118-4 (27 mg, quant.) as a brown solid.

Step 6: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-methoxy-2-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Synthesis of doline-1,3-dione (compound 118)

To a solution of Compound 118-4 (15 mg, 0.036 mmol, 1.0 eq.) in MeOH (1 mL) was added Compound 118-5 (WO 2020/051564) (15 mg, 0.040 mmol), 1 M in MeOH (36 μL). AcOH was added and stirred at room temperature for 12 hours. NaCNBH ₃ (3.4 mg, 0.054 mmol, 1.5 eq.) was added to the reaction, stirred at room temperature for 2 hours, quenched with water, and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 5% MeOH/MC as an eluent to obtain compound 118 (13 mg, 47%) as a yellow solid.

Compound 119. 5-(4-((7-((3-((2,3-dihydro-1H-inden-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-1) Isoindoline-1,3-dione

Step 1: 1-(7-((3-((2,3-dihydro-1H-inden-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one (Compound 119-3)

Pd 2 in a solution of Cs ₂ CO ₃ (326 mg, 1.0 mmol, 10 eq.) in a solution of Compound 119-1 (same as Compound 118-1) (50 mg, 0.1 mmol, 1.0 eq.) in toluene ( ₂ mL) (dba) ₃ (4.6 mg, 0.005 mmol, 0.05 eq.), 1.0 eq.) was added under nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using 30% EA/HEX as eluent to obtain compound 119-3 (35 mg, 69%) as a yellow solid.

Step 2: N ³ -(2,3-dihydro-1H-inden-4-yl)-1-methyl-N ⁶ Synthesis of -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 119-4)

Compound 119-3 (30 mg, 0.0591 mmol, 1.0 eq.) and LiOH·H ₂ O (6.2 mg, 0.148 mmol, 2.5 eq.) in THF (1 mL)/MeOH (0.5 mL ₎ /H 2 O (0.5 mL) .) was stirred at room temperature for 2 hours. TLC was checked, the reaction was quenched with water and extracted with EA. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum to give compound 119-4 (15 mg, 63%) as a yellow solid.

Step 3: 5-(4-((7-((3-((2,3-dihydro-1H-inden-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-day) Synthesis of isoindoline-1,3-dione (Compound 119)

To a solution of Compound 119-4 (15 mg, 0.0365 mmol, 1.0 eq.) in MeOH (1 mL) was added Compound 119-5 (WO 2020/051564) (15 mg, 0.0402 mmol), 1M AcOH in MeOH (36.5 μL). Added and stirred for 12 hours. NaCNBH ₃ (3.4 mg, 0.054 mmol, 1.5 eq.) was added to the reaction, stirred at room temperature for 2 hours, quenched with water, and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 5% MeOH/MC as an eluent to obtain compound 119 (3.3 mg, 12%) as a yellow solid.

Compound 120. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((2-fluoro-4-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Doline-1,3-dione

Step 1: 2,2,2-trifluoro-1-(7-((3-((2-fluoro-4-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]Synthesis of pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 120-3)

Cs ₂ CO ₃ (326 mg, 1.0 mmol, 10 eq.), Pd ₂ ( dba) ₃ (4.6 mg, 0.005 mmol, 0.05 eq.), Xantphos (9.3 mg, 0.016 mmol, 0.16 eq.), Compound 120-2 (TCI, F0529) (2-fluoro-4-methylaniline; 11 μl , 0.1 mmol, 1.0 eq.) was added under nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 120-3 (18 mg, 36%) as a yellow solid.

Step 2: N ³ -(2-fluoro-4-methylphenyl)-1-methyl-N ⁶ Synthesis of -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 120-4)

Compound 120-3 (18 mg, 0.036 mmol, 1.0 eq.) and LiOH·H ₂ O (4 mg, 0.090 mmol, 2.5 eq.) in THF (1 mL)/MeOH (0.5 mL ₎ /H 2 O (0.5 mL) .) was stirred at room temperature for 2 hours. After checking TLC, the reaction was quenched with water and extracted with EA. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum to yield compound 120-4 (14 mg, quant.) as a yellow solid.

Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((2-fluoro-4-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Synthesis of doline-1,3-dione (compound 120)

Compound 120-5 (WO 2020/051564) (14 mg, 0.039 mmol) in a solution of Compound 120-4 (14 mg, 0.035 mmol, 1.0 eq.) in MeOH (1 mL), 1 M AcOH in MeOH (35 μL). was added and stirred for 12 hours. NaCNBH ₃ (3.3 mg, 0.053 mmol, 1.5 eq.) was added to the reaction, stirred at room temperature for 2 hours, quenched with water, and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 5% MeOH/MC as an eluent to obtain compound 120 (14 mg, 53%) as a yellow solid.

Compound 121. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Dolin-1,3-dione

Step 1: 2,2,2-trifluoro-1-(7-((3-((4-fluoro-2-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]Synthesis of pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one (Compound 121-3)

Cs ₂ CO ₃ (326 mg, 1.0 mmol, 10 eq.), Pd ₂ ( dba) ₃ (4.6 mg, 0.005 mmol, 0.05 eq.), Xantphos (9.3 mg, 0.016 mmol, 0.16 eq.), Compound 121-2 (TCI, F0398) (4-fluoro-2-methylaniline; 11 μl , 0.1 mmol, 1.0 eq.) was added under nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 121-3 (14 mg, 28%) as a yellow solid.

Step 2: N ³ -(4-fluoro-2-methylphenyl)-1-methyl-N ⁶ Synthesis of -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 121-4)

Compound 121-3 (14 mg, 0.028 mmol, 1.0 eq.) and LiOH·H ₂ O (3 mg, 0.070 mmol, 2.5 eq.) in THF (1 mL)/MeOH (0.5 mL ₎ /H 2 O (0.5 mL) .) was stirred at room temperature for 2 hours. TLC was checked, the reaction was quenched with water and extracted with EA. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum to give compound 121-4 (11.8 mg, quant.) as a yellow solid.

Step 3: 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2-methylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Synthesis of doline-1,3-dione (compound 121)

Compound 121-5 (WO 2020/051564) (12 mg, 0.032 mmol) in a solution of Compound 121-4 (11.6 mg, 0.029 mmol, 1.0 eq.) in MeOH (1 mL), 1 M AcOH in MeOH (29 μL) was added and stirred for 12 hours. NaCNBH ₃ (2.8 mg, 0.044 mmol, 1.5 eq.) was added to the reaction, stirred at room temperature for 2 hours, quenched with water, and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 5% MeOH/MC as an eluent to obtain compound 121 (5 mg, 23%) as a yellow solid.

Compound 122. N-(4-((6-((2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 3-yl)amino)-3-methylphenyl)-3-(trifluoromethyl)benzamide

Step 1: Synthesis of N-(3-methyl-4-nitrophenyl)-3-(trifluoromethyl)benzamide (Compound 122-2-C)

Compound 122-2-A (SIGMA, 250279) (3-(trifluoromethyl)benzoylchloride; 362 μl, 2.4 mmol, 1.0 eq.), TEA (665 μl, 4.8 mmol) in DCM (15 mL) at 0°C. , 1.2 eq.). Compound 122-2-B (TCI, M1677) (3-methyl-4-nitroaniline; 441 mg, 2.9 mmol, 2.0 eq.) was added dropwise to the reaction at 0°C and stirred at room temperature for 12 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 122-2-C as an ivory solid.

Step 2: Synthesis of N-(4-amino-3-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 122-2)

Compound 122-2-C mixture (800 mg, 2.467 mmol, 1.0 eq) was added with iron powder (689 mg, 12.335 mmol, 5.0 eq.), ethyl alcohol/water (8:1 15 mL) and hydrochloric acid (17 μl, 35 mL). % aqueous solution) and heated to 90° C. under nitrogen protection and stirred for 12 hours. After the reaction is complete, it is filtered, the filtrate is concentrated under reduced pressure, and extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography using 30% EA/HEX as an eluent to obtain compound 122-2 (684 mg, 94%) as a yellow solid.

Step 3: N-(3-methyl-4-((1-methyl-6-((2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline- Synthesis of 7-yl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)amino)phenyl)-3-(trifluoromethyl)benzamide (Compound 122-3)

Cs ₂ CO ₃ (326 mg, 1.0 mmol, 10 eq.), Pd ₂ ( dba) ₃ (4.6 mg, 0.005 mmol, 0.05 eq.), Xantphos (9.3 mg, 0.016 mmol, 0.16 eq.), and compound 122-2 (29 mg, 0.1 mmol, 1.0 eq.) were added under nitrogen. The reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was quenched with water and extracted in ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography using 50% EA/HEX as eluent to obtain compound 122-3 (40 mg, 60%) as a yellow solid.

Step 4: N-(3-methyl-4-((1-methyl-6-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1H-pyrazolo[3,4 Synthesis of -d]pyrimidin-3-yl)amino)phenyl)-3-(trifluoromethyl)benzamide (Compound 122-4)

Compound 122-3 (40 mg, 0.060 mmol, 1.0 eq.) and LiOH·H ₂ O (6.3 mg, 0.15 mmol, 2.5 eq.) in THF (1 mL)/MeOH (0.5 mL ₎ /H 2 O (0.5 mL) .) was stirred at room temperature for 2 hours. TLC was checked, the reaction was quenched with water and extracted with EA. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum to give compound 122-4 (28 mg, 82%) as a yellow solid.

Step 5: N-(4-((6-((2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl )piperidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 3-yl)amino)-3-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 122)

To a solution of Compound 122-4 (20 mg, 0.035 mmol, 1.0 eq.) in MeOH (1 mL) was added Compound 122-5 (WO 2020/051564) (14 mg, 0.039 mmol), 1 M in MeOH (35 μL). AcOH was added and stirred for 12 hours. NaCNBH ₃ (3.3 mg, 0.053 mmol, 1.5 eq.) was added to the reaction, stirred at room temperature for 2 hours, quenched with water, and the reaction mixture was extracted with MC and washed with brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by silica gel column chromatography using 5% MeOH/MC as an eluent to obtain compound 122 (10 mg, 31%) as a yellow solid.

Compound 123. 5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: N ⁶ -(2-(2-chloroethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ Synthesis of -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 123-2)

A stirred solution of compound 123-1 (Korean Patent No. 2128018) (200 mg, 0.450 mmol) in DCM (15 mL) was cooled to 0°C and added with TEA (410 mg, 4.05 mmol) and DMAP (30.0 mg, 0.225 mmol). mmol) and slowly charged p-toluene sulfonylchloride (130 mg, 0.676 mmol) was stirred at room temperature for 12 hours. After completion of the reaction, it was diluted with 20 mL of DCM and washed with water. The aqueous layer was extracted with (25 mL×2) DCM and the combined organic layers were washed with 1 N HCl and brine solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified on a silica gel column and eluted with a 5% MeOH/DCM solvent mixture to obtain Compound 123-2 (156 mg, 0.337 mmol, 75%), a chlorinated compound, as a yellow solid.

Step 2: N ⁶ -(2-(2-azidoethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ Synthesis of -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 123-3)

Sodium azide (42.2 mg, 0.649 mmol) was added to a solution of compound 123-2 (50.0 mg, 0.108 mmol) in 0.5 mL of DMF and stirred at room temperature for 12 hours. TLC analysis showed complete consumption of starting material. Water was added to the reaction mixture, the product was extracted twice with EA, and the organic layer was washed with water and then with brine. The combined organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure to give compound 123-3 (51.0 mg, 0.108 mmol, 100%) as a yellow oil.

Step 3: N ⁶ -(2-(2-aminoethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ Synthesis of -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Compound 123-4)

Pd/C (10%, 5.0 mg) was added to a solution of compound 123-3 (50.0 mg, 0.192 mmol) in MeOH (10 mL) at room temperature and stirred under a hydrogen balloon for 16 hours at room temperature. TLC showed the reaction was complete. The reaction mixture was filtered through Celite and the solvent was evaporated under vacuum and washed with ether to give compound 123-4 (40.0 mg, 0.0903 mmol, 85%) as a yellow solid.

Step 4: 5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Synthesis of compound 123)

To a stirred solution of compound 123-4 (15.0 mg, 0.0338 mmol) in DMSO (2 mL) was added compound 123-5 (Combi-Blocks, HD-3240) (9.33 mg, 0.0338 mmol) and DIPEA (13.1 mg) , 0.101 mmol) was charged and stirred at 90°C for 2 hours. After completion of the reaction, the reaction was diluted with 20 mL of DCM and washed with water. The aqueous layer was extracted with (25 mL×2) EA and the combined organic layers were washed with water (20 mL×2) and (20 mL×2) brine solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude material was purified on a silica gel column and eluted with a 5% MeOH/DCM solvent mixture to obtain the chlorinated compound, Compound 123 (6.0 mg, 0.00858 mmol, 25%) as a yellow solid.

Compound 124. 5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl )Isoindoline-1,3-dione

Step 1: 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonane-2-carboxyl synthesis of acids

7-Azaspiro[3,5]nonane-2-carboxylic acid hydrochloride (Combi-Blocks, ST-6386) (1.07g, 3.90 mmol), 2-(2,6-dioxopiperidin-3-yl )-5-Fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) (810 mg, 3.90 mmol) and DIPEA (2.3 mL, 11.7 mmol) were suspended in DMSO (6.5 mL) and incubated for 120 mL. It was stirred in the microwave for 1 hour at °C. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL × 2), and the organic layer was washed with brine (15 mL × 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and solidified (EtOAc/hexane). ) to obtain 800 mg (50%) of a yellow solid.

Step 2: 5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl ) Synthesis of isoindoline-1,3-dione (Compound 124)

7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-7-azaspiro[3.5]nonane-2-carboxylic acid (34.0 mg, 0.08 mmol), N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3 ,4-d]pyrimidine-3,6-diamine (Korean Patent No. 2128018) (33.4 mg, 0.08 mmol), HATU (45 mg, 0.12 mmol), and DIPEA (0.04 mL, 0.24 mmol) were mixed with DMF (1.5 mmol). mL) and stirred at room temperature for 16 hours. Distilled water (5 mL) was added to the reaction solution and filtered. The solid was washed with distilled water and dried to obtain 17 mg (26%) of a yellow solid.

Compound 125. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione

2-(piperidin-4-yl)acetic acid hydrochloride (Combi-Blocks, OR) instead of 7-azaspiro[3,5]nonane-2-carboxylic acid hydrochloride (Combi-Blocks, ST-6386) Compound 125 was synthesized using the same method as the synthesis of compound 124 using -5687).

Compound 126. 5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione

Instead of 7-azaspiro[3,5]nonane-2-carboxylic acid hydrochloride (Combi-Blocks, ST-6386), use 3-(piperidin-4-yl)propanoic acid hydrochloride (Combi-Blocks, Compound 126 was synthesized using the same method as the synthesis of compound 124 using QE-3962).

Compound 127. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione

Step 1: tert- Butyl 4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Synthesis of 3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethoxy)piperidine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyri Midine-3,6-diamine (Korean Patent No. 2128018) (20.8 mg, 0.05 mmol), 2-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)acetic acid (Combi) -Blocks, SS-3318) (13.5 mg, 0.05 mmol), HATU (30 mg, 0.80 mmol), and DIPEA (0.03 mL, 0.16 mmol) were suspended in DMF (1.5 mL) and stirred at room temperature for 2 hours. Distilled water (5 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 21 mg of a white solid. (63%) was obtained.

Step 2: 1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 Synthesis of ,4-dihydroisoquinolin-2(1H)-yl)-2-(piperidin-4-yloxy)ethan-1-one hydrochloride

tert- Butyl 4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)piperidine-1-carboxylate (21 mg, 0.032 mmol) was suspended in DCM (1 mL) Then, 4 N HCl/dioxane (0.01 mL, 0.26 mmol) was added and stirred at room temperature for 0.5 hours. The reaction solution was concentrated to obtain 16 mg (86%) of a white solid.

Step 3: 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidine-3 -1) Synthesis of isoindoline-1,3-dione (Compound 127)

1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-2-(piperidin-4-yloxy)ethan-1-one hydrochloride (16 mg, 0.03 mmol) was suspended in DMSO (1.5 mL) and then 2 -(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) (7.45 mg, 0.03 mmol), DIPEA (0.01 mL, 0.08 mmol) was added and stirred in a microwave at 120°C for 1 hour. Distilled water (7 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), and the organic layer was washed with brine (10 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by PTLC (2.5 % MeOH/DCM) to give 4 mg (18%) of a yellow solid.

Compound 128. 5-(4-(((1r,4r)-4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexyl)oxy)piperidin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione

(1r,4r)-4-(piperidin-4-yloxy)cyclohexane-1 instead of 7-azaspiro[3,5]nonane-2-carboxylic acid hydrochloride (Combi-Blocks, ST-6386) -Compound 128 was synthesized using the same method as the synthesis of compound 124 using carboxylic acid (eNovation chemicals, K08283).

Compound 129. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxophyll) peridin-3-yl)isoindoline-1,3-dione

2-((1-( tert -butoxycarbonyl)piperidin-4-yl)oxy)acetic acid (Combi-Blocks, SS-3318) instead of 2-(1-( tert -butoxycarbonyl)-4 Compound 129 was synthesized in the same manner as the synthesis of compound 127 using -hydroxypiperidin-4-yl)acetic acid (Combi-Blocks, QK-2527).

Compound 130. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl )Isoindoline-1,3-dione

Step 1: tert- Butyl 4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3, Synthesis of 4-dihydroisoquinoline-2(1H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyri Midine-3,6-diamine (Korean Patent No. 2128018) (50 mg, 0.13 mmol), tert- butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (TCI, B5501) ( 27 mg, 0.13 mmol) was suspended in EtOH (2 mL), TEA (0.03 mL, 0.19 mmol) was added, and the mixture was stirred in a microwave at 120°C for 1 hour. Distilled water (8 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 60 mg of a white solid. (78%) was obtained.

Step 2: 4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Synthesis of 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-4-ol hydrochloride

tert- Butyl 4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-hydroxypiperidine-1-carboxylate (60 mg, 0.09 mmol) was suspended in DCM (1 mL) and then 4 N HCl/dioxane (0.03 mL, 0.9 mmol) was added and stirred at room temperature for 0.5 hours. The reaction solution was concentrated to obtain 48 mg (97%) of a yellow solid.

Step 3: 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) Synthesis of isoindoline-1,3-dione (Compound 130)

4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Dihydroisoquinoline-2(1H)-yl)methyl)piperidin-4-ol hydrochloride (31.30 mg, 0.06 mmol) was suspended in DMSO (1.5 mL) and then 2-(2,6-dioxophyte) Peridin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) (16.0 mg, 0.06 mmol) and DIPEA (0.04 mL, 0.23 mmol) were added and incubated at 120°C. It was stirred in the microwave for 1 hour. Distilled water (7 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), and the organic layer was washed with brine (10 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by PTLC (5). % MeOH/DCM) to give 7.2 mg (16%) of a yellow solid.

Compound 131. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione

Step 1: tert- Synthesis of butyl 4-hydroxy-4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate

t-Butyl 4-hydroxy-4-(2-hydroxyethyl)piperidine-1-carboxylate (Achemblocks, Q61169) (100 mg, 0.40 mmol) was suspended in DCM (2 mL) and p - Toluenesulfonyl chloride (76.3 mg, 0.40 mmol) and TEA (0.11 mL, 0.80 mmol) were added at 0°C and stirred at room temperature for 3 hours. 1 N HCl aqueous solution (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (25% EtOAc/Hex) to obtain a white product. 110 mg (69%) of oil was obtained.

Step 2: tert- Butyl 4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Synthesis of 3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidine-1-carboxylate

t-Butyl 4-hydroxy-4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (53.2 mg, 0.33 mmol), N ³ -(2,6-dimethylphenyl)-1- Methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (Korean Patent No. 2128018) ) (53.2 mg, 0.33 mmol) and K ₂ CO ₃ (55.0 mg, 0.4 mmol) were suspended in DMF (2 mL) and stirred at 70°C for 4 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), and the organic layer was washed with brine (5 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by MPLC (6). % MeOH/DCM) to give 39 mg (46%) of a white solid.

Step 3: 4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)piperidin-4-ol hydrochloride synthesis

t-Butyl 4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidine-1-carboxylate (39 mg, 0.06 mmol) was suspended in DCM (1 mL) Then, 4 N HCl/dioxane (0.02 mL, 0.6 mmol) was added and stirred at room temperature for 0.5 hours. The reaction solution was concentrated to obtain 34 mg (97%) of a yellow solid.

Step 4: 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidine-3 -1) Synthesis of isoindoline-1,3-dione (Compound 131)

4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)ethyl)piperidin-4-ol hydrochloride (34 mg, 0.06 mmol) was suspended in DMSO (1.0 mL) and then 2-(2,6- Dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) (16.0 mg, 0.06 mmol) and DIPEA (0.04 mL, 0.23 mmol) were added and 120 It was stirred in the microwave for 1 hour at °C. Distilled water (7 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), and the organic layer was washed with brine (10 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by PTLC (5). % MeOH/DCM) to give 8.0 mg (17%) of a yellow solid.

Compound 132. 3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3 ,4-b]pyridin-6-yl)piperidine-2,6-dione

tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate instead of t-butyl 4-hydroxy-4-(2-hydroxyethyl) piperidine -1-carboxylate (Achemblocks, Q61169) 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) ) instead of 3-(2-chloro-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (WO2018/140809 ) was used to synthesize compound 132 using the same method as the synthesis method for compound 131.

Compound 133. 3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxo-5,7-dihydro-6H -pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione

3-(2-chloro-5-oxo- instead of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) Compound 130 was synthesized in the same manner as the synthesis method of compound 130 using 5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (WO2018/140809). 133 was synthesized.

Compound 134. 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

Step 1: Synthesis of benzyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate

Benzyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (WO2008/147831) (300 mg, 0.86 mmol) was dissolved in a mixture of EtOH (2 mL) and THF (2 mL). SnCl ₂ (830 mg, 4.40 mmol) was added and stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, the pH was adjusted to 14 by adding 2 N NaOH aqueous solution, extracted with DCM (20 mL), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (60% EtOAc/hexane). 140 mg (52%) of brown oil was obtained.

Step 2: Benzyl 4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine -2-day) Synthesis of piperazine-1-carboxylate

Benzyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (80 mg, 0.28 mmol) was suspended in IPA (3.2 mL) and then 6-chloro-N-(2,6-dimethyl). Phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (Korean Patent No. 2128018) (87 mg, 0.28 mmol) and pTSA (53 mg, 0.28 mmol) were added. It was stirred at 90°C for 12 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 100 mg (64 mg) of yellow solid. %) was obtained.

Step 3: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ Synthesis of -(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine

Benzyl 4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine-2- 1) Piperazine-1-carboxylate (90 mg, 0.16 mmol) was suspended in MeOH (3 mL), then Pd/C (10 wt% Pd, 10 mg) was added and stirred for 4 hours at room temperature under a hydrogen stream. did. The reaction solution was filtered and concentrated to obtain a yellow solid (66 mg, 96%).

Step 4: 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,Synthesis of 3-dione (Compound 134)

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine -3,6-diamine (31.0 mg, 0.07 mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine -4-Carbaldehyde (WO2018/140809) (26.6 mg, 0.07 mmol) was suspended in MeOH (1.5 mL), then NaBH(OAc) ₃ (30.5 mg, 0.14 mmol) was added and stirred at room temperature for 1 hour. NaHCO ₃ aqueous solution (15 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (5% MeOH/DCM) to yield 27 mg of a yellow solid. (50%) was obtained.

Compound 135. 5-(4-((1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

Step 1: Synthesis of (1-(5-aminopyridin-2-yl)piperidin-4-yl)methanol

(1-(5-nitropyridin-2-yl)piperidin-4-yl)methanol (Combi-Blocks, JK-5095) (340 mg, 1.43 mmol) was dissolved in MeOH (7 mL) and then dissolved in Pd/C. (10 wt% Pd, 34 mg) was added and stirred at room temperature under a hydrogen stream for 2 hours. The reaction solution was filtered and concentrated, and the resulting residue was subjected to MPLC (50% EtOAc/hexane) to obtain 250 mg (84%) of brown oil.

Step 2: (1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine Synthesis of -2-yl)piperidin-4-yl)methanol

(1-(5-Aminopyridin-2-yl)piperidin-4-yl)methanol (60 mg, 0.21 mmol) was suspended in IPA (2.5 mL) and then 6-chloro-N-(2,6- Dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (Korean Patent No. 2128018) (43.2 mg, 0.21 mmol), pTSA (40 mg, 0.21 mmol) Added and stirred at 90°C for 12 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 92 mg (95 mg) of a yellow solid. %) was obtained.

Step 3: (1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine Synthesis of -2-yl)piperidin-4-yl)methyl 4-methylbenzenesulfonate

(1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine-2- 1) Piperidin-4-yl) methanol (56 mg, 0.12 mmol) was suspended in DCM (2 mL), then p-toluenesulfonyl chloride (46.5 mg, 0.24 mmol) and TEA (0.05 mL, 0.36 mmol). was added at 0°C and stirred at room temperature for 4 hours. 1 N HCl aqueous solution (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to obtain a yellow color. 58 mg (77%) of solid was obtained.

Step 4: 5-(4-((1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,Synthesis of 3-dione (Compound 135)

(1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine-2- 1) piperidin-4-yl) methyl 4-methylbenzenesulfonate (30 mg, 0.05 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(piperazine-1- 1) Isoindoline-1,3-dione (WO2018/119441) (16.4 mg, 0.05 mmol) and K ₂ CO ₃ (20.3 mg, 0.15 mmol) were suspended in DMF (1.5 mL) and incubated at 70°C for 4 hours. It was stirred for a while. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), and the organic layer was washed with brine (5 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was analyzed by MPLC (8). % MeOH/DCM) to give 6.0 mg (16%) of a yellow solid.

Compound 136. 5-(4-((4-(3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Benzyl 4-(3-aminophenyl)piperazine-1-carboxylate (Tetrahedron, Compound 136 was synthesized using the same method as the synthesis method of compound 134 (2014, 70, 459-464).

Compound 137. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide

Step 1: Synthesis of methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate

Methyl 5-fluoropicolinate (Combi-Blocks, PY-1211) (300 mg, 1.93 mmol), piperidin-4-ylmethanol (Combi-Blocks, OS-7789) (444.6 mg, 3.86 mmol), K ₂ CO ₃ (1.33 g, 9.67 mmol) was suspended in DMSO (9.6 mL) and stirred in a microwave at 120°C for 1 hour. Distilled water (20 mL) was added to the reaction solution, extracted with EtOAc (25 mL×2), and the organic layer was washed with brine solution (20 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC ( 50% EtOAc/HEX) to give 240 mg (50%) of a white solid.

Step 2: Synthesis of methyl 5-(4-((tosyloxy)methyl)piperidin-1-yl)picolinate

Methyl 5-(4-(hydroxymethyl)piperidin-1-yl)picolinate (97 mg, 0.39 mmol) was suspended in DCM (2 mL) and then added to p-toluenesulfonyl chloride (147.0 mg, 0.77 mg). mmol), TEA (0.16 mL, 1.16 mmol) was added at 0°C and stirred at room temperature for 3 hours. 1 N HCl aqueous solution (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the organic layer was dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to obtain a white product. 107 mg (68%) of solid was obtained.

Step 3: Methyl 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)picolinate synthesis

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyri Midine-3,6-diamine (Korean Patent No. 2128018) (32.0 mg, 0.08 mmol), methyl 5-(4-((tosyloxy)methyl)piperidin-1-yl)picolinate (32.4 mg , 0.08 mmol), K ₂ CO ₃ (33.0 mg, 0.24 mmol) were suspended in DMF (1 mL) and stirred at 70°C for 16 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the organic layer was washed with brine solution (5 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC ( 5% MeOH/DCM) to give 35.4 mg (70%) of a white solid.

Step 4: 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Synthesis of amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)picolinic acid

Methyl 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)picolinate (49.0 mg, 0.08 mmol) was dissolved in THF/H ₂ O = 3/1 (1.0 mL) ), lithium hydroxide monohydrate (6.5 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the aqueous layer was adjusted to pH 2 with 1 N HCl aqueous solution, extracted with EtOAc (25 mL×2), and the organic layer was washed with anhydrous sodium sulfate. After drying, filtration, and concentration under reduced pressure, 40 mg (80%) of a white solid was obtained.

Step 5: 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide ( Synthesis of compound 137)

5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)picolinic acid (50.0 mg, 0.08 mmol), 3-aminopiperidine-2,6-dione Hydrochloride (Combi-Blocks, QA-9228) (9.8 mg, 0.06 mmol), HATU (45.6 mg, 0.12 mmol), and DIPEA (0.04 mL, 0.24 mmol) were suspended in DMF (1.0 mL) and incubated at room temperature for 16 hours. It was stirred for a while. Distilled water (15 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 6 mg of a white solid. (10%) was obtained.

Compound 138. 5-(3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Step 1: tert- Butyl 4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -Synthesis of dihydroisoquinoline-2(1H)-yl)piperidine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyri Midine-3,6-diamine (Korean Patent No. 2128018) (32 mg, 0.08 mmol), tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350) (24 mg, 0.12 mmol) ) was suspended in MeCN (3 mL), then NaBH(OAc) ₃ (51 mg, 0.24 mmol) was added and stirred at room temperature for 4 hours. NaHCO ₃ aqueous solution (30 mL) was added to the reaction solution, extracted with DCM (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (2% MeOH/DCM) to yield 10 mg of a bright yellow solid. (21%) was obtained.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6- Synthesis of diamines

tert- Butyl 4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)piperidine-1-carboxylate (13 mg, 0.02 mmol) was suspended in DCM (0.5 mL) and then dissolved in 4 N HCl/dioxane (0.5 mL). ) was added and stirred at room temperature for 1 hour. NaHCO ₃ aqueous solution (30 mL) was added to the reaction solution, extracted with DCM (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 10 mg (93%) of a yellow solid compound.

Step 3: 5-(3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperi Synthesis of din-3-yl)isoindoline-1,3-dione (Compound 138)

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(2-(piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)- 1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine (7 mg, 0.02 mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) (7.4 mg, 0.02 mmol) was suspended in MeCN (2 mL) and then NaBH(OAc) ₃ (9 mg, 0.04 mmol) was added and stirred at room temperature for 2 hours. NaHCO ₃ aqueous solution (20 mL) was added to the reaction solution, extracted with DCM (10 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (10% MeOH/DCM) to yield 4.3 mg of a bright yellow solid. (37%) was obtained.

Compound 139. 5-(4-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxophyll) peridin-3-yl)isoindoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of 1-( of compound 138 using 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) Compound 139 was synthesized using the same method as the synthesis method.

Compound 140. 5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl) amino) -3,4-dihydroisoquinolin-2 (1H)-yl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(3S) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde (WO2020/081450) is used. Compound 140 was synthesized using the same method as that for compound 138.

Compound 141. 5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl) amino) -3,4-dihydroisoquinolin-2 (1H)-yl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(3R) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde (WO2020/081450) is used. Compound 141 was synthesized using the same method as that for compound 138.

Compound 142. 5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl) amino) -3,4-dihydroisoquinolin-2 (1H)-yl) piperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(3S) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) is used. Compound 142 was synthesized using the same method as that for compound 138.

Compound 143. 5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl) amino) -3,4-dihydroisoquinolin-2 (1H)-yl) piperidin-1-yl) methyl) pyrrolidin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

(3R) instead of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) is used. Compound 143 was synthesized using the same method as that for compound 138.

Compound 144. 5-((R)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) instead of (3S) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) is used. Compound 144 was synthesized using the same method as that for compound 87.

Compound 145. 5-((S)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

(3R) instead of 2-(2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) -1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) is used. Compound 145 was synthesized using the same method as that for compound 87.

Compound 146. 5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) amino)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) instead of 2-( Use 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (WO2018/071606) Compound 146 was synthesized using the same method as that for compound 87.

Compound 147. 5-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350), use tert- butyl 4-formylpiperidine-1-carboxylate (Sigma aldrich, 722022) and 1-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of 2-(2,6- Dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) was used in the same manner as the synthesis of compound 138. Compound 147 was synthesized.

Compound 148. 5-((1R,5S,6S)-6-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

2-(2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) (1R, 5S,6r)-3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexane- Compound 148 was synthesized using the same method as that of compound 87 using 6-carbaldehyde (WO2020/081450).

Compound 149. 5-(4-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350), use tert- butyl 3-oxoazetidine-1-carboxylate (Sigma aldrich, 696315) and 1-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of 1-(2-(2) ,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) using the same method as the synthesis method of compound 138 Compound 149 was synthesized.

Compound 150. 5-((R)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione

Instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350), use tert- butyl 3-oxoazetidine-1-carboxylate (Sigma aldrich, 696315) and 1-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of (3S)-1-( of compound 138 using 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) Compound 150 was synthesized using the same method as the synthesis method.

Compound 151. 5-((S)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6 -dioxopiperidin-3-yl)isoindoline-1,3-dione

Instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350), use tert- butyl 3-oxoazetidine-1-carboxylate (Sigma aldrich, 696315) and 1-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of (3R)-1-( of compound 138 using 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) Compound 151 was synthesized using the same method as the synthesis method.

Compound 152. 5-(3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidine -3-day) Isoindoline-1,3-dione

Synthesis of compound 138 using tert -butyl 3-oxoazetidine-1-carboxylate (Sigma aldrich, 696315) instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350) Compound 152 was synthesized in the same manner as above.

Compound 153. 5-((1R,5S,6S)-6-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3, 4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane -3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Instead of tert- butyl 4-oxopiperidine-1-carboxylate (Sigma aldrich, 461350), use tert- butyl 3-oxoazetidine-1-carboxylate (Sigma aldrich, 696315) and 1-(2 -(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) instead of (1R,5S,6r) -3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azabicyclo[3.1.0]hexane-6-carval Compound 153 was synthesized in the same manner as the synthesis of compound 138 using dehyde (WO2020/081450).

Compound 154. 5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of (3S )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) Compound 154 was synthesized using the same method as that for compound 134.

Compound 155. 5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) (3R) )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450) Compound 155 was synthesized using the same method as that for compound 134.

Compound 156. 5-(4-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) pyridin-2-yl) piperazin-1-yl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dion

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of 2- of Compound 134 using (2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3-dione (Compound 88-3) Compound 156 was synthesized using the same method as the synthesis method.

Compound 157. 5-(4-(2-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)pyridin-2-yl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of 2- (1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (WO2018/071606) Compound 157 was synthesized using the same method as that for compound 134.

Compound 158. 5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of 2- Compound 134 using (2,6-dioxopiperidin-3-yl)-5-(3-oxoazetidin-1-yl)isoindoline-1,3-dione (Compound 87-4) Compound 158 was synthesized using the same method as the synthesis method.

Compound 159. 5-(3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-Dion

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of 1- of compound 134 using (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde (WO2020/167518) Compound 159 was synthesized using the same method as the synthesis method.

Compound 160. 5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) instead of (3S )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde (WO2020/081450) Compound 160 was synthesized using the same method as that for compound 134.

Compound 161. 5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione

1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (WO2018/140809) (3R) )-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-3-carbaldehyde (WO2020/081450) Compound 161 was synthesized using the same method as that for compound 134.

Compound 162. 5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

Step 1: tert- Butyl 4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine-3- 1) Synthesis of piperazine-1-carboxylate

6-Chloro-N-(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (Korean Patent No. 2128018) (60.0 mg, 0.2 mmol ), tert- Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) (61.0 mg, 0.22), Pd ₂ (dba) ₃ (18.2 mg , 0.02 mmol), Xantphos (23 mg, 0.04 mmol), and tBuOK (35.0 mg, 0.31 mmol) were suspended in dioxane (2 mL) and stirred in a microwave at 120°C for 2 hours. Distilled water (10 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 40 mg (38 mg) of a yellow solid. %) was obtained.

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ Synthesis of -(5-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine hydrochloride

tert- Butyl 4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)pyridine- 3-day) Piperazine-1-carboxylate (40.0 mg, 0.08 mmol) was suspended in DCM (2 mL), 4 N HCl/dioxane (0.2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 32 mg (98%) of a yellow solid.

Step 3: 5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,Synthesis of 3-dione (Compound 162)

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(5-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine -3,6-diamine hydrochloride (43.0 mg, 0.1 mmol), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p Peridine-4-carbaldehyde (WO2018/140809) (40.8 mg, 0.11 mmol) was suspended in MeOH/DCM = 1/1 (1.5 mL), then NaBH(OAc) ₃ (43 mg, 0.2 mmol) was added. It was stirred at room temperature for 3 hours. NaHCO ₃ aqueous solution (15 mL) was added to the reaction solution, extracted with DCM (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (5% MeOH/DCM) to yield 18 mg of a yellow solid. (23%) was obtained.

Compound 163. 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- Butyl 4-(4-aminophenyl)piperazine-1-carboxylate instead of tert-Butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Compound 163 was synthesized using the same method as for compound 162 using boxylate (Combi-Blocks, AN-1426).

Compound 164. 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyridin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

tert- butyl 4-(5-aminopyridin-2-yl)piperi instead of tert- butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) Compound 164 was synthesized using the same method as the synthesis of compound 162 using dine-1-carboxylate (Combi-Blocks, QK-5999).

Compound 165. 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dion

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Compound 165 was synthesized using carboxylate (TCI, B5832) in the same manner as the synthesis of compound 162.

Compound 166. 5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Carboxylate (TCI, B5832) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4- (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine- instead of carbaldehyde (WO2018/140809) Compound 166 was synthesized using the same method as the synthesis of compound 162 using 3-carbaldehyde (WO2020/081450).

Compound 167. 5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Carboxylate (TCI, B5832) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4- (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)pyrrolidine- instead of carbaldehyde (WO2018/140809) Compound 167 was synthesized using the same method as the synthesis of compound 162 using 3-carbaldehyde (WO2020/081450).

Compound 168. 5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )phenyl)-[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Carboxylate (TCI, B5832) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4- 2-(2,6-dioxopiperidin-3-yl)-5-(4-oxopiperidin-1-yl)isoindoline-1,3-dione ( Compound 168 was synthesized using the same method as the synthesis method for compound 162 using compound 88-3).

Compound 169. 5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Carboxylate (TCI, B5832) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4- 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carbaldehyde instead of carbaldehyde (WO2018/140809) Compound 169 was synthesized using the same method as the synthesis of compound 162 (WO2020/167518).

Compound 170. 3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b ]pyridin-6-yl)piperidine-2,6-dione

tert- butyl 4-(4-aminophenyl)piperidine-1- instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Carboxylate (TCI, B5832) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4- 1-(6-(2,6-dioxopiperidin-3-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b) instead of carbaldehyde (WO2018/140809) ] Compound 170 was synthesized using the same method as the synthesis method for Compound 162 using pyridin-2-yl)piperidine-4-carbaldehyde.

Compound 171. 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)pyrimidin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

tert- butyl 4-(5-aminopyrimidin-2-yl)pipe instead of tert- butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) Compound 171 was synthesized using the same method as that for compound 162 using razine-1-carboxylate (WO2008/141976).

Compound 172. 5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione

tert- Butyl 6-amino-3,4-dihydroisoquinoline-2 instead of tert- Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) Compound 172 was synthesized using the same method as that for compound 162 using (1H)-carboxylate (Combi-Blocks, ST-5411).

Compound 173. 5-((R)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

tert- Butyl 6-amino-3,4-dihydroisoquinoline-2 instead of tert- Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) (1H)-Carboxylate (Combi-Blocks, ST-5411) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- 1) piperidine-4-carbaldehyde (WO2018/140809) instead of (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- Compound 173 was synthesized in the same manner as the synthesis of compound 162 using 5-yl) pyrrolidine-3-carbaldehyde (WO2020/081450).

Compound 174. 5-((S)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

tert- Butyl 6-amino-3,4-dihydroisoquinoline-2 instead of tert- Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) (1H)-Carboxylate (Combi-Blocks, ST-5411) was used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- 1) piperidine-4-carbaldehyde (WO2018/140809) instead of (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- Compound 174 was synthesized in the same manner as the synthesis of compound 162 using 5-yl)pyrrolidine-3-carbaldehyde (WO2020/081450).

Compound 175. 5-(4-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- butyl 3-(4-aminophenyl)azetidine-1-carboxylate instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine -1-carboxylate (Combi-Blocks, QE-9781) Compound 175 was synthesized using the same method as for compound 162 using boxylate (Combi-Blocks, HA-2714).

Compound 176. 5-((R)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

tert- butyl 3-(4-aminophenyl)azetidine-1-carboxylate instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine -1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, HA-2714) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p instead of -4-carbaldehyde (WO2018/140809) Compound 176 was synthesized using the same method as that of compound 162 using rollidine-3-carbaldehyde (WO2020/081450).

Compound 177. 5-((S)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

tert- butyl 3-(4-aminophenyl)azetidine-1-carboxylate instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine -1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, HA-2714) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p instead of -4-carbaldehyde (WO2018/140809) Compound 177 was synthesized using the same method as that of compound 162 using rollidine-3-carbaldehyde (WO2020/081450).

Compound 178. 5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione

Step 1: tert- Synthesis of butyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate

tert- Butyl piperazine-1-carboxylate (Sigma aldrich, 343536) (225 mg, 1.2 mmol) and 2-(chloromethyl)oxirane (TCI, E0012) (0.1 mL, 1.2 mmol) were dissolved in EtOH (2 mL). ) and stirred at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to MPLC (50% EtOAc/HEX) to obtain 242 mg (83%) of a white oil.

Step 2: tert- Butyl 4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Synthesis of 3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)piperazine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4-d]pyri Midine-3,6-diamine (Korean Patent No. 2128018) (46 mg, 0.11 mmol), tert- butyl 4-(oxiran-2-ylmethyl)piperazine-1-carboxylate (27 mg, 0.11) mmol) was suspended in EtOH (2 mL), TEA (0.02 mL, 0.17 mmol) was added, and the mixture was stirred in a microwave at 120°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to MPLC (5% MeOH/DCM) to obtain 74 mg (77%) of a yellow solid.

Step 3: 1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 Synthesis of 4-dihydroisoquinolin-2(1H)-yl)-3-(piperazin-1-yl)propan-2-ol hydrochloride

tert- Butyl 4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazine-1-carboxylate (74 mg, 0.11 mmol) was suspended in DCM (4 mL) and 4N HCl/dioxane (0.4 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain 73 mg (105%) of a yellow solid.

Step 4: 5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)piperazin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Synthesis of isoindoline-1,3-dione (Compound 178)

1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-3-(piperazin-1-yl)propan-2-ol hydrochloride (44 mg, 0.07 mmol) was suspended in DMSO (1 mL) and then 2-( 2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (Combi-Blocks, HD-3240) (21 mg, 0.07 mmol), DIPEA (0.06 mL, 0.38 mmol) ) was added and stirred at 110°C for 16 hours. Distilled water (20 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), and the organic layer was washed with brine solution (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC ( 5% MeOH/DCM) to give 5 mg (5%) of a yellow solid.

Compound 179. 5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

tert- Butyl 4-(4-aminophenyl)piperazine-1-carboxylate instead of tert-Butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, AN-1426) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine (3S)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p instead of -4-carbaldehyde (WO2018/140809) Compound 179 was synthesized using the same method as that of compound 162 using rollidine-3-carbaldehyde (WO2020/081450).

Compound 180. 5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

tert- Butyl 4-(4-aminophenyl)piperazine-1-carboxylate instead of tert-Butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, AN-1426) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine (3R)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p instead of -4-carbaldehyde (WO2018/140809) Compound 180 was synthesized using the same method as that for compound 162 using rollidine-3-carbaldehyde (WO2020/081450).

Compound 181. 5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- Butyl 4-(4-aminophenyl)piperazine-1-carboxylate instead of tert-Butyl 4-(6-aminopyridin-3-yl) piperazine- 1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, AN-1426) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3- instead of -4-carbaldehyde (WO2018/140809) Compound 181 was synthesized using the same method as that for compound 162 using carbaldehyde (WO2020/167518).

Compound 182. 5-(3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

tert- butyl 3-(4-aminophenyl)azetidine-1-carboxylate instead of tert-butyl 4-(6-aminopyridin-3-yl) piperazine -1-carboxylate (Combi-Blocks, QE-9781) Using boxylate (Combi-Blocks, HA-2714) and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3- instead of -4-carbaldehyde (WO2018/140809) Compound 182 was synthesized using the same method as the synthesis of compound 162 using carbaldehyde (WO2020/167518).

Compound 183. 5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione

tert- butyl (S)-4-(4-aminophenyl)-3 instead of tert - butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) -Methylpiperazine-1-carboxylate (WO2014/189466) is used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ase instead of piperidine-4-carbaldehyde (WO2018/140809) Compound 183 was synthesized using the same method as that for compound 162 using thidine-3-carbaldehyde (WO2020/167518).

Compound 184. 5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione

tert- Butyl (R)-4-(4-aminophenyl)-3 instead of tert - Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) -Methylpiperazine-1-carboxylate (WO2014/189466) is used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ase instead of piperidine-4-carbaldehyde (WO2018/140809) Compound 184 was synthesized using the same method as the synthesis of compound 162 using thidine-3-carbaldehyde (WO2020/167518).

Compound 185. 5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione

tert- butyl (S)-4-(4-aminophenyl)-2 instead of tert - butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) -Methylpiperazine-1-carboxylate (WO2015/092431) is used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ase instead of piperidine-4-carbaldehyde (WO2018/140809) Compound 185 was synthesized using the same method as that for compound 162 using thidine-3-carbaldehyde (WO2020/167518).

Compound 186. 5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione

tert- Butyl (R)-4-(4-aminophenyl)-2 instead of tert - Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (Combi-Blocks, QE-9781) -Methylpiperazine-1-carboxylate (WO2015/092431) is used and 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)ase instead of piperidine-4-carbaldehyde (WO2018/140809) Compound 186 was synthesized using the same method as that for compound 162 using thidine-3-carbaldehyde (WO2020/167518).

Compound 187. 3-(2-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine -6-yl)piperidine-2,6-dione

Step 1: tert- Butyl 3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Synthesis of phenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl-N ⁶ -(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6 -Diamine (Korean Patent No. 2128018) (73.0 mg, 0.17 mmol), tert- butyl 3-formylazetidine-1-carboxylate (TCI, B5160) (31.5 mg, 0.17 mmol) was mixed with ACN (1.0 mL). ), NaBH(OAc) ₃ (72.0 mg, 0.34 mmol) was added and stirred at room temperature for 1 hour. NaHCO ₃ aqueous solution (15 mL) was added to the reaction solution, extracted with DCM (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to MPLC (50% EA/Hex) to yield 70 mg of a yellow solid. (69%) was obtained.

Step 2: N ⁶ -(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)phenyl)-N ³ Synthesis of -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine

tert- Butyl 3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) azetidine-1-carboxylate (40.0 mg, 0.07 mmol) was suspended in DCM (4 mL) and then 4 N HCl/dioxane (0.3 mL) was added. Then stirred at room temperature for 1 hour. The reaction solution was neutralized with NaHCO ₃ aqueous solution, extracted with DCM (10 mL×2), dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 26 mg (78%) of a yellow solid.

Step 3: 3-(2-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyri midin-6-yl)amino)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine -6-yl) Synthesis of piperidine-2,6-dione (Compound 187)

N ⁶ -(4-(4-(azetidin-3-ylmethyl)piperazin-1-yl)phenyl)-N ³ -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3 ,4-d]pyrimidine-3,6-diamine (26 mg, 0.05 mmol) was suspended in DMSO (1 mL) and then 3-(2-chloro-5-oxo-5,7-dihydro-6H- Pyrrolo[3,4-b]pyridin-6-yl)piperidine-2,6-dione (WO2018/140809) (15 mg, 0.05 mmol) and DIPEA (0.02 mL, 0.10 mmol) were added and incubated at 100°C. Stirred for 16 hours. Distilled water (20 mL) was added to the reaction solution, extracted with EtOAc (15 mL×2), and the organic layer was washed with brine (15 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subjected to PTLC (5). % MeOH/DCM) to give 7 mg (20%) of a yellow solid.

Compound 188. 3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl) amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) -5-oxo-5,7-dihydro-6H-pyrrolo [3,4-b] Pyridin-6-yl)piperidine-2,6-dione

The same method for synthesizing compound 187 was performed using tert -butyl 4-formylpiperidine-1-carboxylate (TCI, B3873) instead of tert- butyl 3-formylazetidine-1-carboxylate (TCI, B5160). Compound 188 was synthesized using this method.

Compound 189. 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)- N -(3-( N -(2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)acetamide

Step 1: N Synthesis of -(2,6-dioxopiperidin-3-yl)-2-methyl-5-nitrobenzenesulfonamide

Compound 189-2 (Combi-Blocks, QA-9228) in a solution of Compound 189-1 (TCI, M2178) (2-methyl-5-nitrobenzenesulfonyl chloride; 500 mg, 2.12 mmol) in THF (5 mL). (3-aminopiperidine-2,6-dione hydrochloride; 698 mg, 4.24 mmol) and K ₂ CO ₃ (1.47 g, 10.6 mmol) were added at room temperature. The resulting mixture was stirred at room temperature overnight. TLC indicates that a new spot has been created. Complete evaporation of the solvent and direct purification (dry column) under MPLC using 5% MeOH/MC gave compound 189-3 (300 mg, 0.917 mmol, 43%) as an off-white solid.

Step 2: 5-amino- N Synthesis of -(2,6-dioxopiperidin-3-yl)-2-methylbenzenesulfonamide

To a solution of compound 189-3 (200 mg, 0.611 mmol) in MeOH (10 mL) was added 10% Pd/C (40 mg) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. TLC indicates that a new spot has been created. The crude mixture was filtered through a Celite filter and evaporated under vacuum to give compound 189-4 (125 mg, 0.420 mmol, 69%) as a beige solid.

Step 3: 2-chloro- N -(3-( N -Synthesis of (2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)acetamide

To a suspension of Compound 189-4 (50 mg, 0.168 mmol) in THF (1 mL) was added Compound 189-5 (sigma, 104493) (chloroacetyl chloride; 56.4 mg, 0.505 mmol) and TEA (46 uL, 0.336 mmol). did. The reaction mixture was stirred at room temperature for 3 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with EA (25 mL x 2), the combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound. The crude mixture was purified by MPLC using 10% MeOH:DCM as solvent mixture to give compound 189-6 (50 mg, 0.134 mmol, 80%) as a white solid.

Step 4: 2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl)piperidin-1-yl)- N -(3-( N Synthesis of -(2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)acetamide (Compound 189)

To a suspension of compound 189-7 (same as compound 28-4) (15 mg, 0.281 mmol) in DMF (1 mL) was added compound 189-6 (12.6 mg, 0.0338 mmol). The reaction mixture was stirred at 70°C for 14 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with EA (25 mL x 2), the combined organic layers were dried over sodium sulfate and the solvent was evaporated under vacuum. This was purified by column chromatography using DCM/MeOH 5% to obtain compound 189 (11.9 mg, 0.0143 mmol, 51%) as a white solid.

Compound 190. 7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)- N -(3-( N -(2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)-3,4-dihydroisoquinoline-2(1 H )-carboxamide

To a solution of compound 190-1 (same as compound 189-4) (27.9 g, 0.0939 mmol) in DCM (1 mL) was added tryphosgene (139 mg, 0.470 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under vacuum. Compound 190-2 (Korean Patent No. 2128018) (30 mg, 0.0751 mmol) and TEA (26.2 uL, 0.188 mmol) were added to the resulting mixture in THF (1 mL) and stirred at room temperature overnight. TLC showed the formation of product. The reaction mixture was evaporated under vacuum and purified by column chromatography MeOH/DCM (10%) to give compound 190 (6 mg, 0.00830 mmol 11%) as a white solid.

Compound 192. 3-(3-((3-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)-2-oxoethyl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1 H -pyrrol-1-yl)piperidine-2,6-dione

Compound 192-2 (Korean Patent No. 2128018) (17 mg, 0.042 mmol), EDCI (20 mg, 0.105 mmol), HOBt (9 mg, 0.063 mmol), and DIPEA (29 μl, 0.168 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EA (15 mL x 3), and washed with water and brine solution (15 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 192 (17 mg, 0.023 mmol, 55%) as an off-yellow solid.

Compound 193. 3-(3-((3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1 H -pyrrol-1-yl)piperidine-2,6-dione

To a solution of Compound 193-1 (WO2022/065962A1) (15 mg, 0.042 mmol) in DMF (1 mL) was added Compound 193-2 (same as Compound 28-4) (21 mg, 0.042 mmol), EDCI (20 mg, 0.105 mmol), HOBt (9 mg, 0.063 mmol), and DIPEA (29 μl, 0.168 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/MC to give compound 193 (19 mg, 0.023 mmol, 54%) as an off-yellow solid.

Compound 194. 5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: Synthesis of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetic acid

Added to a solution of compound 194-1 (WO2021/155321A1) (119 mg, 0.306 mmol) in 40% TFA/DCM (1.6/2.4 mL). The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated and the beige solid formed was washed with diethyl ether and concentrated in vacuo to give compound 194-2 (70 mg, 0.211 mmol, 69%) as an ivory solid.

Step 2: 5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 194) Synthesis

Compound 194-3 (Korean Patent No. 2128018) (18 mg, 0.045 mmol), HATU (34 mg, 0.090 mmol), and Et were added to a solution of compound 194-2 (15 mg, 0.045 mmol) in DMF (1 mL). ₃ N (19 μl, 0.135 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EA (3×15 mL), and washed with water (3×) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 194 (14 mg, 0.020 mmol, 43%) as an off-yellow solid.

Compound 195. 5-(4-((7-((3-((2-bromo-6-methylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: Synthesis of 2,4-dichloropyrimidine-5-carbonyl chloride

Compound 195-1 (Sigma, 126268) (2,4-dihydroxypyrimidine-5-carboxylic acid; 1.00 g, 6.41 mmol) was added to POCl ₃ (2.40 mL, 25.6 mmol) in a round bottom flask at 0°C. After addition little by little, PCl ₅ (4.67 g, 22.4 mmol) was added slowly. The reaction mixture was warmed to 120° C. and heated to reflux for 12 hours. The mixture was concentrated to dryness, slurried with DCM (50 mL), and the precipitated solid was filtered and washed with Hex and DCM. The filtrate was evaporated under reduced pressure to yield compound 195-2 (1.56 g, 7.38 mmol, >100%) as an orange liquid.

Step 2: N Synthesis of -(2-bromo-6-methylphenyl)-2,4-dichloropyrimidine-5-carboxamide

Compound 195-3 (Alfa, A11884) (2-bromo-6-methylaniline; 1.19 g, 6.39 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 13 hours. Solid formation was observed and the solid was filtered and washed with water (3 x 50 mL). The solid was purified using Hex and EA (trituration) to obtain compound 195-4 (1.84 g, 6.39 mmol, 94%) as an ivory solid.

Step 3: N Synthesis of -(2-bromo-6-methylphenyl)-2-chloro-4-(1-methylhydrazineyl)pyrimidine-5-carboxamide

To compound 195-4 (1.70 g, 4.71 mmol) in THF (30 mL) was added methyl hydrazine sulfate (TCI, M0341) (746 mg, 5.18 mmol) followed by 2 N NaOH (8.24 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and then concentrated to remove THF. The reaction mixture was washed with water, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified under MPLC using 50% EA in Hex to give compound 195-5 (580 mg, 1.90 mmol, 41%) as a white solid.

Step 4: N -(2-bromo-6-methylphenyl)-6-chloro-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-3-amine

To a solution of compound 195-5 (515 mg, 1.39 mmol) in toluene was added PCl ₅ (318 mg, 1.53 mmol) at room temperature. The reaction mixture was stirred at 120°C for 13 hours and then concentrated to remove toluene. Then, water (20 mL) and sodium bicarbonate were added to alkaline the aqueous layer (pH 8-9), the organic layer was extracted, dried over sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 195-6 (yellow solid). 198 mg, 0.561 mmol, 40%) was obtained.

Step 5: 1-(7-((3-((2-bromo-6-methylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)-2,2,2-trifluoroethan-1-one synthesis

After adding compound 195-6 (198 mg, 0.562 mmol) to 50 mL RB, compound 195-7 (Korean Patent No. 2128018) (151 mg, 0.618 mmol), PTSA (116 mg, 0.67 4mmol), IPA ( 10 mL) was added. The reaction mixture was heated to 90° C. for 11 hours. The reaction was concentrated, basified using K ₂ CO ₃ and extracted with DCM (50 mL x 2). The organic layer was dried over sodium sulfate and the solvent was distilled off under vacuum. The reaction mixture was purified under MPLC using 5% MeOH in DCM to give compound 195-8 (260 mg, 0.464 mmol, 83%) as a yellow solid.

Step 6: N ³ -(2-bromo-6-methylphenyl)-1-methyl- N ⁶ -(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

To a solution of compound 195-8 mixture (146 mg, 0.261 mmol) in THF/MeOH/water (2:1:0.5) (1 mL) was added LiOH·H ₂ O (38.3 mg, 0.912 mmol) at room temperature. Stirred for 2 hours. The reaction solvent was concentrated using a rotary evaporator and subjected to acid/base work-up using 1 N HCl and NaHCO ₃ solution to give compound 195-9 (58.0 mg, 0.125 mmol, 48%) as a white solid.

Step 7: 5-(4-((7-((3-((2-bromo-6-methylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H Synthesis of )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 195)

Compound 195-10 (WO 2020/162725) (40.0 mg, 0.108 mmol) was added to a solution of compound 195-9 (45.7 mg, 0.0984 mmol) in DMF (1 mL) with acetic acid (2 drops) and stirred for 1 hour. did. NaBH ₃ CN (9.28 mg, 0.148 mmol) was added to the reaction and stirred at room temperature for 2 hours. After the reaction, the reaction was quenched by adding water to the reaction mixture and extracted with DCM (3×50 mL). The organic layer was washed with brine solution and dried over MgSO ₄ . The crude mixture was purified by MPLC (5% MeOH in DCM) to give compound 195 (42.7 mg, 0.0522 mmol) as a yellow solid.

Compound 199. 5-(4-(((1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)amino)methyl)piperidin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 199-2 (WO 2020/162725) (11.5 g, 0.0310 mmol) was added to a solution of 1 mL of MeOH and added compound 199-1 (15.0 mg, 0.0310 mmol), acetic acid (drop) was added, and the mixture was incubated at room temperature for 2 hours. Stirred for an hour. NaCNBH ₃ (4.87 mg, 0.0775 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. TLC shows that the reaction is complete and the solvent has completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified under MPLC using 5% MeOH/MC to give compound 199 (6.00 mg, 0.0717 mmol, 23%) as a yellow solid.

Compound 201. 3-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2,5-dioxo-2,5-dihydro-1 H -pyrrol-1-yl)piperidine-2,6-dione

To a solution of Compound 200-1 (same as Compound 28-4) (20.0 mg 0.0375 mmol) in dioxane (1.0 mL) was added Compound 200-2 (WO2021/236885) (10.8 mg, 0.0375 mmol), followed by TEA ( 9.47 mg, 0.0937 mmol) was added. The reaction mixture was stirred at 65°C for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (50 mL x 2). The crude mixture was purified by MPLC using 5% MeOH:DCM as solvent mixture to give the following compound 201 (19.0 mg, 0.0270 mmol, 72%) as a brown solid.

Compound 204. N -(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)cyclopropyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-car copymid

Step 1: N ⁶ -(2-((1-aminocyclopropyl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-N ³ Synthesis of -(2,6-dimethylphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine

To a solution of compound 204-1 (same as compound 199-1) (200 mg, 0.414 mmol) in 50 mL anhydrous THF was added BH ₃ ·THF (2.07 mL, 2.07 mmol) and stirred at room temperature for 12 hours. The reaction was quenched with 5 mL MeOH solvent and evaporated under vacuum to give the crude. The crude material was dissolved in 20 mL of MeOH:dimethylaminoethanol (DMAE) (5:1) mixture and refluxed for 3 hours. The solvent was evaporated under vacuum, quenched with water, the aqueous layer was extracted with (EA 15 mL , 94%, crude) was transferred as a white solid without purification and confirmed by LC/MS.

Step 2: N -(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)cyclopropyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-car Synthesis of Vaxamide (Compound 204)

To a solution of compound 204-2 (20.0 mg, 0.0426 mmol) in DMF (1 mL) was added HATU (32.4 mg, 0.0852 mmol), compound 204-3 (WO2021/083949A1) (19.7 mg, 0.0512 mmol) and TEA (12.9 mg). , 0.127 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL x 2), the combined organic layers were washed with water (20 mL x 2), brine (20 mL x 2), washed with saturated aqueous NaHCO ₃ and the combined The organic layer was dried. The solvent was evaporated under vacuum onto sodium sulfate. The crude mixture was purified by MPLC using 10% MeOH:DCM as solvent mixture to give compound 204 (11.0 mg, 0.0131 mmol, 30%) as a yellow solid.

Compound 205. N -(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)cyclopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide

To a solution of Compound 205-1 (same as Compound 204-2) (20.0 mg, 0.0426 mmol) in DMF (1 mL) was added HATU (32.4 mg, 0.0852 mmol), Compound 205-2 (same as Compound 194-2) ( 17.0 mg, 0.0512 mmol) and TEA (12.9 mg, 0.127 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL x 2), the combined organic layers were washed with water (20 mL x 2), brine (20 mL x 2), washed with saturated aqueous NaHCO ₃ and the combined The organic layer was dried. The solvent was evaporated under vacuum onto sodium sulfate. The crude mixture was purified by HPLC under MPLC using 10% MeOH:DCM as solvent mixture to give compound 205 (8.0 mg, 0.0102 mmol, 23%) as a yellow solid.

Compound 206. (3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidin-4-car Voxylate Bistrifluoroacetic Acid

Step 1: 1-( tert- butyl)4-((3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl)piperidine-1,4-dicarboxylate synthesis

To a solution of Compound 206-1 (same as Compound 29) (75.0 mg, 0.0996 mmol) in DMF (1 mL) was added cesium carbonate (97.3 mg, 0.298 mmol) and TBAI (18.4 mg, 0.0498 mmol) and incubated for 20 min. After stirring, compound 206-2 (WO2010/053732 A1) (55.3 mg, 0.199 mmol) was added and stirred at room temperature for 1 hour. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 206-3 (48.0 mg, 0.0482 mmol, 48%) as a fluorescent green solid.

Step 2: (3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methylpiperidine-4-carboxylate Synthesis of bistrifluoroacetic acid (Compound 206)

To a solution of compound 206-3 (30.0 mg, 0.0301 mmol) in DCM (2 mL) was added 2 mL of 40% TFA/DCM and stirred at room temperature for 1 hour. TLC indicated consumption of starting material. The solvent was evaporated, washed with 5 mL of diethyl ether and the product was dried under vacuum to give compound 206 (30.0 mg, 0.0267 mmol, 88%) as a yellow solid.

Compound 207. (3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl 4-methylpentanoate

To a solution of Compound 207-1 (same as Compound 29) (25 mg, 0.0332 mmol) in DMF (1 mL) was added cesium carbonate (21.6 mg, 0.0664 mmol) and TBAI (2.45 mg, 0.0664 mmol) for 20 min. After stirring, compound 207-2 (Journal of Antibiotics (1986), 39(9), 1329-42) (10.9 mg, 0.0664 mmol) was added and stirred at room temperature for 1 hour. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 207 (10.0 mg, 0.0113 mmol, 34%) as a fluorescent green solid.

Compound 208. 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

Step 1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-1,3-dione

Compound 208-1 (BLD, BD10776) (5,6-difluoroisobenzofuran-1,3-dione) (500 mg, 3.621 mmol), Compound 208-2 (Combi-Blocks, QA-9228) (3 To a mixture of -aminopiperidine-2,6-dione hydrochloride) (596 g, 3.62 mmol) and potassium acetate (710 mg, 7.24 mmol), 50 mL of acetic acid was added at room temperature, and incubated at 120°C for 6 hours. It was refluxed. The reaction was cooled, the solvent was evaporated under vacuum, and 150 mL of water was added to the residue and stirred for 1 hour. The solid was filtered under suction and dried under high vacuum to give compound 208-3 (825 mg, 2.80 mmol, 77%) as a purple solid.

Step 2: 5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H Synthesis of )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 208)

To a solution of Compound 208-4 (same as Compound 28-4) (20.0 mg, 0.0375 mmol) in DMSO (1 mL) was added Compound 208-3 (13.2 mg, 0.0450 mmol) and DIPEA (19.4 mg, 0.150 mmol). and stirred at 90°C for 12 hours. TLC shows the reaction is complete. The reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 208 (14.0 mg, 0.0181 mmol, 48%) as a fluorescent green solid.

Compound 209. 3-(5-(1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)acetyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

HATU (16.5 mg, 0.0436 mmol), compound 209-2 (WO2022/081976A1) (7.15 mg, 0.0218 mmol) and TEA (8.81 mg, 0.0872 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL x 2), the combined organic layers were washed with water (20 mL x 2) and brine (20 mL x 2), the combined organic layers were dried over sodium sulfate and the solvent was evaporated. Evaporate under vacuum. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 209 (11.0 mg, 0.0143 mmol, 65%) as a yellow solid.

Compound 210. 5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1, 3-Dion

Step 1: tert- Synthesis of butyl 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxylate

To a solution of Compound 210-2 (Combi-Blocks, QK-3943) ( tert- butyl piperidine-4-carboxylate hydrochloride) (31.4 mg, 0.169 mmol) in DMSO (2 mL) was added Compound 210-1 (Compound Same as 208-3) (50.0 mg, 0.169 mmol) and DIPEA (87.5 mg, 0.676 mmol) were added and stirred at 90°C for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 210-3 (61.0 mg, 0.132 mmol, 78%) as a green solid.

Step 2: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxylic acid

To compound 210-3 (61.0 mg, 0.132 mmol) in DCM (5 mL) was added 2 mL of 40% TFA/DCM and stirred at room temperature for 2 hours. TLC indicated consumption of starting material. The solvent was evaporated, washed with 5 mL of diethyl ether and the product was dried under vacuum to give compound 210-4 (38.0 mg, 0.0942 mmol, 71%) as a yellow solid.

Step 3: 5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H Synthesis of )-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 210)

HATU (21.4 mg, 0.0562 mmol), Compound 210-4 (11.3 mg, 0.0281 mmol) and TEA in a solution of Compound 210-5 (same as Compound 28-4) (15.0 mg, 0.0281 mmol) in DMF (2 mL). (11.4 mg, 0.112 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL x 2), the combined organic layers were washed with water (20 mL x 2) and brine (20 mL x 2), the combined organic layers were dried over sodium sulfate and the solvent was evaporated. Evaporate under vacuum. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 210 (9.00 mg, 0.0102 mmol, 36%) as yellow crystals.

Compound 211. 5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3 -Dion

Step 1: tert- Synthesis of butyl (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)glycinate

To a solution of compound 211-2 (TCI, G0254) ( tert- butyl glycinate hydrochloride) (28.3 mg, 0.169 mmol) in DMSO (2 mL) was added compound 211-1 (same as compound 208-3) (50.0 mg, 0.169 mmol) and DIPEA (87.5 mg, 0.676 mmol) were added and stirred at 90°C for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 211-3 (32.0 mg, 0.0789 mmol, 46%) as a fluorescent green solid.

Step 2: Synthesis of (2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)glycine

2 mL of 40% TFA/DCM was added to compound 211-3 (30.0 mg, 0.0740 mmol) and stirred at room temperature for 2 hours. TLC indicated consumption of starting material. The solvent was evaporated, washed with 5 mL of diethyl ether and the product was dried under vacuum to give compound 211-4 (21.0 mg, 0.0601 mmol, 81%) as a brown-green solid. The crude material was used for the next step without further purification.

Step 3: 5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H Synthesis of )-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 211)

HATU (21.4 mg, 0.0562 mmol), Compound 211-4 (9.81 mg, 0.0281 mmol) and TEA in a solution of Compound 211-5 (same as Compound 28-4) (15.0 mg, 0.0281 mmol) in DMF (2 mL). (11.4 mg, 0.112 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), the combined organic layers were dried over sodium sulfate and the solvents were evacuated. evaporated under The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 211 (7.00 mg, 0.00845 mmol, 30%) as a greenish-brown solid.

Compound 217. 5-(4-((7-((3-((2,6-dibromophenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 195 was synthesized in the same manner as above, using 2,6-dibromoaniline instead of 2-bromo-6-methylaniline.

Compound 218. 5-(4-((7-((3-((2-bromo-6-chlorophenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 195 was synthesized in the same manner as above, using 2-bromo-6-chloroaniline instead of 2-bromo-6-methylaniline.

Compound 219. 5-(4-((7-((3-((2-chloro-6-iodophenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Compound 195 was synthesized in the same manner as above, using 2-chloro-6-iodoaniline instead of 2-bromo-6-methylaniline.

Compound 220. 3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Compound 220-2 (WO2020/118098) (10.2 mg, 0.0362 mmol) and DIPEA (26.0 mg, 0.201 mmol) was added at room temperature. The resulting mixture was stirred at 140°C for 18 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (100 mL x 3) and washed with water (3 x) and brine solution. The organic layer was dried over sodium sulfate and purified by MeOH/DCM (5%) column to obtain compound 220 (2.5 mg, 0.0033 mmol, 9%).

Compound 221. 2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2,6-dimethylphenyl)amino)- 1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione

Compound 195 was synthesized in the same manner as above, using 4-fluoro-2,6-dimethylaniline instead of 2-bromo-6-methylaniline.

Compound 222. 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) )Isoindoline-1,3-dione

Step 1: N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(4-(piperidin-4-yl)phenyl)-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

To a solution of Compound 222-1 (WO2018/208132A1) (200 mg, 0.609 mmol) in IPA (3 mL) was added tert- Butyl 4-(4-aminophenyl)piperidine-1-carboxylate (Compound 222-2) ) (BLD Pharm, BD24501-25 g) (211 mg, 0.765 mmol) and PTSA (144 mg, 0.834 mmol) were added. The reaction mixture was stirred at 90° C. for 12 hours and the solvent was removed under vacuum. 4 M HCl was added to dioxane, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was then concentrated, basified using sodium bicarbonate, and extracted with EtOAc (3 × 15 mL). The resulting white precipitate was dried under reduced pressure to obtain compound 222-3 (197 mg, 0.461 mmol, 66%) as a gray-yellow solid.

Step 2: 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione( Synthesis of compound 222)

To a solution of compound 222-3 (15 mg, 0.035 mmol) in DMF (1 mL) was added compound 222-4 (WO2021/083949) (14 mg, 0.035 mmol), EDCI (17 mg, 0.088 mmol), HOBt (7 mg) , 0.053 mmol), and DIPEA (37 μL, 0.210 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 222 (10 mg, 0.012 mmol, 35%) as an off-yellow solid.

Compound 225. 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

To a solution of Compound 225-1 (same as Compound 222-3) (15 mg, 0.035 mmol) in DMF (1 mL) was added Compound 225-2 (same as Compound 18-2) (14 mg, 0.035 mmol), HATU ( 27 mg, 0.070 mmol) and Et ₃ N (15 μL, 0.105 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 225 (15 mg, 0.019 mmol, 53%) as an off-yellow solid.

Compound 226. 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidine -3-day) Isoindoline-1,3-dione

Step 1: N3-(2,6-dimethylphenyl)-N6-(3-fluoro-4-(piperidin-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-d ]Synthesis of pyrimidine-3,6-diamine

Compound 226-1-B (Combi-blocks, QY-7014) ( tert -butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate) (71 mg, 0.24 mmol), the resulting mixture was stirred at 95°C for 16 hours did. The reaction mixture was concentrated and triturated with ether to obtain compound 226-1 (92 mg, 85%).

Step 2: 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidine -3-day) Synthesis of isoindoline-1,3-dione (Compound 226)

To a solution of Compound 226-1 (15 mg, 0.034 mmol) in DMF (1 mL) was added Compound 226-2 (same as Compound 225-2) (13 mg, 0.034 mmol), HATU (26 mg, 0.067 mmol), Et. ₃ N (14 μL, 0.101 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 226 (14 mg, 0.017 mmol, 50%) as an off-yellow solid.

Compound 227. 5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperi) din-3-yl)isoindoline-1,3-dione

To a solution of Compound 227-1 (same as Compound 226-1) (10 mg, 0.022 mmol) in DMF (1 mL) was added Compound 227-2 (same as Compound 222-4) (9 mg, 0.022 mmol), HATU ( 17 mg, 0.045 mmol) and Et ₃ N (9 μL, 0.067 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 227 (7 mg, 0.008 mmol, 38%) as an off-yellow solid.

Compound 228. 5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione

To a solution of Compound 228-1 (same as Compound 222-3) (15 mg, 0.035 mmol) in DMF (1 mL) was added Compound 228-2 (same as Compound 27-2) (13 mg, 0.035 mmol), HATU ( 27 mg, 0.070 mmol) and Et ₃ N (15 μL, 0.105 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 228 (6 mg, 0.008 mmol, 22%) as an off-yellow solid.

Compound 229. 5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)piperidine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione

To a solution of Compound 229-1 (same as Compound 226-1) (10 mg, 0.022 mmol) in DMF (1 mL) was added Compound 229-2 (same as Compound 228-2) (8 mg, 0.022 mmol), HATU ( 17 mg, 0.045 mmol) and Et ₃ N (9 μL, 0.067 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 229 (4 mg, 0.005 mmol, 23%) as an off-yellow solid.

Compound 230. 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)phenyl)-3,6-dihydropyridin-1(2 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2 H )-Synthesis of carboxylate

tert-Butyl 4-(4,4,5,5) in a solution of 4-bromoaniline (Compound 230-1) (TCI, B1393) (200 mg, 1.17 mmol) in dioxane /water (2/2 mL) -Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1( 2H )-carboxylate (Compound 230-2) (BLD Pharm, BD33046) ( 397 mg, 1.29 mmol), Na ₂ CO ₃ (372 mg, 3.51 mmol), Pd(dppf) ₂ Cl ₂ ·DCM (47 mg, 0.0059 mmol), and DPPF (33 mg, 0.059 mmol) were added. The reaction mixture was stirred at 80° C. under nitrogen gas for 15 hours. After the reaction was over, it was quenched with water, extracted with EtOAc (3×30 mL), and washed with water (3×). The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 50% EtOAc/HEX to give compound 230-3 (265 mg, 0.966 mmol, 82%) as an off-white solid. .

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ Synthesis of -(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine

In a solution of Compound 230-4 (same as Compound 222-1) (70 mg, 0.243 mmol), Compound 230-3 (67 mg, 0.243 mmol) in i -PrOH (1 mL) MeSO ₃ H (42 mg, 0.243 mmol) was added, the reaction mixture was heated to 95° C., and then stirred at the same temperature for 15 hours. After completion, the reaction mixture was concentrated and extracted with EtOAc (3 x 20 mL) and saturated NaHCO ₃ (10 mL). The resulting white precipitate was dried under reduced pressure to obtain compound 230-5 (27 mg, 0.063 mmol, 26%) as a gray-yellow solid.

Step 3: 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)-3,6-dihydropyridin-1(2 H Synthesis of )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 230)

To a solution of Compound 230-5 (20 mg, 0.047 mmol) in MeOH (1 mL) was added Compound 230-6 (same as Compound 195-10) (17 mg, 0.047 mmol), AcOH (3 μL, 0.047 mmol). did. The reaction mixture was stirred at room temperature for 12 hours. Afterwards, NaBH ₃ CN (4 mg, 0.070 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with water, extracted with DCM (3×15 mL), and washed with water (3×) and NaHCO ₃ . The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 230 (11 mg, 0.014 mmol, 30%) as an off-yellow solid.

Compound 231. 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3-fluorophenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione

Step 1: N3-(2,6-dimethylphenyl)-N6-(2-fluoro-4-(piperidin-4-yl)phenyl)-1-methyl-1H-pyrazolo[3,4-d ]Synthesis of pyrimidine-3,6-diamine

Compound 231-1-B (Chemscene, CS- 0096060)( tert -butyl 4-(4-amino-2-fluorophenyl)piperidine-1-carboxylate) (71 mg, 0.24 mmol) was added and the resulting mixture was incubated at 95°C for 16 hours. It was stirred. The reaction mixture was concentrated and triturated with ether to obtain compound 231-1 (91 mg, 85%).

Step 2: 5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3-fluorophenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine-3- 1) Synthesis of isoindoline-1,3-dione (Compound 231)

To a solution of Compound 231-1 (20 mg, 0.045 mmol) in MeOH (1 mL) was added Compound 231-2 (same as Compound 230-6) (17 mg, 0.045 mmol) and AcOH (3 μL, 0.045 mmol). did. The reaction mixture was stirred at room temperature for 12 hours. Afterwards, NaBH ₃ CN (4 mg, 0.067 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, it was quenched with water, extracted with DCM (3×15 mL), and washed with water (3×) and NaHCO ₃ . The combined organic layers were dried over sodium sulfate, filtered, solvents evaporated in vacuo and purified on MPLC using 5% MeOH/DCM to give compound 231 (11 mg, 0.014 mmol, 31%) as an off-yellow solid.

Compound 232. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperi din-3-yl)isoindoline-1,3-dione

Step 1: tert- butyl 4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidine-1-carboxylate

Lawesson's reagent (298 mg, 0.737 mmol) was added to a solution of compound 232-1 (same as compound 43-3) (300 mg, 0.491 mmol) in toluene at room temperature and heated to 120°C for 16 hours. TLC showed that new spots had formed and the reaction was cooled and quenched with water. The aqueous layer was extracted with EA (15 mL x 2) and the combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under vacuum. The residue was attempted to be purified by MPLC using 5% MeOH:MC as solvent mixture to give compound 232-2 (260 mg, 0.415 mmol, 84%) as a slightly impure yellow oil.

Step 2: (7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H )-yl)(piperidin-4-yl)methanethione synthesis

To a solution of compound 232-2 (150 mg, 0.239 mmol) in 25 mL of DCM was added 4N HCl/dioxane (0.150 mL, 0.598 mmol) and stirred for 1 hour. After completion of the reaction, the solvent was evaporated and the residual dioxane was chased with 20 mL chloroform. The residue was neutralized with sodium bicarbonate solution, extracted with DCM (2 x 100 mL), and the solvent was evaporated under vacuum to give compound 232-3 (150 mg, 0.239 mg, 86%) free base as an off-white solid.

Step 3: 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Synthesis of dione (compound 232)

Compound 232-4 (same as Compound 2-1) (3.15 mg, 0.011 mmol) and DIPEA (5.90 mg, 0.046 mmol) were added to a solution of Compound 232-3 (6.0 mg, 0.011 mmol) in DMSO (1 mL) at room temperature. It was added from . The resulting mixture was stirred at 90°C for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (50 mL x 3) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC (eluted at 4%) using 10% MeOH/MC to give compound 232 (2.50 mg, 0.0110 mmol, 28%) as a yellow solid.

Compound 233. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione

To a solution of Compound 233-1 (same as Compound 232-3) (10 mg, 0.019 mmol) in DMSO (1 mL) was added Compound 233-2 (same as Compound 208-3) (5.59 mg, 0.019 mmol) and DIPEA ( 9.83 ㎕, 0.057 mmol) was added and stirred at 90°C for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 233 (9.0 mg, 0.019 mmol, 60%) as a yellow solid.

Compound 234. 5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-carbonyl)piperidin-1-yl)-2- (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

HATU (14.4 mg, 0.0380 mmol) and compound 234-2 (same as compound 230-6) (8.05) in a solution of compound 234-1 (same as compound 233-1) (10 mg, 0.019 mmol) in DMF (2 mL) mg, 0.021 mmol) and TEA (7.68 μl, 0.057 mmol)) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), the combined organic layers were dried over sodium sulfate and the solvents were evacuated. evaporated from the state. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 234 (8.0 mg, 0.019 mmol, 47%) as a yellow solid.

Compound 235. 5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethyl)amino)-2-( 2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

HATU (14.4 mg, 0.038 mmol), Compound 235-2 (same as Compound 12-1) (6.92) in a solution of Compound 235-1 (same as Compound 233-1) (10 mg, 0.019 mmol) in DMF (2 mL) mg, 0.021 mmol) and TEA (7.68 μl, 0.057 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), and the combined organic layers were solvent removed with sodium sulfate in vacuo. Evaporated to dryness. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 235 (11.0 mg, 0.0190 mmol 70%) as a yellow solid.

Compound 236. 5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethoxy)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of compound 236-1 (same as compound 233-1) (20 mg, 0.038 mmol) in DMF (2 mL) was added HATU (28.9 mg, 0.076 mmol), compound 236-2 (same as compound 205-2) ( 13.88 mg, 0.042 mmol) and TEA (0.015 ml, 0.114 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), and the combined organic layers were solvent removed with sodium sulfate in vacuo. Evaporated to dryness. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 236 (11.0 mg, 0.0380 mmol, 35%) as a yellow solid.

Compound 237. 3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperi Din-2,6-dione

Step 1: 3-(5-(4-((benzyloxy)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy ) Synthesis of methyl) piperidine-2,6-dione

Compound 237-1-B (BLD, BD00805044) (4-((benzyloxy)methyl) in a solution of Compound 237-1-A (same as Compound 103-8) (280 mg, 0.618 mmol) in dioxane (3 mL) Piperidine hydrochloride) (179 mg, 0.741 mmol), Cs ₂ CO ₃ (6241 mg, 0.7) mmol), RuPhos (58 mg, 0.124 mmol), and RuPhos Pd G2 (96 mg, 0.124 mmol) were added. The reaction mixture was stirred at 100° C. under nitrogen gas for 16 hours. After checking TLC, the reaction was quenched with water and the mixture was transferred to a separatory funnel with EA and water. The combined organic layers were dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The crude mixture was purified by silica gel column chromatography using EA/HEX as eluent to give compound 237-1-C (152 mg, 0.263 mmol) as an ivory solid.

Step 2: 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl ) Synthesis of piperidine-2,6-dione

To a solution of compound 237-1-C (152 mg, 0.263 mmol) in MeOH at room temperature was added 10% Pd/C (25 mg) and the reaction mixture was stirred under hydrogen balloon pressure at room temperature for 16 hours. TLC analysis showed complete consumption of starting material. The reaction mixture was filtered through a Celite bed and concentrated to remove MeOH to obtain compound 237-1 (105 mg, 0.215 mmol, 82%) as a white oil.

Step 3: Synthesis of 3-(5-(4-(hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Methanesulfonic acid (26.6 μl, 0.410 mmol) was added to a solution of compound 237-1 (50 mg, 0.103 mmol) in MeCN (5 mL) at 0°C and stirred at room temperature for 12 hours. The reaction mixture was cooled to 0°C and half of compound 237-2 (Sigma aldrich D157805) ( N ¹ , N ² -dimethylethane-1,2-diamine; 18.08 mg, 0.205 mmol) was slowly added, followed by TEA (111 μl). , 0.820 mmol) was added and stirred for 2 hours, and the remaining half of compound 237-2 (Sigma aldrich D157805) ( N ¹ , N ² -dimethylethane-1,2-diamine; 18.08 mg, 0.205 mmol) was added. Stirred for 2 hours. The reaction was quenched with water and extracted with DCM (20 mL x 2), the combined organic layers were dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo to give crude compound 237-3 (36.0 mg, 0.103 mmol) as a brown solid. did.

Step 4: Synthesis of (1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-4-yl)methyl methanesulfonate

To a solution of crude compound 237-3 (36 mg, 0.101 mmol) in DCM (1 mL) at 0°C was added MsCl (15.70 μl, 0.201 mmol) and TEA (40.7 μl, 0.302 mmol). The reaction was stirred at 0°C for 1 hour, and TLC showed the reaction was complete. The reaction was quenched with water and extracted with EA (20 mL Compound 237-4 (9.0 mg, 0.101 mmol, 21%) was obtained as a white solid.

Step 5: 3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1 H Synthesis of )-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 237)

Compound 237-4 (Korean Patent No. 2128018) (8.0 mg, 0.018 mmol) and KI (1.525 mg, 9.18 μmol) in a solution of Compound 237-5 (7.34 mg, 0.018 mmol) in ACN (2 mL) at room temperature. and DIPEA (9.52 μl, 0.055 mmol) were added. The resulting mixture was stirred at 80°C for 12 hours. TLC showed the formation of product, water was added to the reaction mixture, extracted with EA (50 mL x 3) and washed with water (3 x) and brine solution. The combined organic layers were dried over sodium sulfate and purified by MPLC using 10% MeOH/MC (eluted at 6%) to give compound 237 (2.60 mg, 0.0180 mmol, 20%) as a yellow solid.

Compound 238. 5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of Compound 238-1 (same as Compound 245-1-C) (20 mg, 0.047 mmol) in DMSO (1 mL) was added Compound 238-2 (same as Compound 2-1) (12.9 mg, 0.047 mmol) and DIPEA (0.040 ml, 0.233 mol) was added, the temperature was raised from room temperature to 90°C, and the mixture was stirred for 16 hours until the reaction was complete. TLC indicates that a new spot has been created. The reaction was quenched with 5 mL of water, extracted with EA, and the combined organic layers were washed with water and brine solution. The combined organic layers were dried over sodium sulfate, then filtered and evaporated under vacuum. The crude mixture was purified under MPLC using 10% MeOH:DCM as solvent mixture to give compound 238 (9 mg, 0.013 mmol, 28%) as a yellow solid.

Compound 239. 5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

To a solution of Compound 239-1 (same as Compound 238-1) (20 mg, 0.047 mmol) in DMSO (1 mL) was added Compound 239-2 (same as Compound 233-2) (13.7 mg, 0.047 mmol) and DIPEA ( 0.040 ml, 0.233 mol) was added, the temperature was raised from room temperature to 90°C, and the mixture was stirred for 16 hours until the reaction was complete. TLC indicates that a new spot has been created. The reaction was quenched with 5 mL of water, extracted with EA, and the combined organic layers were washed with water and brine solution. The combined organic layers were dried over sodium sulfate, then filtered and evaporated under vacuum. The crude mixture was purified under MPLC using 10% MeOH:DCM as solvent mixture to give compound 239 (21.7 mg, 0.031 mmol, 66%) as a yellow solid.

Compound 240. (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-(1-(2-(2,6-dioxopiperidine) -3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)acrylonitrile

Step 1: (E)-3-(1-( tert- Synthesis of butoxycarbonyl)piperidin-4-yl)-2-cyanoacrylic acid

Compound 240-1-A (sigma, 722022) ( tert -butyl 4-formylpiperidine-1-carboxylate) (500 mg, 2.34 mmol), Compound 240-1-B (sigma) in ethanol (20 mL) , C88505) (cyanoacetic acid) (300 mg, 3.51 mmol) and piperidine (sigma, 104094) (100 mg, 1.17 mmol) was stirred and heated at 85°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (15 mL). The layers were split and the aqueous phase was extracted with EtOAc (25 mL). The combined organic layers were washed with 1 M aqueous sodium hydroxide solution (25 mL x 1), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was loaded onto a 15% EtOAc/hexane silica column to give the desired compound, Compound 240-1-C (92.0 mg, 0.328 mmol, 14%) as a sticky oil.

Step 2: tert -Butyl (E)-4-(2-cyano-3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate synthesis of

To a suspension of compound 240-1-C (105 mg, 0.375 mmol) in DMF (10 mL) was added DIPEA (97.0 mg, 0.751 mmol) followed by HATU (190 mg, 0.501 mmol) at room temperature and the reaction mixture was We did it together. Stirred for 15 minutes. Compound 240-1-D (same as Compound 1-1) (100 mg, 0.250 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 240-1-E (137 mg, 0.0207 mmol, 83%) was obtained.

Step 3: (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Synthesis of amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(piperidin-4-yl)acrylonitrile

To a solution of compound 240-1-E (95.0 mg, 0.144 mmol) in DCM (5 ml) was added 4 N HCl in dioxane (11.0 mg, 0.287 mmol). The reaction mixture was stirred at room temperature for 4 hours. The crude material was concentrated in vacuo and the resulting crude material was washed with ether and dried under vacuum to give compound 240-1 (51 mg, 0.0910 mmol, 64%) as a white solid.

Step 4: (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-(1-(2-(2,6-dioxopiperidine) Synthesis of -3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbonyl)piperidin-4-yl)acrylonitrile (Compound 240)

To a suspension of compound 240-1 (10 mg, 0.018 mmol) in DMF (2 mL) was added DIPEA (6.92 mg, 0.053 mmol) followed by HATU (13.54 mg, 0.036 mmol) at room temperature and the reaction mixture was stirred for 15 min. did. Compound 240-2 (same as compound 230-6) (7.55 mg, 0.020 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 240 (10.0 mg, 0.0107 mmol, 60.5%) as a yellow solid. did.

Compound 241. (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-((2-(2,6-dioxopiperi) din-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)acrylonitrile

To a suspension of compound 241-1 (same as compound 240-1) (10 mg, 0.018 mmol) in DMF (2 mL) was added DIPEA (6.92 mg, 0.053 mmol) followed by HATU (13.54 mg, 0.036 mmol) at room temperature. And the reaction mixture was stirred for 15 minutes. Compound 241-2 (same as compound 236-2) (6.51 mg, 0.020 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 241 (10.8 mg, 0.012 mmol, 69.3%) as a yellow solid. did.

Compound 243. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- butyl 4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,2,3, Synthesis of 4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carboxylate

HATU (476 mg, 1.252 mmol) and compound 243-2 (BLD Pharm BD57158 98%) (1) in a solution of compound 243-1 (Korean Patent No. 2128018) (250 mg, 0.626 mmol) in DMF (2 mL) -( tert- butoxycarbonyl)-4-fluoropiperidine-4-carboxylic acid; 155 mg, 0.626 mmol) and TEA (190 mg, 1.877 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), and the combined organic layers were purified in vacuo over sodium sulfate. Evaporated to dryness. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 243-3 (351 mg, 0.558 mmol, 89%) as yellow crystals.

Step 2: (7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin- Synthesis of 2(1H)-yl)(4-fluoropiperidin-4-yl)methanone 2,2,2-trifluoroacetate

Compound 243-3 (351 mg, 0.558 mmol) and 40% TFA/DCM were added to 50 mL rb and stirred at room temperature for 2 hours, and TLC showed that the reaction was complete. The solvent was completely evaporated, the residue was washed with diethyl ether, and the product was dried under high vacuum to give compound 243-4 (324 mg, 0.558 mmol, 90%) as a yellow solid.

Step 3: 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 Synthesis of ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 243)

To a solution of Compound 243-4 (20 mg, 0.032 mmol) in DMSO (2 mL) was added Compound 243-5 (same as Compound 232-4) (9.39 mg, 0.032 mmol) and DIPEA (0.017 ml, 0.096 mmol) It was stirred at 90°C for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 243 (7.0 mg, 0.032 mmol, 28%) as a yellow solid.

Compound 244. 5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6- dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione

To a solution of Compound 244-1 (same as Compound 243-4) (20 mg, 0.032 mmol) in DMSO (1 mL) was added Compound 244-2 (same as Compound 208-3) (8.82 mg, 0.032 mmol) and DIPEA ( 0.017 ml, 0.096 mmol) was added and stirred at 90°C for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 244 (11.0 mg, 0.032 mmol, 43%) as a yellow solid.

Compound 245. 3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione

Step 1: N3-(2,6-dimethylphenyl)-1-methyl-N6-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-3, Synthesis of 6-diamine

Compound 245-1-B (Combi-blocks, AN-1426) (tert-butyl 4-(4- Aminophenyl)piperazine-1-carboxylate) (521 mg, 1.877 mmol) and pTSA (595 mg, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred at 90° C. overnight. After completion of the reaction, the solvent was evaporated under vacuum and water and DCM were added. The aqueous layer was separated with a separatory funnel and saturated NaHCO ₃ solution and DCM were added to provide base work-up. The DCM layer was collected and evaporated under vacuum to give compound 245-1-C (350 mg) as a yellow solid.

Step 2: tert -Butyl 4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino ) Synthesis of phenyl) piperazin-1-yl) methyl) piperidine-1-carboxylate

To a solution of compound 245-1-C (100 mg, 0.233 mmol) in 1 mL of MeOH was added compound 245-1-D (sigma, 722022) (Boc-piperidine aldehyde) (54.7 mg, 0.257 mmol) with acetic acid (1 drop). , catalytic amount) was added and stirred at room temperature overnight. NaCNBH ₃ (22 mg, 0.350 mmol) was added to the reaction and stirred for 1 hour. TLC shows that the reaction is complete and the solvent has completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified under MPLC using 10% MeOH/MC to give compound 245-1-E (66.4 g, 0.106 mmol, 45.5%) as a yellow solid.

Step 3: N3-(2,6-dimethylphenyl)-1-methyl-N6-(4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)phenyl)-1H-pyrazolo Synthesis of [3,4-d]pyrimidine-3,6-diamine

To a solution of compound 245-1-E (60 mg, 0.096 mmol) in DCM (1.0 mL) was added 4 N HCl/dioxane (0.5 ml, excess). The reaction was stirred at room temperature overnight. No starting material was observed in the TLC results. The solvent was evaporated under vacuum and a base work-up was provided with saturated NaHCO ₃ solution. After base treatment, the organic layer was recrystallized from chloroform/Hex to obtain compound 245-1 (42.7 mg, 0.081 mmol, 85%) as an off-white solid.

Step 4: 3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2 Synthesis of ,6-dione (Compound 245)

To a solution of Compound 245-1 (20 mg, 0.038 mmol) in DMSO (1 mL) was added Compound 245-2 (same as Compound 220-2) (10.6 mg, 0.038 mmol) and DIPEA (0.033 ml, 0.190 mol). Then, the temperature was raised from room temperature to 90°C and stirred for 16 hours until the reaction was completed. TLC indicates that a new spot has been created. The reaction was quenched with 5 mL of water, extracted with EA, and the combined organic layers were washed with water and brine solution. The combined organic layers were dried over sodium sulfate, then filtered and evaporated under vacuum. The crude mixture was purified under MPLC using 10% MeOH:DCM as solvent mixture to give compound 245 (3.5 mg, 0.0045 mmol, 11.7%) as a yellow solid.

Compound 246. 5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-carbonyl)piperidin-1-yl )-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

2-( 3H- [1,2,3]triazolo[4,5- b ] in a solution of Compound 246-1 (same as Compound 244-1) (20 mg, 0.031 mmol) in DMF (2 mL) Pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (HATU; 23.6 mg, 0.0620 mmol), compound 246-2 (same as compound 230-6) ( 11.9 mg, 0.0310 mmol) and TEA (0.013 ml, 0.093 mmol) were added and stirred at room temperature for 4 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 246 (16.0 mg, 0.0310 mmol, 57%) as a yellow solid.

Compound 247. 5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethyl)amino) -2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of compound 247-1 (same as compound 244-1) (20 mg, 0.031 mmol) in DMF (2 mL) was added HATU (23.6 mg, 0.0620 mmol), compound 247-2 (same as compound 235-2) ( 10.3 mg, 0.0310 mmol) and TEA (0.013 ml, 0.093 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete. The reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to yield a mixture of compounds 247 (18.0 mg, 0.0310 mmol, 69%) as a yellow solid.

Compound 248. 5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethoxy)- 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

HATU (23.6 mg, 0.0620 mmol), Compound 248-2 (same as Compound 236-2) (10.3) in a solution of Compound 248-1 (same as Compound 244-1) (20 mg, 0.031 mmol) in DMF (2 mL) mg, 0.0310 mmol) and TEA (0.013 ml, 0.093 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to obtain a mixture of compound 248 (16.0 mg, 0.0310 mmol, 61%) as a yellow solid.

Compound 250. 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d] Pyrimidin-6-yl)amino)-2-fluorophenyl)-3,6-dihydropyridine-1(2 H )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

Step 1: tert- butyl 4-(5-amino-2-fluorophenyl)-3,6-dihydropyridine-1(2 H )-Synthesis of carboxylate

3-Bromo-4-fluoroaniline (Compound 250-1) (Alfa Aesar, B25610) (219 mg, 1.17 mmol), tert- butyl 4-(4,4,5,5-tetramethyl) in a sealed tube. -1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1( 2H )-carboxylate (Compound 250-2) (BLD Pharm, BD33046) (397 mg, 1.29 mmol) was added. Pd(dppf) ₂ Cl ₂ ·CH ₂ Cl ₂ complex (47 mg, 0.059 mmol), DPPF (33 mg, 0.059 mmol), Na ₂ CO ₃ (372 mg) in dioxane (2 mL) and water (2 mL). , 3.51 mmol) was added, and the reaction mixture was stirred at 80 degrees for 15 hours. Upon completion, the reaction mixture was extracted with EtOAc (3×20 mL) and water (10 mL) and the organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 250-3 (149 mg, 0.51 mmol, 44%) as a gray-yellow solid.

Step 2: N ³ -(2,6-dimethylphenyl)- N ⁶ -(4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

6-Chloro- N- (2,6-dimethylphenyl)-1-methyl- 1H -pyrazolo[3,4- d ]pyrimidin-3-amine (Compound 250-4) in 2-propanol (1 mL) ) (same as compound 230-4) (70 mg, 0.24 mmol) and tert- butyl 4-(5-amino-2-fluorophenyl)-3,6-dihydropyridine-1( 2H )-carboxyl To a solution of rate (Compound 250-3) (67 mg, 0.24 mmol) was added p -toluenesulfonic acid (42 mg, 0.24 mmol), and the reaction mixture was heated to 95° C. and stirred for 15 hours. After completion of the reaction, the reaction mixture was concentrated and used directly in the next step. (Compound 250-5; 61 mg, 0.137 mmol, 57%)

Step 3: 5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)-3,6-dihydropyridin-1(2 H Synthesis of )-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 250)

N ³ -(2,6-dimethylphenyl)- N ⁶ -(4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-methyl-1 H - 1-(2-(2,6-dioxopiperidine-3-) in a solution of pyrazolo[3,4- d ]pyrimidine-3,6-diamine (Compound 250-5) (15 mg, 0.03 mmol) 1)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (compound 250-6) (same as compound 230-6) (13 mg, 0.03 mmol), MeOH (1 mL) ), acetic acid (2 μL, 0.03 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Afterwards, NaBH ₃ CN (3 mg, 0.05 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and extracted with DCM (3 x 15 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 250 (9 mg, 0.01 mmol, 33%) as an off-yellow solid.

Compound 253. 5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) )Isoindoline-1,3-dione

Step 1: tert- butyl 4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-4-fluoropiperidine-1-carboxylate

To a solution of Compound 253-1 (same as Compound 228-1) (60.0 mg, 0.140 mmol) in tetrahydrofuran (5 ml) was added Compound 253-2 (same as Compound 243-2) (1-( tert- butoxy Carbonyl)-4-fluoropiperidine-4-carboxylic acid) (34.7 mg, 0.140 mmol), HATU (80 mg, 0.210 mmol) and TEA (0.0470ml, 0.351mmol) were added and incubated at room temperature for 4 hours. It was stirred for a while. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 253-3 (50.0 mg, 0.140 mmol, 54%) as a yellow solid.

Step 2: (4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)(4-fluoropiperidin-4-yl)methanone 2,2,2-trifluoroacetate

40% TFA/DCM (1 mL) and compound 253-3 (49 mg, 0.075 mmol) were added to 50 mL rb and stirred at room temperature for 2 hours. TLC showed that the reaction was complete. The solvent was completely evaporated, the residue was washed with diethyl ether, and the product was dried under high vacuum to give compound 253-4 (46 mg, 0.075 mmol, 92%) as a yellow solid.

Step 3: 5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 253 ) synthesis of

Compound 253-5 (same as Compound 232-4) (6.18 mg, 0.022 mmol) and DIPEA (8.69 mg, 0.067 mmol) were added to a solution of Compound 253-4 (15 mg, 0.022 mmol) in DMSO (2 mL) at room temperature. It was added from . The resulting mixture was stirred at 90°C for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with DCM (15 mL ×2), the combined organic layers were washed with water (20 mL ×2) and brine (20 mL ×2), the combined organic layers were dried over sodium sulfate and the solvents were evacuated. evaporated under The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 253 (3.0 mg, 0.022 mmol, 18%) as a yellow solid.

Compound 254. 5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) )-6-fluoroisoindoline-1,3-dione

To a solution of Compound 254-1 (same as Compound 253-4) (15 mg, 0.022 mmol) in DMSO (2 mL) was added Compound 254-2 (same as Compound 208-3) (6.58 mg, 0.022 mmol) and DIPEA ( 8.69 mg, 0.067 mmol) was added at room temperature. The resulting mixture was stirred at 90°C for 12 hours. TLC indicates that a new spot has been created. The reaction was quenched with 10 mL of water and extracted with EA (15 mL x 2), the combined organic layers were washed with water (20 mL x 2) and brine (20 mL x 2), the combined organic layers were dried over sodium sulfate and vacuum. The solvent was evaporated. The crude mixture was purified under MPLC using 5% MeOH:DCM as solvent mixture to give compound 254 (11 mg, 0.022 mmol, 59%) as a yellow solid.

Compound 255. 3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carbonyl)-1-oxoisoindoline- 2-yl)piperidine-2,6-dione

Compound 255-2 (same as Compound 256-2) (8.97 mg, 0.031 mmol), HATU (11.83) in a solution of Compound 255-1 (same as Compound 244-1) (20 mg, 0.031 mmol) in DMF (5 ml) mg, 0.031 mmol) and TEA (4.20 μl, 0.031 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 255 (12.0 mg, 0.0310 mmol, 48%) as a yellow solid.

Compound 256. 3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Compound 256-2 (BLD, BD01396745) (8.22 mg, 0.029 mmol), HATU (21.70 mg, 0.057) in a solution of Compound 256-1 (same as Compound 245-1) (15 mg, 0.029 mmol) in DMF (5 ml) mmol) and TEA (15.39 μl, 0.114 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to yield compound 256 (8.0 mg, 0.029 mmol, 35%) as a yellow solid.

Compound 257. 3-(5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

Compound 257-2 (same as Compound 256-2) (10.11 mg, 0.035 mmol), HATU (26.7) in a solution of Compound 257-1 (same as Compound 253-1) (15 mg, 0.035 mmol) in DMF (2 ml) mg, 0.070 mmol) and TEA (18.92 μl, 0.140 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to give a mixture of compound 257 (12.0 mg, 0.0350 mmol, 49%) as a yellow solid.

Compound 258. 3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]Pyrimidin-6-yl)amino)-3,4-dihydroisoquinoline-2(1 H )-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of Compound 258-1 (same as Compound 201-1) (15 mg, 0.030 mmol) in DMF (1 ml) was added Compound 258-2 (same as Compound 256-2) (8.71 mg, 0.030 mmol), HATU ( 22.97 mg, 0.060 mmol) and TEA (0.012 ml, 0.091 mmol) were added and stirred at room temperature for 12 hours. TLC showed the reaction was complete, the reaction was quenched with water, the aqueous layer was extracted with EtOAc (25 mL x 2), and the combined organic layers were washed with water (20 mL x 2) and brine solution (20 mL x 2). The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The crude mixture was purified by MPLC using 5% MeOH:DCM as eluent to yield a mixture of compound 258 (7.00 mg, 0.0300 mmol, 30%) as a yellow solid.

Compound 259. (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline -5-carbonyl)piperidin-4-yl)acrylonitrile

To a suspension of compound 259-1 (same as compound 260-1) (15.0 mg. 0.027 mmol) in DMF (2 mL) was added DIPEA (10.3 mg, 0.080 mmol) followed by HATU (20.3 mg, 0.053 mmol) at room temperature. And the reaction mixture was stirred for 15 minutes. Compound 259-2 (same as compound 256-2) (8.47 mg, 0.029 mmol) was added and the reaction mixture was allowed to stir at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 259 (8.2 mg, 9.86 μmol, 36.9%) as a yellow solid. did.

Compound 260. (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-((2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)acrylonitrile

To a suspension of Compound 260-1 (same as Compound 240-1) (15 mg, 0.027 mmol) in DMF (2 mL) was added DIPEA followed by HATU (20 mg, 0.053 mmol) at room temperature and the reaction mixture was stirred for 15 min. It was stirred. Compound 260-2 (same as compound 235-2) (9.7 mg, 0.029 mmol) was added and the reaction mixture was allowed to stir at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 260 (12.2 mg, 0.014 mmol, 52.2%) as a yellow solid. did.

Compound 261. (E)-2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3- dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)acrylonitrile

Step 1: Synthesis of (E)-3-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-cyanoacrylic acid

Compound 261-1-A (sigma, 722022) ( tert -butyl 4-formylpiperidine-1-carboxylate (1.0 g, 4.6 mmol), Compound 261-1-B (sigma, A mixture of C88505) (cyanoacetic acid) (479 mg, 5.6 mmol), glacial acetic acid (296 mg, 4.9 mmol), and ammonium acetate (181 mg, 2.3 mmol) was stirred and heated at 85° C. for 3 hours. The reaction mixture was Cooled to room temperature and diluted with ethyl acetate (15 mL). Split the layers and extracted the aqueous phase with EtOAc (25 mL x 1). The combined organic layers were washed with 1 M aqueous sodium hydroxide solution (25 mL x 1). Dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was loaded onto a 15% EtOAc/hexane silica column to give the desired compound 261-1-C (632 mg, 2.255 mmol, 48.1 %) as a beige solid. It was obtained as.

Step 2: tert -Butyl (E)-4-(2-cyano-3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4 ])-d]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)-3-oxoprop-1-en-1-yl)piperidine-1-carboxylate synthesis

To a suspension of compound 261-1-C (19 mg, 0.067 mmol) in DMF (3 mL) was added DIPEA (22 mg, 0.16 mmol) followed by HATU (43 mg, 0.11 mmol) at room temperature and the reaction mixture was incubated for 15 min. It was stirred for a while. Compound 261-1-D (same as compound 225-1) (24 mg, 0.056 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 x 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to yield compound 261-1-E (25 mg, 0.036 mmol, 64.6%). was obtained as a beige solid.

Step 3: (E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Synthesis of amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(piperidin-4-yl)acrylonitrile

To a solution of compound 261-1-E (24 mg, 0.035 mmol) in DCM (5 ml) was added 4 N HCl in dioxane (3.0 mg, 0.070 mmol). The reaction mixture was stirred at room temperature overnight. The crude material was concentrated in vacuo and the resulting crude material was dissolved in water and washed with EA (3x), then the aqueous layer was neutralized using saturated NaHCO ₃ and extracted with EA (3x), the organic layer was evaporated and vacuum Compound 261-1 (12 mg, 0.020 mmol, 58.5%) was obtained as a yellow solid.

Step 4: (E)-2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3- Synthesis of dioxoisoindolin-5-yl)glycyl)piperidin-4-yl)acrylonitrile (Compound 261)

To a suspension of compound 261-1 (11 mg, 0.019 mmol) in DMF (2 mL) was added DIPEA followed by HATU (15 mg, 0.037 mmol) at room temperature and the reaction mixture was stirred for 15 minutes. Compound 261-2 (same as compound 235-2) (7.0 mg, 0.019 mmol) was added and the reaction mixture was stirred at room temperature for 14 hours. The crude reaction mixture was diluted with 10 mL water and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over MgSO ₄ and concentrated in vacuo to give the crude mixture, which was purified by column chromatography using MeOH/DCM 5% to give compound 261 (9.2 mg, 10.19 μmol, 54.6%) as a yellow solid. did.

Compound 262. 3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -Benzo[ d ]imidazol-1-yl)piperidine-2,6-dione

Step 1: tert- butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-5-yl)piperidine-4-carboxylate

tert- Butyl piperidine-4-carboxylate hydrochloride (Compound 262-2) in a solution of Compound 262-1 (WO2020/113233) (100 mg, 0.22 mmol) in 1,4-dioxane (3 mL) (Acadechem, 20190523AP-1X, 50g) (58 mg, 0.26 mmol), cesium carbonate (220 mg, 0.68 mmol), RuPhos (20 mg, 0.04 mmol), and RuPhos Pd G2 (34 mg, 0.04 mmol) were added. The reaction mixture was then bubbled with nitrogen gas for 5 minutes. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 50% EtOAc/HEX to obtain compound 262-3 (51 mg, 0.07 mmol, 42%) as an off-white solid.

Step 2: 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-5-yl)piperidine-4-carboxylic acid

tert - Butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3- in trifluoroacetic acid (1 mL) and DCM (1.5 mL) Methyl-2-oxo-2,3-dihydro- 1H -benzo[ d ]imidazol-5-yl)piperidine-4-carboxylate (Compound 262-3) (51 mg, 0.09 mmol) solution was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion, the solvent was removed under reduced pressure. And the formed ivory solid was washed with diethyl ether and concentrated under vacuum to obtain compound 262-4 (46 mg, 0.09 mmol, quant.) as an ivory solid.

Step 3: 3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(4-(piperidin-4-yl)phenyl)-1 H -pyrazolo[3,4- in DMF (1 mL) d ] 1-(1-(1-(4-methoxybenzyl)- in a solution of pyrimidine-3,6-diamine (compound 262-5) (same as compound 228-1) (20 mg, 0.05 mmol) 2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]imidazol-5-yl)piperidine-4-car Boxylic acid (compound 262-4) (24 mg, 0.05 mmol), 1-[bis(dimethylamino)methylene] -1H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide Hexafluorophosphate (HATU; 36 mg, 0.09 mmol) and triethylamine (20 μL, 0.14 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete, quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x 5 mL) and brine solution. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 262-6 (33 mg, 0.04 mmol, 77%) as a grey-brown solid.

Step 4: 3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-1-yl)piperidine-2,6-dione (Compound 262)

3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidine-1-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo [ d ]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (Compound 262-6) (70 mg, 0.24 mmol) was added to a solution of methanesulfonic acid (47). μL, 0.72 mmol) was added, the reaction mixture was heated to 100°C, and then stirred at the same temperature for 2 hours. The reaction was complete, quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x 5 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 10% MeOH/DCM to obtain compound 262 (5 mg, 0.01 mmol, 17%) as an off-white solid.

Compound 263. 5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-2-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-carbonyl)azetidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione

N ³ -(2,6-dimethylphenyl)- N ⁶ -(4-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1 in DMF (1 mL) 1- ( 2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)azetidine-3-carboxylic acid (Compound 263-2) (Compound 228-2 and Same) (12 mg, 0.03 mmol), 1-[bis(dimethylamino)methylene]-1H - 1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU) ; 26 mg, 0.07 mmol) and triethylamine (14 μL, 0.10 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete, quenched with water, extracted with EtOAc (3×15 mL) and washed with water (3×5 mL) and brine solution. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 263 (10 mg, 0.01 mmol, 38%) as an off-yellow solid.

Compound 264. 3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3- dihydro-1 H -Benzo[ d ]imidazol-1-yl)piperidine-2,6-dione

Step 1: tert- butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-5-yl)piperidine-4-carboxylate

To a solution of Compound 264-1 (same as Compound 262-1) (70 mg, 0.15 mmol) in 1,4-dioxane (3 mL) was added tert- butyl piperidine-4-carboxylate hydrochloride (Compound 264). -2) (Acadechem, 20190523AP-1X, 50 g) (41 mg, 0.18 mmol), cesium carbonate (154 mg, 0.47 mmol), RuPhos (14 mg, 0.03 mmol), RuPhos Pd G2 (24 mg, 0.03 mmol) was added. The reaction mixture was then bubbled with nitrogen gas for 5 minutes. The reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 50% EtOAc/HEX to obtain compound 264-3 (35 mg, 0.06 mmol, 41%) as an off-white solid.

Step 2: 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-5-yl)piperidine-4-carboxylic acid

tert -Butyl 1-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3 in toluene (1 mL) -Dihydro-1 H -benzo[ d ]imidazol-5-yl)piperidine-4-carboxylate (compound 264-3) (35 mg, 0.06 mmol) was added to a solution of methanesulfonic acid (81 μL, 1.24 mmol) was added, the reaction mixture was heated to 100° C., and then stirred at the same temperature for 2 hours. The reaction was complete, quenched with water, extracted with EtOAc (3 x 15 mL) and washed with water (3 x 5 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting white precipitate was dried under reduced pressure to obtain compound 264-4 (18 mg, 0.05 mmol, 75%) as an off-white solid.

Step 3: 3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1 H -benzo[ d ]Synthesis of imidazol-1-yl)piperidine-2,6-dione (Compound 264)

1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro- 1H -benzo[ d ]imidazole in DMF (1 mL) -5-yl)piperidine-4-carboxylic acid (compound 264-4) (15 mg, 0.04 mmol) in a solution of N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -( 1,2,3,4-Tetrahydroisoquinolin-7-yl) -1H -pyrazolo[3,4- d ]pyrimidine-3,6-diamine (Compound 264-5) (Korean Patent No. 2128018 Ho) (15 mg, 0.04 mmol), 1-[bis(dimethylamino)methylene] -1H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate (HATU) ; 29 mg, 0.08 mmol) and triethylamine (16 μL, 0.11 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was complete, quenched with water, extracted with EtOAc (3×15 mL) and washed with water (3×5 mL) and brine solution. The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 264 (7 mg, 0.01 mmol, 24%) as an off-white solid.

Compound 268. 5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)pyridazin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) )Isoindoline-1,3-dione

Step 1: tert- Synthesis of butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate

3,6-dichloropyridazine (SIGMA, D73200) (compound 268-1; 1.0 g, 6.7 mmol) and tert- butyl piperazine-1-carboxylate (SIGMA, 15502) (SIGMA, 15502) in DMF (5.0 mL) at room temperature. DIPEA (1.8 mL, 10.1 mmol) was added to a solution of compound 268-2 (1.3 g, 6.7 mmol). The reaction mixture was stirred at 80°C for 12 hours. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 30% EtOAc/Hx to obtain compound 268-3 (1.7 g, 5.77 mmol, 86%) as an off-white solid.

Step 2: tert- Synthesis of butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate

Cs ₂ CO ₃ (916) in a solution of tert- butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (Compound 268-3; 420.0 mg, 1.4 mmol) in toluene (5.0 mL). mg, 2.81 mmol), Pd ₂ (dba) ₃ (64 mg, 0.070 mmol), BINAP (88 mg, 0.141 mmol), diphenylmethanimine (SIGMA, 293733) (compound 268-4; 364 μl, 2.11 mmol) was added. The reaction mixture was stirred at 100° C. for 12 hours under nitrogen gas. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 50% EtOAc/Hx to obtain compound 268-5 (382 mg, 0.860 mmol, 61%) as an off-white solid.

Step 3: tert- Synthesis of butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate

tert- Butyl 4-(6-((diphenylmethylene)amino)pyridazin-3-yl)piperazine-1-carboxylate (Compound 268-5) (380 mg, 0.857 mmol) in THF (5.0 mL). was dissolved. Then, 2 M aqueous citric acid solution (2.6 ml, 5.14 mmol) was added and the mixture was stirred at room temperature for 12 hours. The reaction solution was neutralized with saturated aqueous sodium bicarbonate solution, quenched with water, and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The obtained crude product was washed with ether to obtain compound 268-6 (180 mg, 0.643 mmol, 75%) as an off-white solid.

Step 4: tert- butyl-4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl- 1H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate

6-Chloro- N -(2,6-dimethylphenyl)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin _- 3-amine in toluene/H 2 O (1.0 mL/4 μL) (Compound 268-7) (same as Compound 230-4) (50 mg, 0.17 mmol) in solution of K ₃ PO ₄ (55 mg, 0.26 mmol), Pd ₂ (dba) ₃ (8 mg, 0.0087 mmol), and Phos (10 mg, 0.017 mmol) and tert- butyl 4-(6-aminopyridazin-3-yl)piperazine-1-carboxylate (compound 268-6) (58 mg, 0.21 mmol) were added. The reaction mixture was stirred at 100°C for 12 hours under nitrogen gas. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 268-8 (56 mg, 0.104 mmol, 61%) as an off-yellow solid.

Step 5: N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(6-(piperazin-1-yl)pyridazin-3-yl)-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

tert- Butyl-4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidine- in DCM (1.0 mL) A solution of 6-yl)amino)pyridazin-3-yl)piperazine-1-carboxylate (Compound 268-8) (55 mg, 0.104 mmol) in 4 M HCl/1,4-dioxane (0.26 mL) , 1.04 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give compound 268-9 (50 mg, 0.116 mmol, quant.) as an off-yellow solid.

Step 6: tert- butyl-4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)pyridazin-3-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate

N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(6-(piperazin-1-yl)pyridazin-3-yl)-1 H -pyrazolo[ in MeOH (3.0 mL) 3,4- d ]pyrimidine-3,6-diamine (compound 268-9) (65 mg, 0.151 mmol) in a solution of tert- butyl 4-formylpiperidine-1-carboxylate (SIGMA, 722022) (Compound 268-10) (35 mg, 0.166 mmol) and 1M AcOH/MeOH (151 μL) were added. The reaction mixture was stirred at room temperature for 12 hours. Afterwards, NaBH ₃ CN (14 mg, 0.226 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, it was quenched with water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 268-11 (73 mg, 0.116 mmol, 77%) as an off-yellow solid.

Step 7: N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyridazin-3-yl)-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

tert- Butyl-4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl- 1H -pyrazolo[3,4- d) in DCM (1.5 mL) ]Pyrimidin-6-yl)amino)pyridazin-3-yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (Compound 268-11) (70 mg, 0.112 mmol) 4 M HCl/1,4-dioxane (0.278 mL, 1.12 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, it was quenched with water and extracted with DCM (3 × 10 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give compound 268-12 (63 mg, 0.119 mmol, quantitative) as an off-yellow solid.

Step 8: 5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)pyridazin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione Synthesis of (Compound 268)

N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(6-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pyridazine in DMSO (1 mL) -3-yl) -1H -pyrazolo[3,4- d ]pyrimidine-3,6-diamine (Compound 268-12) (15 mg, 0.028 mmol) and Compound 268-13 (Compound 232-4 and The reaction mixture of (7.9 mg, 0.028 mmol) and DIPEA (25 μL, 0.142 mmol) was stirred at 90°C for 12 hours. After completion of the reaction, it was quenched with water and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure. The resulting mixture was purified by column chromatography using 5% MeOH/DCM to obtain compound 268 (18 mg, 0.023 mmol, 81%) as an off-yellow solid.

Compound 272. 3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -Pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin- 2,6-dione

Step 1: tert- butyl 4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidin-6-yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate

To a solution of Compound 272-1 (same as Compound 222-3) (100 mg, 0.234 mmol) in MeOH (1 mL) was added Compound 272-2 (TCI B3873) (54.9 mg, 0.257 mmol) with acetic acid (1 drop, catalytic amount). ) was added and stirred for 15 hours. Afterwards, NaBH ₃ CN (22 mg, 0.350 mmol) was added to the reaction and stirred for 1 hour. It was confirmed that the reaction was complete through TLC. Afterwards, the solvent was completely evaporated. The residue was dissolved in MC and washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under vacuum. The residue was purified under MPLC using 10% MeOH/MC to give compound 272-3 (56.1 mg, 0.090 mmol, 38.4%).

Step 2: N ³ -(2,6-dimethylphenyl)-1-methyl- N ⁶ -(4-(1-(piperidin-4-ylmethyl)piperidin-4-yl)phenyl)-1 H -pyrazolo[3,4- d ]Synthesis of pyrimidine-3,6-diamine

To a solution of compound 272-3 (50 mg, 0.080 mmol) in DCM (1.0 mL) was added 4 N HCl/dioxane (0.5 ml, excess). The reaction was stirred at room temperature for 12 hours. No starting material was observed in the TLC results. The solvent was evaporated under vacuum and a base work-up was provided with saturated NaHCO ₃ solution. After base treatment, the organic layer was recrystallized from chloroform/Hex to obtain compound 272-4 (17 mg, 0.032 mmol, 41%) as an off-white solid.

Step 3: 3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1 H -pyrazolo[3,4- d ]pyrimidin-6-yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 272) synthesis

To a solution of Compound 272-4 (15 mg, 0.029 mmol) in DMSO (1 mL) was added Compound 272-5 (same as Compound 220-2) (8.01 mg, 0.029 mmol) and DIPEA (0.025 ml, 0.143 mol). Then, the temperature was raised from room temperature to 90°C and stirred for 13 hours until the reaction was completed. TLC indicates that a new spot has been created. The reaction was quenched with 5 mL of water, extracted with EA, and the combined organic layers were washed with water and brine solution. The combined organic layers were dried over sodium sulfate, then filtered and evaporated under vacuum. The crude mixture was purified under MPLC using 10% MeOH:DCM as solvent mixture to give compound 272 (3.5 mg, 0.00045 mmol, 16%) as a yellow solid.

<Physical data for exemplary compounds of Example 1>

¹ H NMR spectra and mass spectrometry (LCMS) data were obtained for the example compounds reported in Example 1. These experimental data are provided in Table 1.

compound number 1H NMR/Mass Spec(LCMS) Compound 1 LC/MS 385 [M/2], 769 [M+H], 791 [M+Na],
^1H NMR (500 MHz, Chloroform-d) δ 10.95 (s, 1H), 9.08 (s, 1H), 8.10 (s, 1H), 7.64-7.56 (m, 1H), 7.54-7.47 (m, 1H) , 7.48-7.39 (m, 1H), 7.19 (d, J = 9.5 Hz, 3H), 7.14-7.08 (m, 2H), 6.92 (dd, J = 12.6, 8.5 Hz, 1H), 6.28 (dt, J = 25.1, 5.9 Hz, 1H), 6.14 (s, 0.5H), 6.00 (d, J = 9.3 Hz, 0.5H), 4.94 (td, J = 11.5, 5.2 Hz, 1H), 4.76 (d, J = 6.0 Hz, 1H), 4.54 (s, 2=1H), 3.82 (d, J = 4.6 Hz, 4H), 3.70-3.64 (m, 1H), 3.39-3.26 (m, 2H), 2.91-2.69 (m , 5H), 2.49-2.35 (m, 2H), 2.30 (d, J = 4.7 Hz, 6H), 2.19z-2.12 (m, 1H), 1.80-1.68 (m, 3H), 1.67 (s, 2H) , 1.56-1.45 (m, 2H). compound 2 LC/MS: 801[M+H] ^+
1H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.62 (d, J = 8.3 Hz, 1H), 8.33 (d, J = 3.0 Hz, 1H), 8.09 (s, 1H), 7.74-7.59 (m, 2H), 7.53 (dd, J = 19.5, 8.3 Hz, 1H), 7.21-6.98 (m, 6H), 6.87 (dd, J = 22.4, 8.2 Hz, 1H), 5.02 (dd, J = 12.9, 5.3 Hz, 1H), 4.58 (d, J = 5.3 Hz, 2H), 4.26 (d, J = 13.9 Hz, 2H), 3.69-3.64 (m, 1H), 3.63-3.55 (m, 8H) ), 2.98-2.64 (m, 6H), 2.58 (s, 2H), 2.20 (s, 6H), 1.94 (s, 2H) Compound 3 LC/MS: 801.2 [M+H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.34 (s, 1H), 8.26 (d, J = 4.9 Hz, 2H), 7.91 (d, J = 10.5 Hz, 1H) , 7.71-7.51 (m, 3H). 7.18-6.99 (m, 6H), 6.55 (s, 1H), 5.01 (dd, J = 12.3, 4.0 Hz, 1H), 4.59 (s, 2H), 4.25 (s, 2H), 3.63 (s, 11H) , 3.47 (s, 2H), 2.99-2.70 (m, 6H), 2.22 (s, 6H), 2.10-1.91 (m, 2H). Compound 4 LC/MS: 912.4[M+H] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.63 (d, J = 12.4 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.09 (s, 1H) , 7.88 (s, 1H), 7.73-7.56 (m, 3H), 7.29 (d, J = 9.2 Hz, 2H), 7.10-7.07 (m, 4H), 5.09 (dd, J = 12.8, 5.4 Hz, 1H) ), 4.59 (d, J = 5.4 Hz, 2H), 4.27 (d, J = 9.3 Hz, 2H), 3.79-3.49 (m, 9H), 3.48-3.36 (m, 3H), 3.22 (d, J = 7.0 Hz, 2H), 2.93-2.60 (m, 5H), 2.33 (s, 2H), 2.20 (s, 5H), 2.08-1.95 (m, 2H), 1.76 (s, 4H). Compound 5 LC/MS 1000 [M+H] ⁺ 1023.0[M+Na] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.63 (d, J = 10.3 Hz, 1H), 8.37-8.28 (m, 1H), 8.09 (s, 1H), 7.90- 7.82 (m, 1H), 7.74-7.58 (m, 3H), 7.32 (d, J = 7.7 Hz, 2H), 7.16-7.02 (m, 4H), 5.09 (dd, J = 12.9, 5.4 Hz, 1H) ,4.59 (d, J = 10.0 Hz, 2H), 4.25 (d, J = 9.3 Hz, 2H), 3.75-3.44 (m, 18H), 3.43-3.35 (m, 3H)), 3.24-3.15 (m, 2H), 2.97-2.64 (m, 6H), 2.37-2.28 (m, 2H), 2.20 (s, 6H), 2.10-1.96 (m, 2H), 1.77 (s, 4H). Compound 6 LC/MS: 1124.2 [M+H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.78 (s, 1H), 9.55 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.90 ( s, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.6 Hz, 3H), 7.13 (d, J = 8.6 Hz, 1H), 7.03 (d, J = 6.5 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 6.72 (s, 2H), 6.60 (t, J = 5.8 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.12- 4.05 (m, 2H), 4.01 (t, J = 4.7 Hz, 2H), 3.74-3.50 (m, 18H), 3.48-3.40 (m, 2H), 2.93-2.72 (m, 5H), 2.70-2.57 ( m, 2H), 2.16 (s, 6H), 2.07-95 (m, 2H), 1.75 (s, 6H), 1.24 (s, 2H). Compound 7 LC/MS 853.2 [M+H] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.63 (d, J = 8.6 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.64-7.53 (m, 2H), 7.16 7.05 (m, 4H), 7.02 (d, J = 7.1 Hz, 1H), 6.52 (s, 1H), 5.05 (dd, J = 13.0, 5.4 Hz, 1H), 4.66-4.54 (m, 2H), 3.69-3.59 (m, 4H), 3.28 (t, J = 6.7 Hz, 2H), 2.94-2.56 (m, 5H), 2.46-2.32 (m, 3H) , 2.20 (s, 5H), 2.10-1.95 (m, 2H), 1.62-1.45 (m, 4H), 1.38-1.16 (m, 14H). Compound 8 LC/MS ESI 889.4 [M + H]+,912.5[M+Na] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.69-9.60 (m, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.72-7.60 (m, 2H) ), 7.55 (d, J = 8.4 Hz, 1H), 7.19-7.06 (m, 5H), 7.00 (s, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 12.5, 5.4 Hz, 1H), 4.59 (d, J = 13.2 Hz, 2H), 4.25 (d, J = 13.2 Hz, 2H), 3.71-3.42 (m, 22H), 2.92-2.63 (m, 4H), 2.20 ( s, 6H), 2.04-1.95 (m, 1H). Compound 9 LC/MS 947.4 [M + H] +, 969.4 [M + Na] ⁺ .
^1H NMR (400 MHz, Chloroform-d) δ 10.49 (s, 1H), 8.33 (s, 1H), 7.87-7.34 (m, 5H), 7.30 (dd, J = 8.3, 2.3 Hz, 1H), 7.24 -6.99 (m, 5H), 6.06 (d, J = 55.5 Hz, 1H), 4.97 (dd, J = 12.2, 5.3 Hz, 1H), 4.76-4.45 (m, 4H), 4.26 (d, J = 28.6) Hz, 2H), 3.86-3.51 (m, 19H), 2.95-2.66 (m, 5H), 2.28 (s, 6H), 2.20-1.96 (m, 2H). Compound 10 LC/MS 947.2 [M + H] ⁺ .
^1H NMR (500 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.65 (d, J = 13.1 Hz, 1H), 8.36 (s, 1H), 8.21-8.14 (m, 1H), 8.11 ( s, 1H), 7.73-7.55 (m, 3H), 7.16-7.05 (m, 4H), 6.95 (d, J = 5.6 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 5.08 (dd , J = 12.5, 5.4 Hz, 1H), 4.59 (d, J = 12.1 Hz, 2H), 4.25 (d, J = 12.9 Hz, 2H), 3.94 (d, J = 5.6 Hz, 2H), 3.66-3.38 (m, 17H), 3.26 (d, J = 8.1 Hz, 2H), 3.13-3.07 (m, 4H), 2.94-2.59 (m, 4H), 2.20 (s, 5H), 2.07-1.99 (m, 1H) ). Compound 11 LC/MS (ESI) 925.4 [M + H] +, 947.8 [M + Na] ^+
1H NMR (400 MHz, Methanol-d ₄ ) δ 8.00-7.91 (m, 2H), 7.48-7.33 (m, 3H), 7.04-6.99 (m, 3H), 6.95 (d, J = 7.6 Hz, 2H ), 6.72 (d, J = 8.5 Hz, 1H), 4.92 (dd, J = 12.4, 5.5 Hz, 1H), 4.49 (dt, J = 22.4, 5.0 Hz, 3fH), 3.92-3.64 (m, 8H) , 3.56 (d, J = 7.3 Hz, 3H), 3.45-3.30 (m, 6H), 2.82 (s, 4H), 2.76-2.49 (m, 3H), 2.16 (s, 6H), 2.02-1.85 (m , 2H). Compound 12 LC/MS (ESI) 926.0 [M + H] +, 949.1 [M + Na] ^+
1H NMR (400 MHz, Chloroform-d) δ 10.44-9.85 (m, 2H), 8.05-7.67 (m, 3H), 7.62 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.24 -7.06 (m, 5H), 6.99 (s, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.17 (s, 1H), 5.97 (s, 1H), 4.96 (dd, J = 12.0, 5.2 Hz, 1H), 4.56 (t, J = 4.9 Hz, 2H), 3.85 (d, J = 43.9 Hz, 10H), 3.67-3.40 (m, 7H), 3.21-2.57 (m, 8H), 2.29 (s) , 6H), 2.17-2.00 (m, 2H). Compound 13 LC/MS (ESI) 890.2 [M+H] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.62 (d, J = 10.2 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H) , 7.70-7.53 (m, 3H), 7.16-7.05 (m, 5H), 7.02 (d, J = 7.1 Hz, 1H), 6.63-6.50 (m, 1H), 5.05 (dd, J = 12.8, 5.4 Hz) , 1H), 4.58 (d, J = 11.4 Hz, 2H), 4.24 (d, J = 10.0 Hz, 2H), 3.68-3.37 (m, 21H), 2.94-2.63 (m, 4H), 2.20 (s, 6H), 2.07-1.91 (m, 2H). Compound 14 LC/MS 904.2 [M + H] +, 926.2 [M + Na] ^+
1 H NMR (400 MHz, Methanol-d ₄ ) δ 7.96 (s, 1H), 7.80 (s, 1H), 7.58-7.32 (m, 3H), 7.04 (s, 4H), 6.94-6.84 (m, 2H) ), 4.96-4.87 (m, 1H), 4.61 (d, J = 23.3 Hz, 2H), 3.73-3.26 (m, 22H), 2.85-2.47 (m, 7H), 2.16 (s, 6H), 2.04- 1.87 (m, 2H). Compound 15 LC/MS 904.0 [M + H] +, 926.1 [M + Na] ^+
1 H NMR (400 MHz, Methanol-d ₄ ) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.67-7.48 (m, 3H), 7.21-7.08 (m, 4H), 6.99 (dd, J = 7.2, 2.2 Hz, 1H), 6.88-6.78 (m, 1H), 5.03 (dd, J = 12.3, 5.4 Hz, 1H), 4.73 (d, J = 21.1 Hz, 2H), 3.92-3.42 (m, 22H), 2.92-2.65 (m, 7H), 2.28 (s, 6H), 2.06 (t, J = 12.0 Hz, 2H). Compound 16 LC/MS 962.3 [M + H] ⁺ , 984.3 [M+Na] ^+
1H NMR (400 MHz, Methanol-d ₄ ) δ 7.97 (s, 1H), 7.80 (s, 1H), 7.67 (dd, J = 8.3, 3.9 Hz, 1H), 7.50 (s, 1H), 7.48- 7.40 (m, 1H), 7.29 (dd, J = 7.0, 2.3 Hz, 1H), 7.22 (td, J = 8.2, 2.3 Hz, 1H), 7.07-6.94 (m, 4H), 3.73-3.62 (m, 3H), 3.57 (s, 3H), 3.52-3.30 (m, 16H), 2.83-2.48 (m, 7H)), 2.16 (s, 6H), 2.04-1.83 (m, 2H). Compound 17 LC/MS 962.3 [M + H] ⁺ , 984.3 [M + Na] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.62 (d, J = 9.2 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 8.09 (s, 1H) , 8.00 (t, J = 5.7 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.17-7.04 (m, 4H), 5.11 (dd, J = 13.0, 5.4 Hz, 1H), 4.78 (s, 2H), 4.61 (d, J = 28.7 Hz, 2H), 3.73-3.56 (m, 7H), 3.56-3.41 (m, 13H), 2.96-2.55 (m, 8H), 2.20 (s, 6H), 2.0-1.89 ( m, 2H). Compound 18 LC/MS 1030.3 [M + H] +, 1052.4 [M + Na] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.62 (d, J = 10.0 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H) , 7.78 (s, 1H), 7.72-7.58 (m, 3H), 7.35 (s, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.16-7.05 (m, 4H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 (d, J = 27.4 Hz, 2H), 3.71-3.58 (m, 7H), 3.55-3.38 (m, 17H), 3.26 (d, J = 6.0 Hz, 2H) , 3.03-2.54 (m, 13H), 2.20 (s, 6H), 2.04-1.91 (m, 2H). Compound 19 LC/MS 981.0 [M - H] ^-
1H NMR (500 MHz, Methanol-d ₄ ) δ 8.34 (s, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.04 (s, 4H), 6.93 (t, J = 6.3 Hz, 1H), 6.75-6.66 (m, 1H), 5.17 (s, 1H), 4.68-4.60 (m, 1H), 4.55 (s, 2H), 4.16 (s, 1H), 3.83 (d, J = 11.7 Hz, 4H), 3.65-3.24 (m, 17H), 2.90-2.79 (m, 2H), 2.37 (d, J = 7.9 Hz, 1H), 2.27-2.22 (m, 1H), 2.17 (s, 6H), 1.93 (d, J = 11.8 Hz, 2H). Compound 20 LC/MS: 869.7 [M + H] ^+
1H NMR (300 MHz, Chloroform-d) δ 11.05 (s, 1H), 8.36 (s, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.64 (s, 1H), 7.18 (s, 3H), 7.12-6.97 (m, 3H), 5.92 (s, 1H), 4.97 (dd, J = 12.3, 5.1 Hz, 1H), 3.88-3.56 (m, 10H), 3.38 (t, J = 6.4, 4H), 3.11 (d, J = 7.4 Hz, 2H), 3.00-2.61 (m, 12H), 2.28 (s, 6H), 2.18-2.10 (m, 1H) , 2.03 (d, J = 5.7 Hz, 2H). Compound 21 LC/MS 854.3 [M + H] ^+
1H NMR (300 MHz, Chloroform-d) δ 8.41-7.99 (m, 1H), 7.68-7.53 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 7.21-6.91 (m, 6H) , 6.82 (d, J = 8.5 Hz, 1H), 6.07 (s, 1H), 5.15-5.03 (m, 1H), 3.96-3.74 (m, 4H), 3.73 (s, 3H), 3.64 (s, 4H) ), 3.47 (s, 1H), 2.96 (s, 9H), 2.24 (s, 6H), 2.09-2.01 (m, 2H). Compound 22 LC/MS 960.2 [M + H] ^+
1 H NMR (400 MHz, Chloroform-d) δ 10.48 (s, br 1H), 8.15 (s, 1H), 7.83-7.54 (m, 3H), 7.45 (s, 1H), 7.24-7.02 (m, 5H) ), 6.95-6.85 (m, 1H), 6.44 (s, 1H), 5.95 (s, 1H), 5.00-4.90 (m, 1H), 4.81 - 4.55 (m, 2H), 3.93-3.40 (m, 24H) ), 3.01-2.67 (m, 6H), 2.56-2.49 (m, 1H), 2.30 (s, 5H), 2.10-2.00 (m, 2H) Compound 23 LC/MS: 801.2 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 10.33 (s, 1H), 9.50 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.07 ( s, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.61-7.45 (m, 2H), 7.16-7.04 (m, 3H), 6.97 (d) , J = 8.3 Hz, 1H), 5.11 (dd, J = 12.8, 5.4 Hz, 1H), 4.19 (s, 2H), 3.74-3.50 (m, 10H), 2.95-2.55 (m, 9H), 2.19 ( s, 6H), 2.09-1.93 (m, 2H). Compound 24 LC/MS: 854.2 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.54 (s, 1H), 8.32 (s, 2H), 8.08 (s, 1H), 7.88 (t, J = 5.2 Hz 2H ), 7.64-7.52 (m, 3H), 7.29 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.17-7.05 (m, 3H), 7.02 (s, 1H) , 5.08 (dd, J = 12.9, 5.5 Hz, 1H), 3.60 (s, 8H), 3.52-3.44 (m, 3H), 3.28-3.21 (m, 2H), 2.96-2.58 (m, 11H), 2.20 (s, 6H), 2.01 (d, J = 16.5 Hz, 2H), 1.73 (s, 4H). Compound 25 LC/MS: 801.1 [M + H] ^+
1H NMR (500 MHz, Methanol-d ₄ ) δ 8.06 (s, 1H), 7.93 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 2.2 Hz, 1H), 7.21 (dt, J = 8.5, 2.0 Hz, 1H), 7.18-7.13 (m, 3H), 7.02 (d, J = 8.3 Hz, 1H), 5.10 (dd, J = 12.8, 5.3 Hz, 1H), 4.59 (s, 2H), 3.88-3.80 (m, 2H), 3.75 (t, J = 5.4 Hz, 2H), 3.68 (s) , 3H), 3.63 (t, J = 5.3 Hz, 2H), 3.57-3.51 (m, 2H), 3.03-2.80 (m, 7H), 2.78-2.63 (m, 2H), 2.30 (s, 6H), 2.16-2.07 (m, 2H). Compound 26 LC/MS: 865.0 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.63 (d, J = 9.1 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.80-7.52 ( m, 3H), 7.33 (s, 1H), 7.24 (d, J = 9.7 Hz, 1H), 7.17-7.02 (m, 4H), 5.06 (dd, J = 13.0, 5.7 Hz, 1H), 4.97-4.59 (m, 4H), 4.54-4.42 (m, 1H), 4.07 (d, J = 13.1 Hz, 2H), 3.62 (s, 2H), 3.16-2.99 (m, 2H), 2.94-2.65 (m, 6H) ), 2.20 (s, 6H), 1.96 (q, J = 12.9, 11.7 Hz, 5H), 1.76 (s, 3H), 1.47 (s, 3H). Compound 27 LC/MS: 843.2 [M + H ₃ O] ^+
1H NMR (400 MHz, Methanol-d ₄ ) δ 8.11 (s, 1H), 7.75 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 8.5, 2.2 Hz, 1H), 7.29-7.09 (m, 4H), 6.99 (s, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.05 (dd, J = 12.5, 5.4 Hz, 1H), 4.46 (s, 2H) ), 3.86 (s, 2H), 3.80-3.67 (m, 5H), 3.63-3.55 (m, 2H), 3.54-3.39 (m, 5H), 3.24 (q, J = 7.3 Hz, 4H), 2.91- 2.64 (m, 4H), 2.29 (s, 6H), 2.15-2.01 (m, 2H). Compound 28 LC/MS: 864.2 [M + H] ^+
1H NMR (400 MHz, Acetone-d ₆ ) δ 9.76 (s, 1H), 8.41 (s, 1H), 8.04-7.82 (m, 2H), 7.68-7.43 (m, 3H), 7.18 (s, 1H) ), 7.12 (dd, J = 8.5, 2.4 Hz, 1H), 7.06-6.96 (m, 3H), 6.92 (d, J = 8.3 Hz, 1H), 4.93 (dd, J = 12.7, 5.3 Hz, 1H) , 4.42 (d, J = 13.4 Hz, 1H), 4.07-3.92 (m, 3H), 3.54 (s, 3H), 3.07-2.96 (m, 3H), 2.94-2.56 (m, 14H), 2.52-2.28 (m, 3H), 2.13 (s, 6H), 2.09-2.00 (m, 1H), 1.70 (s, 5H). Compound 29 LC/MS 753.4 [M + H] ^+
1H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 7.70 (dd, J = 8.3, 2.3 Hz, 1H), 7.47 (dd, J = 9.3, 4.9 Hz, 2H), 7.37 (d) , J = 7.4 Hz, 2H), 7.31 (s, 1H), 7.17 (s, 3H), 7.08 (t, J = 7.0 Hz, 2H), 6.05 (s, 1H), 5.01-4.91 (m, 1H) , 3.98 (d, J = 12.9 Hz, 2H), 3.82 (d, J = 2.3 Hz, 3H), 3.64 (s, 2H), 3.02 (t, J = 12.5 Hz, 2H), 2.96-2.82 (m, 4H), 2.82-2.69 (m, 3H), 2.42 (d, J = 6.6 Hz, 2H), 2.29 (s, 6H), 2.21-2.10 (m, 1H), 2.04-1.87 (m, 3H), 1.44 -1.29 (m, 2H). Compound 30 LC/MS: 812.0 [M + H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.57 (s, 1H), 8.35 (d, J = 11.2 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.65-7.52 (m, 2H), 7.42 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.16-7.05 (m, 3H), 7.02 (d, J = 8.3 Hz, 1H), 5.36-5.02 (m, 3H), 4.31 (d, J = 12.8 Hz, 1H), 3.81 (d, J = 13.4 Hz, 1H), 3.62 (s, 3H), 3.54 (s) , 2H), 3.46-3.40 (m, 2H), 3.13-3.03 (m, 1H), 2.95-2.82 (m, 1H), 2.75 (s, 2H), 2.71-2.56 (m, 5H), 2.41-2.29 (m, 3H), 2.21 (s, 6H), 2.15-1.65 (m, 6H). Compound 31 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.54 (s, 1H), 8.32 (d, J = 2.0 Hz, 2H), 8.08 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.61-7.50 (m, 2H), 7.35 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.15-7.05 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 5.07 (dd, 1H), 4.35 (d, J = 12.7 Hz, 1H), 4.05 (d, J = 12.9 Hz, 1H), 3.61 (s, 3H), 3.48 (d, J = 28.1 Hz, 6H), 3.17-2.80 (m, 5H), 2.78-2.59 (m, 7H), 2.31 (d, J = 8.9 Hz, 2H), 2.20 (s, 6H), 2.07-1.84 (m, 4H), 1.84-1.70 (m, 2H). Compound 32 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (d, J = 8.2 Hz, 1H), 9.64 (d, J = 8.6 Hz, 1H), 8.40-8.18 (m, 2H), 8.12-8.01 ( m, 1H), 7.76-7.42 (m, 3H), 7.35 (s, 1H), 7.29-7.16 (m, 1H), 7.15-7.05 (m, 3H), 5.20-4.24 (m, 7H), 3.91- 3.53 (m, 7H), 3.2-3.0 (m, 3H), 2.95-2.74 (m, 3H), 2.72-2.65 (m, 2H), 2.34 (d, J = 9.0 Hz, 2H), 2.27-2.17 ( m, 6H), 2.07-1.66 (m, 6H), 1.55 -1.42 (m, 1H). Compound 33 LC/MS: 879.2 [M + H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H), 9.34 (s, 1H), 8.29-8.20 (m, 2H), 7.89 (d, J = 13.1 Hz, 1H), 7.68 ( d, J = 9.3 Hz, 1H), 7.61 (s, 1H), 7.34 (s, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 11.0 Hz, 5H), 5.09- 4.64 (m, 6H), 3.88-3.37 (m, 18H), 2.81-2.57 (m, 4H), 2.22 (d, J = 2.7 Hz, 6H), 2.12-1.89 (m, 2H). Compound 34 LC/MS: 811.2 [M + H] ^+
1 H NMR (500 MHz, DMSO-d ⁶ , 60°C) δ 10.88 (s, 1H), 9.32 (s, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H) , 7.71-7.57 (m, 2H), 7.38 (d, J = 33.3 Hz, 1H), 7.11 (s, 4H), 5.03 (d, J = 52.3 Hz, 3H), 4.73-4.49 (m, 2H), 3.67 (dd, J = 27.7, 8.4 Hz, 5H), 2.96-2.62 (m, 7H), 2.23 (d, J = 8.1 Hz, 7H), 1.90 (d, J = 92.1 Hz, 5H). Compound 35 LC/MS: 810.2 [M + H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 10.82 (s, 1H), 9.31 (s, 1H), 8.25 (d, J = 3.0 Hz, 1H), 7.88 (s, 1H), 7.75-7.48 ( m, 3H), 7.17-7.08 (m, 4H), 7.03-6.72 (m, 3H), 5.07-4.94 (m, 2H), 4.71 (d, J = 15.5 Hz, 1H), 4.16 (d, J = 17.1 Hz, 1H), 4.02 (d, J = 17.2 Hz, 1H), 3.76-3.48 (m, 7H), 2.93-2.71 (m, 3H), 2.70-2.57 (m, 2H), 2.22 (s, 6H) ), 2.09-1.91 (m, 4H), 1.82 (s, 2H). Compound 36 LC/MS: 810.2 [M + H] ^+
1H NMR (400 MHz, Acetone-d ⁶ ) δ 9.88 (s, 1H), 8.53 (s, 1H), 8.03 (s, 1H), 7.67 (d, J = 9.5 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.32 (s, 1H), 7.21-7.10 (m, 5H), 7.06 (d, J = 8.2 Hz, 1H), 6.41-6.36 (m, 1H), 5.06 (dd, J = 12.7, 5.4 Hz, 1H), 4.57 (d, J = 13.1 Hz, 1H), 4.27-4.03 (m, 4H), 3.74-3.60 (m, 5H), 3.18 (t, J = 12.8 Hz, 2H) , 2.74 (d, J = 11.7 Hz, 3H), 2.42 (s, 2H), 2.29 (s, 6H), 2.24-2.15 (m, 3H), 2.01 (d, J = 12.7 Hz, 3H), 1.58 ( s, 3H). Compound 37 ^1H NMR (400 MHz, Methanol-d ₄ ) δ 8.08 (s, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.92 (s, 2H), 7.69 (dd, J = 9.3, 2.8 Hz, 1H), 7.55 (d, J = 5.9 Hz, 3H), 7.16 (s, 3H), 7.10 (d, J = 8.8 Hz, 1H), 5.90 (dd, J = 11.4, 5.5 Hz, 1H), 4.58 ( d, J = 18.9 Hz, 2H), 4.17 (d, J = 13.3 Hz, 3H), 3.72 (d, J = 18.5 Hz, 5H), 3.28-3.02 (m, 5H), 3.01-2.80 (m, 7H) ), 2.78-2.64 (m, 2H), 2.59-2.48 (m, 2H), 2.36 (dd, J = 13.2, 6.9 Hz, 1H), 2.28 (s, 6H), 2.10-1.96 (m, 4H), 1.97-1.79 (m, 7H). Compound 38 ^1H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.50-7.34 (m, 5H), 7.23-7.12 (m, 4H), 7.08 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 5.90 (s, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.78-3.69 (m, 2H), 3.64 (s, 2H), 2.91- 2.80 (m, 4H), 2.79-2.69 (m, 2H), 2.41 (dd, J = 13.1, 6.8 Hz, 2H), 2.29 (s, 6H), 2.11 (s, 1H), 2.08-2.00 (m, 2H), 1.99-1.77 (m, 5H). Compound 39 ^1H NMR (300 MHz, Chloroform-d) δ 8.75 (d, J = 22.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.49-7.39 (m, 2H), 7.35 (s, 1H) ), 7.15 (s, 3H), 7.09-7.01 (m, 2H), 5.95 (d, J = 3.3 Hz, 1H), 4.94 (dd, J = 12.0, 5.1 Hz, 1H), 4.34 (t, J = 8.5 Hz, 1H), 4.18 (t, J = 9.1 Hz, 1H), 4.04-3.92 (m, 1H), 3.82-3.72 (m, 4H), 3.66 (s, 2H), 3.50-3.40 (m, 3H) ), 3.08 (s, 2H), 3.01-2.91 (m, 2H), 2.90-2.83 (m, 3H), 2.83-2.74 (m, 4H), 2.72-2.63 (m, 4H), 2.27 (s, 6H) ), 2.19-1.98 (m, 3H). Compound 40 ^1H NMR (300 MHz, Chloroform-d) δ 8.70 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.52-7.43 (m, 1H), 7.38 (s, 1H) ), 7.32 (s, 1H), 7.18 (s, 3H), 7.12-7.03 (m, 2H), 5.97 (s, 1H), 4.96 (dd, J = 11.9, 5.1 Hz, 1H), 4.35 (t, J = 8.2 Hz, 1H), 4.16 (t, J = 9.1 Hz, 1H), 4.06-3.92 (m, 3H), 3.81 (s, 3H), 3.73 (d, J = 13.8 Hz, 2H), 3.04 ( q, J = 11.0 Hz, 3H), 2.96-2.69 (m, 8H), 2.47 (dd, J = 10.3, 5.7 Hz, 1H), 2.29 (s, 6H), 2.22-2.10 (m, 1H), 2.09 -1.80 (m, 6H). Compound 41 ^1H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.56 (d, J = 10.3 Hz, 1H), 7.50 (s, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.18 (s, 3H), 7.11- 6.99 (m, 2H) ), 6.02 (d, J = 13.4 Hz, 1H), 4.96 (dd, J = 12.2, 5.4 Hz, 1H), 4.00-3.87 (m, 3H), 3.82 (s, 3H), 3.05-2.70 (m, 5H), 2.63 (d, J = 6.0 Hz, 2H), 2.29 (s, 6H), 2.19-2.00 (m, 3H), 1.99-1.83 (m, 4H). Compound 42 ^1H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.56-7.41 (m, 2H) ), 7.34 (d, J = 7.9 Hz, 1H), 7.18 (s, 3H), 7.06 (t, J = 8.1 Hz, 1H), 5.99 (d, J = 14.0 Hz, 1H), 4.96 (dd, J = 12.2, 5.4 Hz, 1H), 4.64 (d, J = 13.7 Hz, 2H), 4.03-3.73 (m, 7H), 3.06 (t, J = 12.3 Hz, 2H), 2.98-2.69 (m, 5H) , 2.66-2.52 (m, 2H), 2.29 (s, 6H), 2.22-2.11 (m, 1H), 2.11-2.01 (m, 2H), 1.99-1.79 (m, 8H). Compound 43 LC/MS: 825.2 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.64 (d, J = 10.0 Hz, 1H), 8.35 (s, 1H), 8.32 (s, 1H), 8.10 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 5.6 Hz, 4H), 5.13 (dt, J = 13.6, 6.8 Hz, 3H), 4.75 (s, 1H), 4.60 (s, 1H), 4.32 (s, 1H), 3.79 (s, 3H), 3.63 (d, J = 3.0 Hz, 4H), 3.26-2.55 (m, 6H), 2.20 (s, 6H), 2.11-1.91 (m, 2H), 1.70 (m, 3H) , 1.43 (s, 1H). Compound 44 ^1H NMR (400 MHz, Methanol-d ₄ ) δ 8.09 (s, 1H), 7.92 (s, 3H), 7.69 (t, J = 9.9 Hz, 2H), 7.58 (t, J = 8.2 Hz, 1H) , 7.39 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 7.15 (d, J = 11.4 Hz, 4H), 5.09 (dd, J = 12.5, 5.4 Hz, 2H), 4.72 (s, 1H), 4.62-4.52 (m, 1H), 4.35-4.16 (m, 1H), 3.88 (t, J = 6.1 Hz, 1H), 3.71 (d, J = 4.3 Hz, 4H), 3.52 (s, 6H) ), 2.95 (s, 1H), 2.90-2.76 (m, 4H), 2.71 (d, J = 5.1 Hz, 4H), 2.29 (s, 6H), 2.05 (d, J = 9.4 Hz, 1H), 1.83 (d, J = 14.8 Hz, 4H), 1.70-1.58 (m, 3H). Compound 45 ^1H NMR (400 MHz, Methanol-d ₄ ) δ 8.09 (s, 1H), 7.68 (d, J = 9.7 Hz, 1H), 7.60 (q, J = 8.6 Hz, 2H), 7.17 (s, 4H) , 7.09 (s, 1H), 6.95 (s, 1H), 5.07 (dd, J = 12.4, 5.4 Hz, 2H), 4.73 (s, 1H), 4.58 (d, J = 14.3 Hz, 2H), 4.19 ( t, J = 7.2 Hz, 2H), 4.05 (s, 1H), 3.95-3.85 (m, 2H), 3.71 (d, J = 3.9 Hz, 4H), 3.01-2.68 (m, 9H), 2.29 (s) , 6H), 2.18 (s, 1H), 2.05 (d, J = 9.6 Hz, 2H), 1.91-1.78 (m, 3H). Compound 46 ^1H NMR (400 MHz, Methanol-d ₄ ) δ 8.12-8.08 (m, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.77 (s, 1H), 7.72- 7.61 (m, 1H), 7.56 (s, 1H), 7.24 (dd, J = 22.2, 8.5 Hz, 1H), 7.16 (s, 3H), 5.95-5.85 (m, 1H), 4.35 (s, 1H) , 4.20 (d, J = 13.7 Hz, 1H), 4.16-4.08 (m, 1H), 3.84-3.75 (m, 1H), 3.73 (s, 1H), 3.71 (s, 2H), 3.66 (s, 1H) ), 3.55-3.48 (m, 1H), 3.19-3.06 (m, 3H), 3.02-2.92 (m, 2H), 2.89-2.80 (m, 2H), 2.68 (s, 1H), 2.29 (s, 6H) ), 2.06 (s, 2H), 1.94-1.72 (m, 3H), 1.65-1.40 (m, 5H). Compound 47 ^1H NMR (300 MHz, Chloroform-d) δ 8.59 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.51-7.36 (m, 3H), 7.16 (s, 3H), 7.09 (d) , J = 8.3 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 8.3, 2.1 Hz, 1H), 5.94-5.89 (m, 1H), 4.93 (dd, J = 12.1, 5.3 Hz, 1H), 4.19 (t, J = 8.0 Hz, 2H), 3.87-3.69 (m, 5H), 3.27-3.11 (m, 1H), 3.04-2.66 (m, 7H), 2.62 (s) , 1H), 2.27 (s, 6H), 2.19-2.08 (m, 1H), 2.03 (d, J = 5.9 Hz, 2H). Compound 48 ¹ H NMR (300 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.19-8.13 (m, 1H), 7.70-7.60 (m, 2H), 7.52-7.40 (m, 3H), 7.38 (s, 1H), 7.22-7.13 (m, 3H), 7.09 (d, J = 8.3 Hz, 1H), 6.04 (s, 1H), 5.85-5.74 (m, 1H), 5.00-4.85 (m, 2H), 4.58 (d, J = 13.3 Hz, 1H), 3.94-3.61 (m, 6H), 3.15 (t, J = 12.6 Hz, 1H), 3.06-2.62 (m, 8H), 2.56-2.34 (m, 3H), 2.29 (s, 6H), 2.15-1.80 (m, 5H). Compound 49 LC/MS 783.3[M + H] ^+
1 H NMR (300 MHz, Chloroform-d), rotamer pattern observed. δ 10.96 (s, 0.5H), 10.23 (s, 0.5H), 8.41 (s, 1H), 8.01-7.75 (m, 2H), 7.68-7.57 (m, 2H), 7.44-7.38 (m, 1H) , 7.25-7.14 (m, 3H), 7.13-6.95 (m, 2H), 5.94-5.88 (m, 3H), 4.99 (dd, 1H), 4.90-4.65 (m, 2H), 4.46 (t, J = 8.6 Hz, 1H), 4.32-4.16 (m, 1H), 4.10-4.00 (m, 1H), 3.93-3.73 (m, 4H), 3.66 (dd, J = 10.3, 4.9 Hz, 1H), 3.60-3.36 (m, 2H), 3.03-2.54 (m, 9H), 2.30 (s, 6H), 2.23-2.14 (m, 1H), 2.09-1.98 (m, 1H). Compound 50 ^1H NMR (300 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 10.7 Hz, 2H), 7.26-7.04 (m, 5H) ), 6.79 (s, 1H), 6.53 (d, J = 8.3 Hz, 1H), 5.93 (s, 1H), 5.36 (s, 1H), 5.02-4.86 (m, 1H), 4.23 (td, 2H) , 3.92-3.54 (m, 6H), 3.41-3.01 (m, 3H), 3.00-2.66 (m, 7H), 2.64 (s, 1H), 2.60-2.41 (m, 2H), 2.29 (s, 6H) , 2.22-1.78 (m, 10H). Compound 51 ¹ H NMR (300 MHz, Chloroform-d) rotamer pattern observed. δ 8.93 (s, 0.5H), 8.68 (s, 0.5H), 8.08 (d, J = 23.7 Hz, 1H), 7.73-7.39 (m, 4H), 7.18 (s, 4H), 7.09 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 12.5 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.90 (s, 1H), 5.01-4.89 (m, 1H), 4.29 (dd , J = 15.2, 9.1 Hz, 2H), 3.81 (s, 5H), 3.62 (s, 2H), 2.98 (s, 1H), 2.94-2.70 (m, 8H), 2.29 (s, 6H), 2.25 - 2.10 (m, 2H), 2.05 (d, J = 6.0 Hz, 2H). Compound 52 ^1H NMR (300 MHz, Chloroform-d) δ 8.94 (d, J = 28.0 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.52-7.32 (m, 3H), 7.24 (d, J = 2.6 Hz, 1H), 7.16 (d, J = 3.9 Hz, 4H), 7.09 (d, J = 8.3 Hz, 1H), 6.09-5.95 (m, 2H), 5.78 (dd, J = 11.3, 5.7 Hz) , 1H), 4.66 (d, J = 13.3 Hz, 1H), 4.01 (d, J = 3.8 Hz, 2H), 3.86-3.73 (m, 4H), 3.67 (s, 2H), 3.24-2.66 (m, 10H), 2.55-2.34 (m, 3H), 2.29 (s, 6H), 2.12-1.86 (m, 4H). Compound 53 ^1H NMR (300 MHz, Chloroform-d) δ 8.25 (s, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.48-7.29 (m, 5H), 7.18 (s, 3H), 7.10 (d) , J = 8.9 Hz, 2H), 5.87 (s, 1H), 5.84-5.75 (m, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.82 (d, J = 1.1 Hz, 3H), 3.70 -3.64 (m, 1H), 3.14-2.99 (m, 3H), 3.01-2.85 (m, 5H), 2.81 (d, J = 17.5 Hz, 3H), 2.44 (s, 3H), 2.29 (s, 6H) ), 2.02 (d, J = 13.3 Hz, 4H). Compound 54 ^1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 15.3 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.41 (s, 2H), 7.29 (s, 1H), 7.16 (s, 3H), 7.11 (d, J = 9.1 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.07-5.95 (m, 1H), 4.94 (dd, J = 12.2, 5.3 Hz, 1H), 4.74 (d, J = 9.8 Hz, 1H), 4.67 (s, 1H), 4.61 (s, 1H), 4.07 -3.88 (m, 3H), 3.88-3.67 (m, 5H), 3.19 (t, J = 11.8 Hz, 1H), 3.06 (t, J = 12.2 Hz, 2H), 2.96-2.63 (m, 8H), 2.27 (s, 6H), 2.19-2.08 (m, 1H), 2.06-1.64 (m, 8H). Compound 55 ^1H NMR (400 MHz, Chloroform-d) δ 9.17 (s, 0.2H), 8.87 (s, 0.2H), 8.39 (s, 0.5H), 8.15 (d, J = 8.8 Hz, 1H), 7.64 ( d, J = 12.1 Hz, 3H), 7.57-7.35 (m, 3H), 7.17 (s, 3H), 7.11 (t, J = 8.2 Hz, 1H), 6.08-5.87 (m, 1H), 5.79 (s) , 1H), 4.91 (s, 2H), 4.78-4.61 (m, 2H), 4.51 (d, J = 12.7 Hz, 1H), 3.77 (d, J = 23.5 Hz, 6H), 3.26 (d, J = 12.2 Hz, 1H), 3.04-2.77 (m, 7H), 2.40 (s, 1H), 2.27 (s, 6H), 2.17 (s, 2H), 2.03 (d, J = 7.9 Hz, 1H), 1.88- 1.73 (m, 4H). Compound 56 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.65 (d, J = 13.2 Hz, 1H), 8.33 (d, J = 11.1 Hz, 1H), 8.10 (s, 1H) , 7.72-7.58 (m, 3H), 7.34 (s, 1H), 7.25 (s, 1H), 7.16-7.04 (m, 4H), 5.12-5.01 (m, 1H), 4.76 (, 1H), 4.59 ( s, 1H), 4.08 (s, 2H), 3.80 (s, 1H), 3.72-3.59 (m, 4H), 3.39 (s, 5H), 3.10 (t, J = 12.7 Hz, 2H), 2.92-2.78 (m, 2H), 2.68 (d, J = 10.1 Hz, 1H), 2.20 (s, 6H), 1.80-1.57 (m, 4H). Compound 57 ^1H NMR (400 MHz, Chloroform-d) δ 9.10-8.83 (m, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.72-7.52 (m, 2H), 7.43 (s, 2H), 7.16 -7.10 (m, J = 10.5 Hz, 5H), 6.16-5.96 (m, 2H), 5.78 (s, 1H), 4.80-4.64 (m, 2H), 4.57 (t, J = 14.7 Hz, 1H), 4.00 (s, 2H), 3.92-3.67 (m, 6H), 3.20 (s, 1H), 3.06-2.70 (m, 7H), 2.45-2.32 (m, 1H), 2.26 (s, 6H), 2.06- 1.73 (m, 5H). Compound 58 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 9.68-9.63 (m, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 8.06-7.96 (m, 1H) ), 7.79-7.66 (m, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 7.22-6.97 (m, 4H), 5.89 (dd, J = 12.2, 5.4 Hz, 1H), 4.77 (s, 1H), 4.59 (s, 1H), 4.21-3.99 (m, 2H), 3.81 (t, J = 5.9 Hz, 1H), 3.72-3.56 (m, 3H), 3.29-3.21 (m, 1H), 3.21-2.88 (m, 4H), 2.84 (s, 1H), 2.77-2.59 (m, 3H), 2.20 (s, 6H), 2.02-1.88 (m, 1H), 1.85-1.72 (m, 2H), 1.72-1.56 (m, 2H). Compound 59 ^1H NMR (400 MHz, Chloroform-d)ROTOMER PATTERN δ 9.63 (s, 0.4H), 9.33 (s, 0.6H), 7.86-7.76 (m, 1H), 7.76-7.60 (m, 3H), 7.58- 7.38 (m, 2H), 7.28-7.22 (m, 1H), 7.22-7.06 (m, 4H), 6.25-6.05 (m, 1H), 5.76 (t, J = 13.9 Hz, 1H), 4.76 (s, 1H), 4.69 (s, 1H), 3.82 (s, 4H), 3.79-3.70 (m, 1H), 3.65 -3.50 (m, 2H), 3.07-2.74 (m, 8H), 2.36 (t, J = 7.7 Hz, 1H), 2.28 (s, 6H), 2.23-2.14 (m, 1H), 1.88 (s, 3H). Compound 60 ¹ H NMR (300 MHz, Chloroform-d: acetone (98:2)) Rotamers δ 9.09-8.86 (m, 1H), 8.18-8.07 (m, 0.25H), 7.81 (d, J = 8.5 Hz, 0.65H ), 7.68-7.29 (m, 4H), 7.22-7.06 (m, 4H), 6.89-6.73 (m, 2H), 6.10-5.98 (m, 1H), 4.83-4.71 (m, 2H), 4.71-4.53 (m, 2H), 4.09-3.96 (m, 1H), 3.90-3.71 (m, 6H), 3.25-2.65 (m, 11H), 2.27 (s, 6H), 2.05-1.59 (m, 10H). Compound 61 ^1H NMR (300 MHz, Chloroform-d) δ 8.62 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.47-7.39 (m, 2H) ), 7.35 (s, 1H), 7.16 (s, 3H), 7.07 (d, J = 8.3 Hz, 1H), 6.87-6.76 (m, 2H), 5.93 (s, 1H), 4.78 (dd, J = 12.7, 5.8 Hz, 1H), 4.64 (d, J = 13.0 Hz, 1H), 3.97-3.84 (m, 2H), 3.80 (s, 3H), 3.68-3.54 (m, 2H), 3.07 (t, J = 12.2 Hz, 1H), 2.98-2.77 (m, 6H), 2.75-2.53 (m, 4H), 2.43-2.32 (m, 2H), 2.27 (s, 6H), 2.06-1.76 (m, 7H), 1.19-1.07 (m, 2H). Compound 62 ^1H NMR (300 MHz, Chloroform-d)Rotamers δ 9.42 (s, 0.5H), 9.25 (s, 0.5H), 7.78 (t, J = 8.0 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.47-7.34 (m, 4H), 7.24 (s, 1H), 7.14 (s, 3H), 7.05 (d, J = 8.3 Hz, 1H), 6.24-6.11 (m, 1H), 5.75 (dd , J = 11.4, 5.3 Hz, 1H), 4.65 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.80 (s, 3H), 3.68-3.47 (m, 4H) , 3.11-2.51 (m, 13H), 2.43-2.29 (m, 3H), 2.26 (s, 6H), 2.21-2.08 (m, 2H), 1.95 (s, 1H), 1.82 (d, J = 13.7 Hz) , 4H), 1.22-1.04 (m, 2H). Compound 63 ^1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.10 (s, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.43 (s, 1H) ), 7.34 (s, 1H), 7.24-7.18 (m, 1H), 7.16 (s, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.56 (s, 2H), 5.88 (s, 1H) , 5.50 (s, 1H), 4.81-4.72 (m, 1H), 4.63 (d, J = 13.3 Hz, 1H), 4.31-4.20 (m, 1H), 3.87 (s, 2H), 3.80 (s, 3H) ), 3.62 (s, 2H), 3.10 (t, J = 12.7 Hz, 1H), 3.04-2.92 (m, 1H), 2.90-2.80 (m, 3H), 2.79-2.66 (m, 4H), 2.39 ( s, 2H), 2.27 (s, 6H), 2.07-1.96 (m, 2H), 1.96-1.83 (m, 3H). Compound 64 ^1H NMR (500 MHz, Chloroform-d) δ 9.17 (d, J = 23.8 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.48-7.30 (m, 6H), 7.14 (s, H) ), 7.04 (d, J = 8.2 Hz, 1H), 6.09 (s, 1H), 5.22 (d, J = 13.2 Hz, 1H), 4.58 (d, J = 13.3 Hz, 1H), 4.52-4.35 (m , 2H), 3.79 (s, 4H), 3.66-3.51 (m, 2H), 3.06-2.95 (m, 2H), 2.96-2.87 (m, 2H), 2.87-2.76 (m, 3H), 2.76-2.62 (m, 4H), 2.56 (t, J = 14.6 Hz, 1H), 2.42-2.29 (m, 3H), 2.26 (s, 6H), 2.24-2.16 (m, 2H), 1.89-1.72 (m, 4H) ). Compound 65 ^1H NMR (500 MHz, Chloroform-d) δ 10.47 (s, 1H), 9.01 (s, 1H), 8.09 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.80-7.70 (m , 2H), 7.55 (d, J = 13.4 Hz, 2H), 7.48-7.38 (m, 6H), 7.19-7.11 (m, 8H), 7.05 (d, J = 7.9 Hz, 1H), 6.03 (s, 2H), 5.30 (dd, J = 13.0, 5.4 Hz, 1H), 5.20 (dd, J = 13.4, 5.1 Hz, 1H), 4.77-4.59 (m, 3H), 4.55-4.26 (m, 6H), 3.89 (dt, J = 13.0, 6.7 Hz, 1H), 3.80 (d, J = 7.9 Hz, 6H), 3.67 (dt, J = 12.6, 6.0 Hz, 1H), 3.59 (q, J = 5.8 Hz, 2H) , 3.06 (dt, J = 23.7, 6.9 Hz, 4H), 2.93 - 2.69 (m, 13H), 2.27 (d, J = 7.7 Hz, 12H). Compound 66 ^1H NMR (500 MHz, Chloroform-d) δ 8.23-8.11 (m, 1H), 7.66 (dd, J = 15.0, 9.2 Hz, 2H), 7.53-7.38 (m, 3H), 7.19-7.15 (m, 3H), 7.15-7.10 (m, 1H), 6.96 (d, J = 6.1 Hz, 1H), 6.70 (t, J = 7.9 Hz, 1H), 5.89 (d, J = 11.6 Hz, 1H), 4.98- 4.89 (m, 1H), 4.78 (d, J = 5.2 Hz, 1H), 4.74 (d, J = 5.7 Hz, 1H), 3.84-3.72 (m, 6H), 3.71-3.45 (m, 2H), 2.98 -2.67 (m, 6H), 2.34 (d, J = 8.1 Hz, 1H), 2.27 (s, 8H), 2.15-1.97 (m, 1H). Compound 67 ^1H NMR (400 MHz, Chloroform-d) δ 9.28-9.11 (m, 1H), 7.73-7.63 (m, 1H), 7.63-7.56 (m, 1H), 7.54-7.39 (m, 3H), 7.28 ( d, J = 2.4 Hz, 1H), 7.15 (s, 3H), 7.13-6.98 (m, 2H), 6.14-5.99 (m, 1H), 4.94 (dd, J = 12.1, 5.4 Hz, 1H), 4.85 -4.60 (m, 2H), 4.05-3.88 (m, 3H), 3.89-3.53 (m, 8H), 3.54-3.26 (m, 2H), 3.11-2.98 (m, 2H), 2.99-2.95 (m, 1H), 2.95-2.79 (m, 4H), 2.79-2.70 (m, 1H), 2.70-2.58 (m, 1H), 2.44 (dq, J = 14.5, 8.6, 7.8 Hz, 1H), 2.27 (s, 6H), 2.21-1.99 (m, 3H), 1.99-1.78 (m, 4H). Compound 68 ^1H NMR (300 MHz, Chloroform-d) δ 8.86 (d, J = 71.7 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 18.4 Hz, 1H), 7.46 ( d, J = 12.7 Hz, 2H), 7.39 (d, J = 2.6 Hz, 1H), 7.21-7.06 (m, 4H), 6.56 (d, J = 6.4 Hz, 1H), 6.22 (d, J = 27.2 Hz, 1H), 6.07 (d, J = 21.1 Hz, 1H), 5.48 (s, 1H), 4.70 (d, J = 20.5 Hz, 2H), 4.56 (s, 1H), 4.00 (s, 1H), 3.92-3.83 (m, 2H), 3.79 (s, 3H), 3.75 (s, 1H), 3.18 (s, 1H), 3.04 (d, J = 6.8 Hz, 1H), 2.90 (d, J = 9.6 Hz) , 3H), 2.80 (t, J = 7.7 Hz, 4H), 2.26 (s, 6H), 1.94 (m, J = 11.7 Hz, 3H), 1.77 (m, J = 11.8, 7.8 Hz, 3H). Compound 69 ^1H NMR (400 MHz, Chloroform-d) δ 8.89-8.38 (m, 1H), 8.10 (d, J = 45.2 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 98.5, 32.3 Hz, 6H), 6.12 (s, 1H), 5.83 (s, 1H), 5.45 (d, J = 62.7 Hz, 2H), 5.01-4.58 (m, 3H), 4.28-3.98 (m, 3H), 3.82 (s, 4H), 3.56 (s, 1H), 3.11 (dq, J = 38.6, 14.4, 13.4 Hz, 2H), 3.00-2.67 (m, 10H), 2.40 (s, 1H), 2.29 (d, J = 2.6 Hz, 7H). Compound 70 LC/MS: 656.2 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.67 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.63 (dd, J = 8.3, 2.2 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.30 (dd, J = 8.7, 2.4 Hz, 1H), 7.19-7.04 (m, 4H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.65 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 3.64 (s) , 3H), 2.96-2.83 (m, 3H), 2.64-2.54 (m, 2H), 2.21 (s, 6H), 2.07-1.96 (m, 1H). Compound 71 LC/MS: 656.4 [M + H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 11.15 (s, 1H), 9.69 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 2.2 Hz, 1H), 7.67-7.58 (m, 2H), 7.51 (d, J = 2.5 Hz, 1H), 7.21-7.04 (m, 4H), 5.90 (dd, J = 12.4, 5.5 Hz, 1H), 4.69 (s, 2H), 3.80 (t, J = 5.9 Hz, 2H), 3.65 (s, 3H), 3.00-2.89 (m, 3H), 2.73-2.61 (m, 2H), 2.29-2.22 (m, 1H), 2.20 (s, 6H). Compound 72 LC/MS: 713 [M + H] ⁺ .
^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.68 (d, J = 17.9 Hz, 1H), 8.36 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H) , 7.72 (d, J = 5.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 12.0 Hz, 6H), 7.05 (d, J = 8.5 Hz, 1H), 5.05 (dd, J = 12.6, 5.3 Hz, 1H), 4.75 (s, 1H), 4.65 (s, 1H), 4.33-4.21 (m, 2H), 3.75 ( q, J = 6.2 Hz, 2H), 3.64 (d, J = 6.8 Hz, 3H), 2.93-2.81 (m, 2H), 2.79-2.71 (m, 1H), 2.58 (d, J = 16.4 Hz, 2H) ), 2.21 (d, J = 1.8 Hz, 6H), 2.07-1.94 (m, 1H). Compound 73 ^1H NMR (400 MHz, Chloroform-d) δ 8.84 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.63 (s, 1H), 7.54 (s, 1H), 7.51-7.43 (m , 2H), 7.40 (s, 1H), 7.20-7.14 (m, 4H), 7.08 (dd, J = 8.6, 2.4 Hz, 1H), 7.02 (s, 1H), 6.00 (s, 1H), 4.96 ( dd, J = 12.2, 5.4 Hz, 1H), 3.98 (t, J = 14.1 Hz, 5H), 3.87-3.76 (m, 3H), 3.03 (t, J = 12.0 Hz, 2H), 2.96-2.62 (m , 5H), 2.29 (s, 6H), 2.20-1.97 (m, 4H), 1.86 (d, J = 12.1 Hz, 2H), 1.43-1.32 (m, 2H). Compound 74 ^1H NMR (400 MHz, Chloroform-d) δ 8.39-8.30 (m, 1H), 8.15 (dd, J = 9.0, 0.9 Hz, 1H), 8.05 (d, J = 7.2 Hz, 1H), 7.83-7.76 (m, 1H), 7.65-7.57 (m, 1H), 7.53-7.46 (m, 1H), 7.45-7.36 (m, 2H), 7.32 (dd, J = 9.1, 2.6 Hz, 1H), 7.22-7.14 (m, 3H), 5.94 (d, J = 11.7 Hz, 1H), 5.81 (dd, J = 11.5, 5.4 Hz, 1H), 4.44 (d, J = 7.0 Hz, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.86 (s, 3H), 3.58 (t, J = 6.6 Hz, 1H), 3.11-2.78 (m, 9H), 2.46-2.35 (m, 1H), 2.30 (d, J = 1.2 Hz, 6H), 2.19-1.97 (m, 3H), 1.89 (d, J = 13.1 Hz, 2H). Compound 75 LC/MS 767.4 [M + H] ^+
1H NMR (500 MHz, Chloroform-d) δ 8.53 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.47 (s, 1H), 7.45 (d, J = 2.8 Hz, 1H), 7.40 (d, J = 9.0 Hz, 2H), 7.35 (s, 1H), 7.30 (d, J = 2.4 Hz, 1H), 7.21-7.15 (m, 3H), 7.07 (d, J = 8.7 Hz, 2H) ), 5.96 (d, J = 7.2 Hz, 1H), 4.96 (dd, J = 12.4, 5.3 Hz, 1H), 3.98 (d, J = 13.0 Hz, 2H), 3.82 (s, 3H), 3.57 (d , J = 6.3 Hz, 1H), 3.41 (d, J = 10.4 Hz, 1H), 3.17-3.09 (m, 1H), 3.08-2.96 (m, 3H), 2.96-2.81 (m, 3H), 2.81- 2.63 (m, 3H), 2.56-2.39 (m, 2H), 2.35 (q, J = 6.9 Hz, 1H), 2.29 (s, 6H), 2.26 (d, J = 13.4 Hz, 1H), 2.21-2.10 (m, 1H), 2.06-1.92 (m, 2H), 1.39 (d, J = 6.3 Hz, 3H). Compound 76 LC/MS 827.3 [M + H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 10.34 (s, 1H), 10.13 (s, 1H), 8.59 (s, 1H), 8.46 (s, 1H), 7.72 ( d, J = 2.2 Hz, 1H), 7.70-7.66 (m, 2H), 7.38 (d, J = 2.3 Hz, 1H), 7.29 (dd, J = 8.8, 2.3 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.16-7.08 (m, 3H), 5.08 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 (d, J = 15.2 Hz, 1H), 4.33 (dd, J = 15.7, 7.6 Hz, 1H), 4.12 (d, J = 13.1 Hz, 2H), 3.76-3.68 (m, 2H), 3.64 (s, 3H), 3.49 (ddd, J = 13.2, 5.8, 2.9 Hz, 1H), 3.45-3.29 (m, 2H), 3.26-3.18 (m, 1H), 3.15 (t, J = 6.0 Hz, 2H), 3.10-2.96 (m, 3H), 2.95-2.83 (m, 1H), 2.64- 2.54 (m, 2H), 2.36-2.27 (m, 1H), 2.21 (s, 6H), 2.05-1.89 (m, 3H), 1.32 (q, J = 12.2, 11.5 Hz, 2H). Compound 77 ^1H NMR (300 MHz, DMSO) δ 11.09 (s, 1H), 9.82 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.83-7.68 (m , 2H), 7.33 (d, J = 8.4 Hz, 1H), 7.11 (dt, J = 8.7, 4.5 Hz, 3H), 6.98 (d, J = 8.5 Hz, 1H), 5.09 (dd, J = 12.6, 5.4 Hz, 1H), 4.80 (d, J = 19.6 Hz, 4H), 3.65 (s, 3H), 3.03-2.70 (m, 2H), 2.59 (d, J = 15.1 Hz, 2H), 2.21 (s, 6H), 2.08-1.96 (m, 1H). Compound 78 LC/MS 795.3 [M + H] ^+
1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 7.70 (dd, J = 12.7, 8.5 Hz, 1H), 7.48 (d, J = 12.7 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.35-7.31 (m, 1H), 7.18 (d, J = 3.1 Hz, 3H), 7.06 (dd, J = 8.6, 2.5 Hz, 2H), 5.98 (s, 1H), 5.01 -4.92 (m, 1H), 3.97 (q, J = 11.4, 9.4 Hz, 2H), 3.81 (s, 4H), 3.45-3.15 (m, 1H), 3.04 (dt, J = 23.5, 9.3 Hz, 3H) ), 2.95-2.68 (m, 6H), 2.56 (d, J = 16.6 Hz, 1H), 2.49-2.37 (m, 1H), 2.29 (s, 6H), 2.25 (d, J = 6.6 Hz, 1H) , 2.21-2.09 (m, 1H), 2.09-2.01 (m, 1H), 1.95 (d, J = 13.2 Hz, 3H), 1.86-1.75 (m, 1H), 1.09 (d, J = 6.3 Hz, 3H) ), 0.97 (d, J = 6.5 Hz, 3H). Compound 79 LC/MS: 768.0 [M+H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.65 (d, J = 8.8Hz, 1H), 7.58 (dd, J = 8.0 2.4Hz, 1H), 7.54 (s, 1H), (d, J = 2.2 Hz, 1H), 7.24 (dd, J = 8.8, 2.4 Hz, 1H), 7.15-7.06 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 5.13 (dd, J = 12.8, 5.4 Hz, 1H), 4.05 (d, J = 12.8 Hz, 2H), 3.61 (s, 3H), 3.54 (s, 2H) ), 3.06-2.90 (m, 6H), 2.82-2.72 (m, 3H), 2.70-2.54 (m, 3H), 2.34 (d, J = 6.8 Hz, 2H), 2.20 (s, 6H), 2.07- 1.94 (m, 2H), 1.84 (d, J = 12.8 Hz, 2H), 1.23-1.13 (m, 2H). Compound 80 LC/MS [M+2H] ⁺ 797.0.
^1H NMR (300 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 9.55 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.65-7.48 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.17-7.05 (m, 3H), 7.02 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H) ), 6.36-6.24 (h, J = 3.0 Hz, 1H), 5.02 (dd, J = 17.6, 6.8 Hz, 1H), 4.37 (s, 1H), 4.05-3.86 (m, 2H), 3.61 (s, 3H), 3.53 (s, 2H), 3.14-2.82 (m, 5H), 2.82-2.59 (m, 6H), 2.44-2.26 (m, 3H), 2.20 (s, 6H), 2.04-1.87 (m, 3H), 1.87-1.69 (m, 3H). Compound 81 LC/MS: 699.2 [M+H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.64 (d, J = 20.8 Hz, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.74-7.61 ( m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.21-7.04 (m, 4H), 6.81 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.39 (s, 1H) ), 5.01 (dd, J = 13.3, 5.1 Hz, 1H), 4.73 (s, 1H), 4.64 (s, 1H), 4.28 (d, J = 16.8 Hz, 1H), 4.21-4.07 (m, 3H) , 3.79-3.69 (m, 2H), 3.63 (d, J = 6.5 Hz, 3H), 2.97-2.83 (m, 2H), 2.79-2.71 (m, 1H), 2.58 (d, J = 16.7 Hz, 1H) ), 2.36 (dd, J = 14.0, 9.4 Hz, 1H), 2.20 (d, J = 1.7 Hz, 6H), 2.03-1.92 (m, 1H). Compound 82 LC/MS: 793.50 [M + H ⁺ ]
^1H NMR (400 MHz, CDCl ₃ ) δ 9.09 (s, 1H), 8.11 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.54-7.46 (m, 1H), 7.39 (t, J = 5.9 Hz, 3H), 7.28 (d, J = 2.4 Hz, 1H), 7.15-7.02 (m, 3H), 6.38 (s, 1H), 4.94 (dd, J = 12.2 , 5.4 Hz, 1H), 3.95 (d, J = 12.7 Hz, 2H), 3.82 (s, 3H), 3.63 (s, 2H), 2.99 (t, J = 12.5 Hz, 2H), 2.93-2.81 (m , 4H), 2.75 (dt, J = 11.8, 7.3 Hz, 3H), 2.40 (d, J = 6.5 Hz, 2H), 2.12 (dd, J = 11.4, 5.7 Hz, 1H), 1.93 (t, J = 14.7 Hz, 3H), 1.34 (dd, J = 19.0, 7.4 Hz, 2H). Compound 83 ^1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.89-9.88 (m, 1H), 8.85 (s, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.87-7.77 (m , 1H), 7.77-7.72 (m, 1H), 7.68-7.66 (m, 2H), 7.38 (s, 1H), 7.33-7.26 (m, 1H), 7.22-7.21 (m, 1H), 7.02 (s) , 1H), 6.98-6.96 (m, 1H), 5.09-5.07 (m, 1H), 4.62 (m, 1H), 4.37-4.36 (m, 1H), 4.13-4.12 (m, 2H), 3.75-3.74 (m, 3H), 3.18 (s, 3H), 3.07-2.99 (m, 3H), 2.95-2.85 (m, 1H), 2.67-2.55 (m, 2H), 2.53 (s, 1H), 2.28 (s) , 3H), 2.26 (s, 3H), 2.06-1.99 (m, 1H), 1.96-1.89 (m, 2H), 1.37-1.27 (m, 2H).
LC/MS: 753.74 [M + H+] Compound 84 LC/MS: 739.56 [M + H+]
^1H NMR (500 MHz, CDCl ₃ ) δ 9.14 (s, 1H), 8.41 (d, J = 15.9 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.3 Hz) , 1H), 7.53-7.47 (m, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.23-7.17 (m, 2H), 7.13- 7.02 (m, 2H), 6.99 (q, J = 7.5, 6.4 Hz, 1H), 6.18 (d, J = 27.8 Hz, 1H), 4.93 (dd, J = 12.4, 5.4 Hz, 1H), 3.96 (d) , J = 13.2 Hz, 2H), 3.85 (d, J = 5.5 Hz, 3H), 3.63 (s, 2H), 3.49 (s, 1H), 3.00 (t, J = 12.3 Hz, 2H), 2.90- 2.86 (m, 2H), 2.85-2.78 (m, 1H), 2.74 (q, J = 6.0, 5.5 Hz, 2H), 2.40 (d, J = 6.7 Hz, 2H), 2.33 (s, 3H), 2.14 ( dd, J = 19.7, 11.7 Hz, 2H), 1.95 (d, J = 13.9 Hz, 2H), 1.33 (d, J = 11.9 Hz, 2H). Compound 85 LC/MS: 773.51 [M+H+]
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, br,1H), 7.84 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.2, 2.3 Hz, 1H), 7.35-7.34 (m, 1H), 7.35-7.31 (m, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.24 (s, 1H), 7.22-7.18 (m, 1H), 7.15 -7.11 (m, 1H), 7.11-7.06 (m, 1H), 7.07-7.02 (m, 1H), 6.12 (s, 1H), 4.94-4.91 (m, 1H), 3.97-3.94 (m, 2H) , 3.81 (s, 3H), 3.63 (s, 2H), 3.03-3.00 (m, 2H), 2.93-2.83 (m, 3H), 2.82-2.81 (m, 1H), 2.77-2.70 (m, 2H) , 2.41-2.40 (m, 2H), 2.28 (s, 3H), 2.16-2.09 (m, 1H), 1.97-1.93 (m, 2H), 1.37-1.34 (m, 2H). Compound 86 LC/MS: 781.62 [M+H+]
^1H NMR (500 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.46-7.44 (m, 1H), 7.35 (s, 1H), 7.28 (s, 2H), 7.15 (s, 2H), 7.11-7.00 (m, 3H), 5.85 (s, 1H), 4.96-4.91 (m, 1H), 4.90-4.84 (m, 1H), 3.97-3.95 (m, 2H), 3.61 (s, 2H), 3.00-2.99 (m, 2H), 2.87-2.76 (m, 4H), 2.73 (s, 2H), 2.40 (s, 2H), 2.27 (s, 6H), 2.19 -2.08 (m, 2H), 1.95 (s, 2H), 1.53 (s, 3H), 1.52 (s, 3H), 0.88 (s, 2H). Compound 87 ¹ H NMR (500 MHz, Acetone) δ 9.95 (s, 1H), 8.77 (s, 1H), 8.08-7.99 (m, 2H), 7.92-7.89 (m, 1H), 7.75-7.69 (m, 1H) , 7.60-7.49 (m, 1H), 7.47-7.40 (m, 1H), 7.32-7.27 (m, 1H), 7.20-7.15 (m, 2H), 7.13-7.09 (m, 2H), 4.83 (s, 2H), 4.45 (s, 1H), 3.90-3.82 (m, 1H), 3.72 (s, 3H), 3.62-3.60 (m, 2H), 3.52-3.49 (m, 2H), 2.85-2.77 (m, 4H), 2.64 (d, J = 18.0, 2H), 2.28 (s, 6H), 2.21-2.12 (m, 2H). Compound 88 LC/MS 739.56 [M + H+].
^1H NMR (500 MHz, chloroform-d) δ 8.72 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 2.5) Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.20-7.12 (m, 3H), 7.10-7.03 (m, 2H), 5.96 (s, 1H), 4.98-4.91 (dd, 1H) , 4.03 (d, J = 13.0 Hz, 2H), 3.80 (d, J = 8.5 Hz, 5H), 3.08-2.99 (m, 2H), 2.90-2.82 (m, 5H), 2.82-2.68 (m, 2H) ), 2.16-2.11 (m, 1H), 2.05 (d, J = 12.5 Hz, 2H), 1.78-1.72 (m, 3H); Compound 89 ^1H NMR (500 MHz, Methanol-d ₄ ) δ 8.28 (m, 1H), 7.93-7.86 (m, 1H), 7.64-7.57 (m, 1H), 7.52 (s, 1H), 7.46-7.38 (m , 3H), 7.35-7.31 (m, 1H), 7.25-7.22 (m, 1H), 7.17 (m, 4H), 4.65 (m, 1H), 4.46 (s, 1H), 4.01-3.90 (m, 1H) ), 3.69 (s, 3H), 3.62 (s, 2H), 3.53 (d, J = 6.5 Hz, 2H), 3.01 (s, 1H), 2.88 (s, 2H), 2.79-2.70 (m, 1H) , 2.68-2.63 (m, 2H), 2.28 (d, J = 3.0 Hz, 6H), 2.26 (s, 3H), 2.16-2.13 (m, 1H), 2.06-1.96 (m, 1H). Compound 90 LC/MS: 810.2 [M+H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 10.35 (s, 1H), 9.53 (s, 1H), 8.33 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 8.09-8.04 (m, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.60-7.55 (m, 1H), 7.55-7.52 (m, 1H), 7.14-7.06 (m, 3H) , 7.01 (d, J = 8.4 Hz, 1H), 5.13 (dd, J = 12.9, 5.3 Hz, 1H), 3.61 (s, 3H), 3.52 (s, 2H), 3.30 (s, 2H), 3.19 ( s, 2H), 2.95-2.84 (m, 3H), 2.78-2.72(m, 2H), 2.63 (t, J = 5.6 Hz, 3H), 2.36-2.29 (m, 2H), 2.20 (s, 6H) , 2.17 (d, J = 10.8 Hz, 2H), 2.09-1.94 (m, 1H), 1.73 (d, J = 12.5 Hz, 2H), 1.64 (s, 1H), 1.35-1.26 (m, 2H). Compound 91 LC/MS: 796.4 [M + H] ^+
1H NMR (400 MHz, Methanol-d ₄ ) δ 8.13-8.04 (m, 2H), 7.78 (d, J = 8.3 Hz, 1H), 7.63 (dd, J = 8.3, 1.8 Hz, 1H), 7.58- 7.53 (m, 2H), 7.20-7.13 (m, 3H), 7.10 (d, J = 8.2 Hz, 1H), 5.15 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (s, 2H), 4.55 -4.43 (m, 2H), 3.74 (s, 2H), 3.69 (s, 3H), 3.25 (s, 2H), 3.02 (d, J = 11.3 Hz, 2H), 2.98-2.90 (m, 3H), 2.90-2.76 (m, 4H), 2.58-2.51 (m, 2H), 2.37-2.30 (m, 2H), 2.28 (s, 6H), 2.22-2.14 (m, 1H), 2.05 (d, J = 9.4 Hz, 1H), 1.89 (d, J = 13.2 Hz, 2H), 1.80 (s, 1H), 1.52-1.41 (m, 2H). Compound 92 LC/MS: 782.3
^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.96 (s, 1H), 9.54 (s, 1H), 8.82 (s, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.82- 7.77 (m, 1H), 7.62-7.51 (m, 4H), 7.11 (q, J = 5.4 Hz, 3H), 7.02 (d, J = 8.3 Hz, 1H), 5.07 (dd, J = 13.3, 5.1 Hz) , 1H), 4.43-4.34 (m, 1H), 4.29-4.21 (m, 1H), 4.14 (d, J = 12.7 Hz, 2H), 3.61 (s, 3H), 3.54 (s, 2H), 2.98- 2.72 (m, 6H), 2.70-2.60 (m, 3H), 2.36-2.31 (m, 2H), 2.20 (s, 6H), 2.04-1.84 (m, 3H), 1.79 (d, J = 12.3 Hz, 2H), 1.14-1.03 (m, 2H). Compound 93 LC/MS: 782.4 [M+H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.14 (s, 1H), 9.67-9.55 (m, 1H), 8.37-8.30 (m, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.76-7.58 (m, 3H), 7.43-7.33 (m, 1H), 7.10 (dt, J = 9.4, 4.7 Hz, 4H), 5.90 (dd, J = 12.2, 5.3 Hz, 1H), 4.77 (s, 0.7H), 4.61 (s, 1.3H), 3.78 (t, J = 5.7 Hz, 1H), 3.69 (t, J = 6.0 Hz, 1H), 3.62 (d, J = 2.9 Hz, 3H), 3.54-3.48 (m, 2H), 3.45-3.40 (m, 2H), 3.04-2.81 (m, 2H), 2.77-2.57 (m, 8H), 2.28-2.23 (m, 1H) ), 2.20 (s, 6H). Compound 94 LC/MS: 713.3 [M+H] ^+
1H NMR (500 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 9.58 (s, 1H), 8.51 (t, J = 6.3 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.5, 2.2 Hz, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.16-7.08 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 5.11 (dd, J = 13.4, 5.1 Hz, 1H), 4.48-4.39 (m, 3H) , 4.34-4.27 (m, 1H), 3.65 (s, 2H), 3.60 (s, 3H), 3.19 (s, 2H), 2.96-2.87 (m, 1H), 2.87-2.80 (m, 2H), 2.77 -2.68 (m, 2H), 2.63-2.55 (m, 1H), 2.43-2.32 (m, 1H), 2.20 (s, 6H), 2.05-1.90 (m, 1H). Compound 95 LC/MS: 782.4 [M+H] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.55 (s, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.62-7.52 (m, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.25 (dd, J = 8.7, 2.3 Hz, 1H), 7.18-7.06 (m, 3H), 7.02 (d) , J = 8.4 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 3.85-3.72 (m, 2H), 3.70-3.57 (m, 7H), 3.50 (s, 4H), 3.41 ( s, 2H), 2.94-2.81 (m, 1H), 2.81-2.67 (m, 4H), 2.63-2.54 (m, 2H), 2.20 (s, 6H), 2.07-2.00 (m, 1H). Compound 96 LC/MS: 685.3.
^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.99 (s, 1H), 9.69 (s, 1H), 8.97 (s, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.85 ( s, 1H), 7.71 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.60 (h, J = 5.4, 4.5 Hz, 2H), 7.16 - 7.06 (m, 4H), 5.09 (dd , J = 13.3, 5.1 Hz, 1H), 4.68 (s, 2H), 4.41 (d, J = 17.2 Hz, 1H), 4.27 (d, J = 17.0 Hz, 1H), 3.74 (t, J = 5.9 Hz) , 2H), 3.64 (s, 3H), 2.96-2.86 (m, 1H), 2.81 (t, J = 5.9 Hz, 2H), 2.66-2.57 (m, 1H), 2.44-2.33 (m, 1H), 2.21 (s, 6H), 2.04-1.95 (m, 1H). Compound 97 LC/MS: 796.2 [M+H] ^+
1H NMR (300 MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 9.55 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 9.1 Hz, 2H), 7.33 (s, 1H), 7.30-7.20 (m, 1H), 7.17-7.05 (m, 3H) ), 7.02 (d, J = 8.1 Hz, 1H), 5.06 (dd, J = 12.7, 5.3 Hz, 1H), 4.02 (d, J = 13.5 Hz, 2H), 3.72-3.53 (m, 5H), 3.19 -3.04 (m, 4H), 2.89-2.59 (m, 6H), 2.20 (s, 6H), 2.09-1.91 (m, 3H), 1.78 (d, J = 8.2 Hz, 2H), 1.63-1.48 (m , 2H). Compound 98 LC/MS: 713.0 [M+H] ⁺ .
^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 9.35 (s, 1H), 8.28-8.24 (m, 1H), 7.90 (s, 1H), 7.71-7.52 (m, 3H) ), 7.40 (s, 1H), 7.16-7.01 (m, 4H), 5.01 (s, 1H), 4.88-4.50 (m, 3H), 4.35-4.10 (m, 2H), 3.90 (s, 1H), 3.76 - 3.43 (m, 8H), 2.85 (s, 1H), 2.77-2.58 (m, 3H), 2.22 (s, 6H), 2.05-1.89 (m, 1H). Compound 99 LC/MS: 699.0 [M+H] ⁺ .
^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.97 (s, 1H), 9.64 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.78-7.56 (m, 3H), 7.48 (s, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 5.8 Hz, 1H), 7.20-7.02 (m, 4H), 5.10 (dd, J = 13.3, 5.1 Hz) , 1H), 4.53 (s, 2H), 4.49-4.23 (m, 4H), 3.63 (s, 3H), 3.62-3.57 (m, 1H), 2.99-2.84 (m, 1H), 2.73 (t, J = 6.0 Hz, 2H), 2.70-2.56 (m, 2H), 2.45-2.32 (m, 1H), 2.20 (s, 6H), 2.05-1.95 (m, 1H). Compound 100 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 9.61 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.90 (t, J = 5.6 Hz, 1H), 7.80-7.72 (m, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.17-7.04 (m, 5H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.05 (d, J = 13.1 Hz, 2H), 3.62 (s, 3H), 3.29-3.21 (m, 3H) , 3.07-2.83 (m, 4H), 2.70-2.63 (m, 2H), 2.20 (s, 6H), 2.06-1.96 (m, 2H), 1.79-1.70 (m, 2H), 1.68-1.55 (m, 2H). compound 101 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 10.33 (s, 1H), 9.60 (s, 1H), 8.34 (s, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.11-8.03 (m, 2H), 7.88 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.15- 7.06 (m, 4H), 5.13 (dd, J = 13.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.29-3.21 (m, 3H), 3.18 (s, 2H), 2.96-2.83 (m, 3H), 2.70-2.59 (m, 3H), 2.20 (s, 6H), 2.15-1.97 (m, 4H), 1.79-1.67 (m, 2H), 1.67-1.59 (m, 2H). Compound 102 ^1H NMR (500 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.63 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.90 ( t, J = 5.6 Hz, 1H), 7.82-7.74 (m, 3H), 7.58 (d, J = 8.3 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.18-7.06 (m, 5H) ), 5.08 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 17.1 Hz, 1H), 4.25 (d, J = 17.1 Hz, 1H), 4.14 (d, J = 13.0 Hz, 2H) ), 3.62 (s, 3H), 3.26 (m, 2H), 2.98-2.87 (m, 1H), 2.83 (t, J = 12.6 Hz, 2H), 2.72-2.61 (m, 3H), 2.42-2.30 ( m, 2H), 2.21 (s, 6H), 2.04-1.96 (m, 1H), 1.69 (d, J = 12.5 Hz, 2H), 1.57-1.43 (m, 2H). Compound 103 ^1H NMR (400 MHz, DMSO) δ 9.56 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.61-7.58 (m, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.38 (s, 1H), 7.11-7.08 (m, 4H), 5.13 (d, J = 8.2 Hz, 1H) , 5.07-5.01 (m, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.20 (dd, J = 17.0, 3.5 Hz, 1H), 3.75 (s, 2H), 3.65 (t, J = 7.6) Hz, 4H), 3.61 (d, J = 1.6 Hz, 3H), 3.04 (s, 2H), 2.76 (dd, J = 11.0, 6.3 Hz, 6H), 2.34 (td, J = 7.8, 4.8 Hz, 2H) ), 2.20 (s, 6H), 2.03-1.93 (m, 2H). Compound 104 ^1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 9.62 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.10 (s, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.60 (d, J = 6.7 Hz, 1H), 7.50 (d, J = 12.7 Hz, 1H), 7.11 (s, 3H), 7.08 (s, 2H), 5.06-5.02 (m , 1H), 4.77 (s, 1H), 4.61 (s, 1H), 4.31 (s, 1H), 4.19 (s, 1H), 3.78 (s, 2H), 3.68 (d, J = 5.9 Hz, 2H) , 3.62 (s, 3H), 2.87 (d, J = 19.0 Hz, 4H), 2.73 (s, 2H), 2.61 (s, 6H), 2.39-2.32 (m, 2H), 2.20 (s, 6H). Compound 105 ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.71-8.65 (m, 1H), 8.40-8.37 (m, 1H), 8.12-8.08 (m, 1H), 7.79-7.69 (m, 1H), 7.68 -7.55 (m, 1H), 7.49-7.43 (m, 1H), 7.22-7.11 (m, 6H), 5.16-5.08 (m, 1H), 5.09-5.02 (m, 1H), 4.82-4.74 (m, 1H), 4.47-4.41 (m, 1H), 4.39 (s, 1H), 3.87-3.80 (m, 1H), 3.70 (s, 3H), 3.69 (s, 1H), 3.53 (t, J = 6.3 Hz , 1H), 3.11 (t, J = 6.3 Hz, 1H), 3.03-2.86 (m, 3H), 2.82-2.75 (m, 1H), 2.53-2.40 (m, 1H), 2.28 (s, 6H), 2.19-2.12 (m, 1H). Compound 106 ^1H NMR (500 MHz, Methanol-d ₄ ) δ 8.11 (s, 1H), 7.76-7.69 (m, 1H), 7.63 (s, 1H), 7.59-7.56 (m, 1H), 7.36-7.29 (m , 1H), 7.21-7.11 (m, 6H), 5.31-5.22 (m, 1H), 5.20-5.12 (m, 1H), 4.82 (s, 1H), 4.50-4.40 (m, 2H), 4.01 (s) , 2H), 3.95-3.87 (m, 1H), 3.86-3.77 (m, 2H), 3.70 (s, 3H), 3.67-3.56 (m, 2H), 3.11 (s, 2H), 3.05-3.00 (m , 2H), 2.97-2.88 (m, 1H), 2.84-2.77 (m, 1H), 2.52-2.42 (m, 1H), 2.29 (s, 6H), 2.20-2.15 (m, 1H), 2.12-2.03 (m, 2H), 1.88-1.77 (m, 2H). Compound 107 ^1H NMR (500 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 7.16-7.06 (m, 3H), 7.02 (d, J = 8.4 Hz, 1H), 5.65 (s, 2H), 5.26 (dd, J = 13.0, 5.3 Hz, 1H), 4.07 (d, J = 12.9 Hz, 2H), 3.61 (s, 3H), 3.54 (s, 2H) ), 3.11-2.97 (m, 3H), 2.83 (d, J = 16.9 Hz, 1H), 2.80-2.72 (m, 2H), 2.69-2.62 (m, 2H), 2.58 (dd, J = 13.3, 4.4 Hz, 1H), 2.33 (d, J = 7.1 Hz, 2H), 2.20 (s, 6H), 2.12-2.05 (m, 1H), 1.98 (s, 1H), 1.84 (d, J = 12.8 Hz, 2H) ), 1.20 (d, J = 11.9 Hz, 2H), 1.11 (s, 9H). Compound 108 LCMS: 699.2 [M + H] ⁺
1H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 10.15 (s, 1H), 9.57 (d, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.09 (s, 1H) ), 8.03 (d, J = 1.7 Hz, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.62 (dd, J = 8.4, 2.2 Hz) , 1H), 7.58-7.52 (m, 1H), 7.16-7.03 (m, 4H), 5.09 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 17.3 Hz, 1H), 4.29 ( d, J = 17.4 Hz, 1H), 3.74 (s, 2H), 3.60 (s, 3H), 3.38 (s, 2H), 2.98-2.66 (m, 5H), 2.67-2.55 (m, 1H), 2.46 -2.31 (m, 1H), 2.20 (s, 6H), 2.05-1.95 (m, 1H). Compound 109 LCMS: 753.1 [M + H] ⁺
1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.51-7.40 (m, 3H), 7.31 (d, J = 2.4 Hz, 1H) , 7.24-7.13 (m, 4H), 7.07 (dd, J = 8.6, 2.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 5.93 (s, 1H), 4.96 (dd, J = 12.3 , 5.4 Hz, 1H), 3.99 (d, J = 13.1 Hz, 2H), 3.82 (s, 3H), 3.62 (s, 2H), 3.02 (t, J = 12.3 Hz, 2H), 2.96-2.85 (m , 3H), 2.85-2.70 (m, 3H), 2.48-2.36 (m, 2H), 2.29 (s, 6H), 2.18-2.09 (m, 1H), 2.07-2.02 (m, 1H), 1.98 (d) , J = 12.9 Hz, 3H), 1.36-1.31 (m, 2H). Compound 110 LCMS: 810.2 [M + H] ⁺ .
1H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.51-7.41 (m, 3H), 7.35 (s, 1H), 7.17 (s, 3H), 7.04-6.94 (m, 2H), 6.85 (dd, J = 8.3, 2.2 Hz, 1H), 6.04 (s, 1H), 5.97 (t, J = 3.9 Hz, 1H), 4.95 (dd, J = 12.2, 5.4 Hz, 1H), 4.66 (d, J = 13.2 Hz, 1H), 3.97 (d, J = 3.9 Hz, 2H), 3.88-3.73 (m, 4H), 3.67-3.53 (m, 2H) , 3.13 (t, J = 12.7 Hz, 1H), 2.99-2.66 (m, 8H), 2.41 (d, J = 6.8 Hz, 2H), 2.29 (s, 6H), 2.19-2.10 (m, 1H), 2.08-1.99 (m, 1H), 1.92 (d, J = 12.8 Hz, 2H), 1.25-1.14 (m, 2H). Compound 111 LCMS: 771.4 [M + H] ⁺
1H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 7.81-7.70 (m, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.50-7.36 (m, 3H), 7.22-7.15 (m, 3H), 7.14-7.05 (m, 1H), 7.01 (dd, J = 8.6, 2.0 Hz, 1H), 6.16 (s, 1H), 4.72 (s, 1H), 4.60 (s, 1H), 3.91 (s, 3H), 3.87-3.80 (m, 4H), 3.78-3.65 (m, 3H), 3.19-2.97 (m, 1H), 2.94-2.78 (m, 5H), 2.44-2.32 ( m, 2H), 2.28 (s, 6H), 2.27-2.14 (m, 2H), 1.99-1.62 (m, 4H). Compound 112 LC/MS 771.5 [M+H]
1H NMR (300 MHz, DMSO-d ₆ ) δ 10.46-10.23 (m, 2H), 9.79-9.64 (m, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 7.73-7.53 (m, 2H), 7.42-7.26 (m, 2H), 7.20-7.01 (m, 5H), 4.71-4.55 (m, 2H), 4.50-4.23 (m, 1H), 3.87-3.81 (m, 3H), 3.74- 3.65 (m, 5H), 3.60-3.55 (m, 2H), 2.84-2.75 (m, 2H), 2.75-2.62 (m, 3H), 2.44-2.33 (m, 2H), 2.20 (s, 6H), 2.09-1.96 (m, 1H), 1.72 (s, 2H), 1.30-1.07 (m, 3H). Compound 113 LC/MS 703.98 [M + H ⁺ ].
^1H NMR (300 MHz, DMSO) δ 10.37 (s, 1H), 9.67 (d, J = 10.0 Hz, 1H), 8.55-8.53 (m, 1H), 8.37-8.35 (m, 1H), 8.11 (s) , 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.75-7.69 (m, 1H), 7.65-7.62 (m, 1H), 7.21-7.17 ( m, 1H), 7.12-7.08 (m, 3H), 4.71 (s, 1H), 4.60 (s, 1H), 4.21 (d, J = 6.7 Hz, 2H), 3.86 (s, 3H), 3.77-3.66 (m, 2H), 3.62 (d, J = 6.9 Hz, 4H), 3.31 (s, 3H), 2.84 (s, 1H), 2.75-2.67 (m, 2H), 2.19 (s, 6H). Compound 114 ^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.42-10.32 (m, 1H), 9.65 (s, 1H), 8.38-8.30 (m, 1H), 8.11 (s, 1H), 7.63 (s, 2H) ), 7.51-7.41 (m, 2H), 7.22-7.04 (m, 5H), 4.69 (s, 2H), 3.94-3.82 (m, 3H), 3.69-3.53 (m, 6H), 2.87 (d, J = 45.8 Hz, 5H), 2.19 (d, J = 5.7 Hz, 5H), 1.87 (d, J = 89.4 Hz, 4H), 1.32-1.14 (m, 6H). Compound 115 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 8.07 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.43-7.41 (m, 2H), 7.19-7.18 (m, 3H), 7.14-7.11 (m, 2H), 7.04-7.01 (m, 1H), 6.92 (s, 1H), 5.25-5.21 (m, 1H), 4.51 (s, 2H), 4.48-4.44 (m, 1H), 4.33-4.30 (m, 1H), 3.94 (s, 2H), 3.86-3.83 (m, 2H), 3.81 (s, 3H), 3.60-3.57 (m, 2H), 3.40 (s, 4H), 2.95-2.89 (m, 4H), 2.39-2.34 (m, 1H), 2.29 (s, 6H), 2.25-2.20 (m, 1H). Compound 116 ^1H NMR (500 MHz, MeOD) δ 8.64 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.14 (s, 1H), 7.84 (s, 1H), 7.63 ( d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.47-7.42 (m, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.16 (d, J = 5.1 Hz, 1H), 5.31-5.29 (m, 1H), 5.24-5.21 (m, 1H), 4.54-4.43 (m, 3H), 4.39 (d, J = 16.9 Hz, 1H), 3.83 (s, 1H), 3.71 (s, 5H), 3.62 (s, 2H), 3.46 (s, 1H), 3.37 (s, 2H), 3.22 (s, 2H), 3.07- 2.84 (m, 3H), 2.53-2.50 (m, 1H), 2.29 (s, 6H), 2.13-1.98 (m, 2H), 1.88 (s, 2H). Compound 117 ^1H NMR (500 MHz, MeOD) δ 8.14-8.11 (m, 2H), 7.84-7.71 (m, 1H), 7.67-7.57 (m, 1H), 7.52-7.50 (m, 1H), 7.45-7.43 ( m, 1H), 7.32-7.30 (m, 1H), 7.17-7.13 (m, 3H), 5.19-5.16 (m, 1H), 4.77 (s, 1H), 4.69 (s, 1H), 4.59-4.47 ( m, 2H), 4.32-4.30 (m, 2H), 3.86 (s, 1H), 3.72-3.71 (m, 5H), 3.45 (s, 2H), 3.37-3.36 (m, 2H), 3.05-3.00 ( m, 1H), 2.99-2.85 (m, 3H), 2.82-2.80 (m, 1H), 2.63-2.60 (m, 1H), 2.28 (s, 6H), 2.19 (s, 2H), 2.09-1.97 ( m, 2H). Compound 118 ^1H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.00 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.49-7.46 (m, 1H), 7.42 (s) , 1H), 7.40-7.34 (m, 2H), 7.28 (d, J = 2.3 Hz, 1H), 7.10-7.03 (m, 2H), 6.81 (d, J = 2.9 Hz, 1H), 6.76-6.73 ( m, 1H), 5.99 (s, 1H), 4.95-4.92 (m, 1H), 3.96 (d, J = 12.6 Hz, 2H), 3.88-3.83 (m, 1H), 3.80 (d, J = 4.8 Hz) , 6H), 3.63 (s, 2H), 3.00 (t, J = 11.8 Hz, 2H), 2.87 (t, J = 5.5 Hz, 3H), 2.79-2.72 (m, J = 12.6, 6.0 Hz, 3H) , 2.40 (d, J = 6.5 Hz, 2H), 2.29 (s, 3H), 2.19-2.08 (m, 2H), 1.95 (d, J = 12.9 Hz, 2H), 1.32 (d, J = 11.9 Hz, 2H). Compound 119 ^1H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 1H), 8.56 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55-7.52 (m, 1H), 7.49-7.41 (m, 3H), 7.31 (d, J = 2.4 Hz, 1H), 7.19-7.06 (m, 3H), 6.95 (d, J = 7.4 Hz, 1H), 6.14 (s, 1H), 4.99-4.94 ( m, 1H), 3.99 (d, J = 12.9 Hz, 2H), 3.88 (s, 3H), 3.67 (s, 2H), 3.07-2.98 (m, 4H), 2.95-2.87 (m, 5H), 2.82 -2.71 (m, 3H), 2.44 (d, J = 6.5 Hz, 2H), 2.21-2.13 (m, 3H), 2.09-1.95 (m, 4H), 1.36 (d, J = 12.1 Hz, 2H). Compound 120 ^1H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 8.64 (s, 1H), 7.96 (t, J = 8.5 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.62 (s, 1H), 7.55-7.53 (m, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H) ), 7.06-7.02 (m, 1H), 6.93 (d, J = 10.2 Hz, 2H), 6.48 (d, J = 3.2 Hz, 1H), 4.97-4.92 (m, 1H), 3.96 (d, J = 12.8 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.04-2.95 (m, 2H), 2.93-2.81 (m, 5H), 2.79-2.70 (m, 3H), 2.41 (d) , J = 6.6 Hz, 2H), 2.31 (s, 3H), 2.16-2.10 (m, 1H), 1.96 (d, J = 13.1 Hz, 2H), 1.33 (d, J = 11.6 Hz, 2H). Compound 121 ^1H NMR (400 MHz, Chloroform-d) δ 8.59 (s, 1H), 8.24 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.52-7.46 (m, 2H), 7.39-7.33 (m, 2H), 7.29 (d, J = 2.4 Hz, 1H), 7.13-7.03 (m, 2H), 6.98-6.85 (m, 2H), 5.97 (s, 1H), 4.96-4.92 (m, 1H) ), 3.96 (d, J = 13.0 Hz, 2H), 3.83 (s, 3H), 3.63 (s, 2H), 3.00 (t, J = 12.5 Hz, 2H), 2.93-2.84 (m, 4H), 2.83 -2.71 (m, 4H), 2.41 (d, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.17-2.11 (m, 1H), 1.96 (d, J = 13.1 Hz, 2H), 1.33 ( d, J = 11.4 Hz, 2H). Compound 122 ^1H NMR (400 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.32 (s, 1H), 8.14 (s, 1H), 8.10 - 8.05 (m, 1H), 7.85-7.76 (m, 2H) , 7.70-7.56 (m, 4H), 7.53-7.46 (m, 1H), 7.41 (d, J = 9.6 Hz, 2H), 7.32-7.28 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H) ), 7.06-7.04 (m, 1H), 6.08 (s, 1H), 4.96-4.92 (m, 1H), 3.96 (d, J = 12.9 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.05-2.94 (m, 2H), 2.94-2.84 (m, 4H), 2.82-2.79 (m, 1H), 2.74 (q, J = 6.8, 6.1 Hz, 3H), 2.41 (d, J = 6.6 Hz, 2H), 2.37 (s, 3H), 2.17-2.08 (m, 1H), 1.96 (d, J = 13.0 Hz, 2H), 1.33 (d, J = 11.8 Hz, 2H). Compound 123 LCMS: 699.2 [M + H] ⁺
1H NMR (400 MHz, Chloroform-d) δ 7.72-7.53 (m, 2H), 7.52-7.41 (m, 2H), 7.37 (s, 1H), 7.17 (d, J = 13.9 Hz, 5H), 7.02 ( s, 1H), 6.90 (s, 1H), 5.92 (s, 1H), 4.95 (dd, J = 12.2, 5.4 Hz, 1H), 3.81 (s, 5H), 3.52 (s, 1H), 3.15-2.69 (m, 8H), 2.29 (s, 6H), 2.25-2.09 (m, 2H), 2.06 (d, J = 8.0 Hz, 1H). Compound 124 ^1H NMR (600 MHz, DMSO) δ 11.07 (s, 1H), 9.62 (s, 1H), 8.34 (d, J = 4.9 Hz, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.69-7.61 (m, 2H), 7.32 (s, 1H), 7.24 (s, 1H), 7.17 - 6.97 (m, 4H), 5.05 (m, 1H), 4.59 (s, 1H), 4.52 (s, 1H), 3.68 (m, 1H), 3.62 (s, 3H), 3.58 (m, 1H), 3.51 - 3.41 (m, 3H), 3.37 (s, 2H), 2.88 (t, J = 12.8 Hz, 1H) ), 2.73 (d, J = 36.2 Hz, 2H), 2.64 - 2.54 (m, 2H), 2.20 (d, J = 2.5 Hz, 6H), 2.07 (s, 2H), 2.03 - 1.92 (m, 3H) , 1.71 (s, 2H), 1.51 (s, 2H). m/z 807.35 [M+H] ⁺ . Compound 125 ^1H NMR (600 MHz, DMSO) δ 11.06 (s, 1H), 9.62 (d, J = 8.5 Hz, 1H), 8.32 (m, 1H), 8.08 (m, 1H), 7.68 (s, 1H), 7.65 - 7.59 (m, 2H), 7.29 (s, 1H), 7.23 - 7.18 (m, 1H), 7.11 - 7.08 (m, 4H), 5.07 - 5.02 (m, 1H), 4.63 (s, 1H), 4.59 (s, 1H), 4.02 (m, 2H), 3.69 - 3.65 (m, 2H), 3.60 (d, J = 5.4 Hz, 3H), 3.18 (s, 1H), 3.15 (s, 1H), 3.00 - 2.93 (m, 2H), 2.88 - 2.84 (m, 2H), 2.80 - 2.74 (m, 2H), 2.71 - 2.65 (m, 1H), 2.61 - 2.55 (m, 3H), 2.40 - 2.35 (m, 2H), 2.20 - 2.16 (m, 6H), 1.77 (d, J = 12.0 Hz, 2H), 1.27 - 1.23 (m, 2H). m/z 781.31 [M+H] ⁺ . Compound 126 ^1H NMR (600 MHz, DMSO) δ 11.05 (s, 1H), 9.62 (d, J = 15.6 Hz, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.72 - 7.59 (m, 3H) ), 7.29 (d, J = 3.8 Hz, 1H), 7.23 - 7.18 (m, 1H), 7.16 - 7.00 (m, 4H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 4.63 (s, 1H), 4.56 (s, 1H), 4.04 - 4.00 (m, 2H), 3.66 (dd, J = 11.7, 5.8 Hz, 2H), 3.61 (d, J = 5.8 Hz, 3H), 2.88 (m, 3H) ), 2.78 (t, J = 5.6 Hz, 1H), 2.67 (t, J = 5.7 Hz, 1H), 2.61 - 2.51 (m, 2H), 2.43 (m, 2H), 2.18 (s, 6H), 1.99 (m, 1H), 1.77 (d, J = 12.8 Hz, 2H), 1.59 - 1.51 (m, 1H), 1.48 (m, 2H), 1.20 - 1.13 (m, 2H). m/z 795.39 [M+H] ⁺ . Compound 127 ^1H NMR (600 MHz, DMSO) δ 11.08 (s, 1H), 9.64 (d, J = 5.8 Hz, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.74 - 7.57 (m, 3H) ), 7.33 (d, J = 15.0 Hz, 1H), 7.28 - 7.21 (m, 1H), 7.10 (m, 4H), 5.06 (dd, J = 12.8, 5.3 Hz, 1H), 4.64 (s, 1H) , 4.58 (s, 1H), 4.31 (d, J = 16.9 Hz, 2H), 3.82 - 3.75 (m, 2H), 3.72 - 3.65 (m, 2H), 3.62 (s, 3H), 3.28 - 3.19 (m , 2H), 2.91 - 2.86 (m, 2H), 2.84 - 2.77 (m, 1H), 2.74 - 2.68 (m, 1H), 2.63 - 2.57 (m, 2H), 2.20 (s, 6H), 2.02 - 2.00 (m, 1H), 1.97 - 1.94 (m, 2H), 1.58 - 1.49 (m, 2H). m/z 797.35 [M+H] ⁺ . Compound 128 ^1H NMR (600 MHz, DMSO) δ 11.08 (s, 1H), 9.63 (d, J = 11.0 Hz, 1H), 8.34 (d, J = 4.3 Hz, 1H), 8.10 (s, 1H), 7.75 - 7.56 (m, 3H), 7.32 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.18 - 7.00 (m, 4H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.68 (s, 1H), 4.57 (s, 1H), 3.84 - 3.76 (m, 2H), 3.74 - 3.69 (m, 2H), 3.68 - 3.64 (m, 1H), 3.62 (d, J = 3.9 Hz, 2H) ), 3.26 - 3.19 (m, 2H), 2.93 - 2.84 (m, 1H), 2.80 (s, 1H), 2.66 (d, J = 18.9 Hz, 2H), 2.63 - 2.56 (m, 2H), 2.55 - 2.52 (m, 2H), 2.20 (s, 6H), 2.04 - 1.93 (m, 2H), 1.92 - 1.83 (m, 2H), 1.76 - 1.64 (m, 2H), 1.50 - 1.38 (m, 4H), 1.30 - 1.23 (m, 2H). m/z 865.43 [M+H] ⁺ . Compound 129 ^1H NMR (600 MHz, DMSO) δ 11.06 (s, 1H), 9.62 (d, J = 15.2 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 8.08 (s, 1H), 7.68 ( s, 1H), 7.65 - 7.58 (m, 2H), 7.30 (d, J = 6.8 Hz, 1H), 7.22 - 7.24 (m, 1H), 7.14 - 7.00 (m, 4H), 5.11 (d, J = 10.9 Hz, 1H), 5.04 (dd, J = 12.6, 5.8 Hz, 1H), 4.69 (s, 1H), 4.60 (s, 1H), 3.81 - 3.75 (m, 1H), 3.73 - 3.65 (m, 2H) ), 3.60 (d, J = 2.0 Hz, 3H), 2.90 - 2.85 (m, 2H), 2.80 - 2.78 (m, 1H), 2.72 - 2.68 (m, 2H), 2.64 - 2.57 (m, 3H), 2.40 - 2.33 (m, 2H), 2.18 (d, J = 2.9 Hz, 6H), 2.01 - 1.96 (m, 1H), 1.70 - 1.61 (m, 2H). m/z 797.32 [M+H] ⁺ . Compound 130 ^1H NMR (600 MHz, DMSO) δ 11.05 (s, 1H), 9.51 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.7, 2.2 Hz, 1H), 7.10 - 7.05 (m , 3H), 6.97 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 12.8, 5.5 Hz, 1H), 4.40 (s, 1H), 3.74 (d, J = 13.0 Hz, 2H), 3.68 (s, 2H), 3.58 (s, 3H), 2.89 - 2.82 (m, 2H), 2.79 (d, J = 5.3 Hz, 2H), 2.71 (d, J = 5.2 Hz, 2H), 2.60 - 2.56 ( m, 2H), 2.54 (m, 1H), 2.52 - 2.50 (m, 1H), 2.45 (s, 1H), 2.17 (s, 6H), 2.00 - 1.96 (m, 1H), 1.65 - 1.54 (m, 4H). m/z 796.47 [M+H] ⁺ . Compound 131 ^1H NMR (600 MHz, DMSO) δ 11.08 (s, 1H), 9.56 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.32 (s, 1H), 7.24 (dd, J = 8.7, 2.2 Hz, 1H), 7.10 (m, 3H), 7.02 (d, J = 8.1 Hz, 1H), 5.06 (dd, J = 12.8, 5.5 Hz, 1H), 3.78 (d, J = 12.9 Hz, 2H), 3.61 (s, 3H), 3.57 (s, 2H), 3.31 - 3.26 (m, 2H), 2.95 - 2.82 (m, 2H), 2.74 (s, 2H), 2.65 - 2.60 (m, 3H), 2.63 - 2.59 (m, 2H), 2.57 (m, 2H), 2.40 - 2.37 (m, 1H), 2.20 ( s, 6H), 2.04 - 2.00 (m, 1H), 1.72 - 1.54 (m, 4H). m/z 783.34 [M+H] ⁺ . Compound 132 ^1H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 9.55 (s, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.54 (s, 1H), 7.14 - 7.06 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H) ), 5.06 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 12.3 Hz, 2H), 4.26 (d, J = 17.3 Hz, 1H), 4.08 (d, J = 17.3 Hz, 1H) ), 3.60 (s, 3H), 3.53 (s, 2H), 3.02 - 2.95 (m, 2H), 2.94 - 2.86 (m, 2H), 2.85 - 2.73 (m, 2H), 2.66 - 2.62 (m, 2H) ), 2.59 - 2.57 (d, J = 15.2 Hz, 2H), 2.37 (m, 1H), 2.35 - 2.32 (d, J = 7.1 Hz, 1H), 2.19 (s, 6H), 1.98 - 1.94 (m, 1H), 1.89 (s, 2H), 1.83 (d, J = 10.6 Hz, 2H). m/z 740.42 [M+H] ⁺ . Compound 133 ^1H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 9.54 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.50 (s, 1H), 7.12 - 7.07 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H) ), 5.05 (dd, J = 13.3, 5.1 Hz, 2H), 4.40 (s, 1H), 4.24 (d, J = 17.3 Hz, 1H), 4.11 - 4.09 (m, 2H), 3.69 (s, 2H) , 3.60 (s, 3H), 2.94 - 2.84 (m, 2H), 2.81 (m, 2H), 2.73 (m, 2H), 2.61 (d, J = 1.8 Hz, 1H), 2.59 - 2.53 (m, 1H) ), 2.46 (s, 2H), 2.39 - 2.31 (m, 1H), 2.19 (s, 6H), 1.97 - 1.93 (m, 1H), 1.59 (s, 4H). m/z 756.38 [M+H] ⁺ . Compound 134 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.29 (s, 1H), 7.85 (dd, J = 9.0, 2.6 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H) , 7.40 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.17 - 7.12 (m, 3H), 7.06 - 7.03 (m, 1H), 6.94 (s, 1H), 6.67 (d, J = 9.1 Hz, 1H), 5.85 (s, 1H), 4.94 (m, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.77 (s, 3H), 3.50 (m, 4H), 2.99 (m , 2H), 2.92 - 2.79 (m, 3H), 2.76 - 2.69 (m, 2H), 2.57 - 2.50 (m, 4H), 2.26 (s, 6H), 2.13 (m,1H), 1.93 (d, J = 12.7 Hz, 2H), 1.85 (s, 1H), 1.34 - 1.27 (m, 2H). m/z 783.53 [M+H] ⁺ . Compound 135 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 8.23 (d, J = 14.0 Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 8.5 Hz) , 1H), 7.38 (s, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.18 - 7.12 (m, 3H), 7.09 - 7.06 (m, 1H), 6.95 (s, 1H), 6.39 ( d, J = 9.5 Hz, 1H), 5.86 (s, 1H), 4.94 (m, 1H), 3.76 (s, 3H), 3.64 (s, 4H), 3.57 (m, 2H), 3.46 (m, 4H) ), 3.12 (m, 1H), 2.90 (m, 1H), 2.84 - 2.79 (m, 2H), 2.77 - 2.71 (m, 2H), 2.67 (s, 2H), 2.55 (s, 2H), 2.26 ( s, 6H), 2.16 - 2.12 (m, 1H), 1.73 (m, 2H). m/z 783.45 [M+H] ⁺ . Compound 136 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.47 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.44 (s, 2H), 7.29 (s, 1H), 7.24 (s, 1H) , 7.22 - 7.19 (m, 1H), 7.18 - 7.12 (m, 3H), 7.12 - 7.08 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H) ), 5.89 (s, 1H), 4.94 (m, 1H), 3.97 (d, J = 12.8 Hz, 2H), 3.81 (s, 3H), 3.23 (s, 4H), 2.98 (m, 2H), 2.84 (m, 3H), 2.77 - 2.69 (m, 2H), 2.58 (s, 4H), 2.27 (s, 6H), 2.16 - 2.09 (m, 1H), 1.91 (d, J = 13.2 Hz, 2H), 1.84 (s, 1H), 1.32 (m, 2H). m/z 782.49 [M+H] ⁺ . Compound 137 ^1H NMR (600 MHz, DMSO) δ 10.84 (s, 1H), 9.55 (s, 1H), 8.62 (d, J = 8.2 Hz, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.09 (m, 3H), 7.03 - 6.94 (m, 2H), 4.76 - 4.70 (m, 1H), 3.67 - 3.58 (s, 3H), 3.57 (d, J = 10.4 Hz, 1H), 3.51 - 3.44 (m, 2H), 3.44 - 3.40 (m, 2H), 3.37 (m , 3H), 3.03 - 2.99 (m, 1H), 2.82 - 2.73 (m, 2H), 2.70 - 2.64 (m, 2H), 2.62 - 2.59 (m, 1H), 2.57 - 2.53 (m, 2H), 2.40 - 2.34 (m, 1H), 2.22 - 2.13 (s, 6H), 2.05 - 1.97 (m, 1H), 1.78 - 1.65 (m, 3H). m/z 728.52 [M+H] ⁺ . Compound 138 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.65 (d, J = 12.0 Hz, 1H), 7.53 (d, J = 6.0 Hz, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 7.19 - 7.15 (m, 3H), 7.05 (d, J = 6.0 Hz, 1H), 6.80 (d, J = 1.8 Hz, 1H), 6.51 (dd, J = 8.4, 1.8 Hz, 1H), 5.90 (s, 1 H), 4.94 (dd, J = 12.0, 6.0 Hz, 1H), 4.19 - 4.16 (m, 2H), 3.79 (s, 2H), 3.72 (s, 3H), 3.74 - 3.71 (m, 2H), 3.05 - 3.00 (m, 2 H), 2.95 (d, J = 10.8 Hz, 2H), 2.91 - 2.90 (m, 1H), 2.87 - 2.81 (m, 4H), 2.75 - 2.72 (m, 2H), 2.65 (d, J = 12.0 Hz, 2H), 2.55 (t, J = 10.8 Hz, 2H), 2.27 (s, 6H), 2.14 - 2.07 (m, 3H), 1.87 (d, J = 12.0 Hz, 2H) . m/z 404.89 [M+2H] ²⁺ . Compound 139 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.66 (brs, 1H), 7.67 (d, J = 12.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.18 - 7.14 (m, 3H), 7.06 - 7.03 (m, 2H), 5.93 ( s, 1H), 4.94 (dd, J = 12.6, 5.4 Hz, 1H), 3.96 (d, J = 12.6 Hz, 2H), 3.80 (s, 2H), 3.78 (s, 1H), 3.74 (s, 1H) ), 2.99 (d, J = 12.0 Hz, 2H), 2.96 - 2.93 (m, 2H), 2.91 (t, J = 3.0 Hz, 1H), 2.88 - 2.87 (m, 1H), 2.85 (s, 3H) , 2.81 (dd, J = 12.6, 4.2 Hz, 1H), 2.76 - 2.70 (m, 2H), 2.52 - 2.47 (m, 1H), 2.27 (s, 6H), 2.21 (d, J = 6.6 Hz, 2H) ), 2.15 - 2.11 (m, 1H), 2.0 (t, J = 11.4 Hz, 2H), 1.86 (d, J = 12.0 Hz, 4H), 1.72 - 1.66 (m, 2H), 1.34 - 1.28 (m, 3H). m/z 418.83 [M+2H] ²⁺ . Compound 140 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.67 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.38 (s, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.20 (s, 1H), 7.15 (s, 2H), 7.08 - 7.03 (m, 3H), 6.27 (s, 1H), 6.00 (s, 1H), 4.94 (dd, J = 12.6 , 5.4 Hz, 1H), 3.97 (d, J = 13.2 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.84 - 3.80 (m, 4H), 3.71 - 3.68 (m, 1H), 3.14 - 3.10 (m, 1H), 3.07 - 3.02 (m, 2H), 2.87 (s, 3H), 2.77 - 2.70 (m, 2H), 2.59 - 2.49 (m, 3H), 2.29 (d, J = 4. .2 Hz, 6H), 2.17 - 2.10 (m, 3H), 2.06 (t, J = 10.5 Hz, 2H), 1.90 - 1.75 (m, 8H), 1.2 - 1.18 (m, 2H). m/z 418.99 [M+2H] ²⁺ . Compound 141 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.67 (d, J = 9.0 Hz, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.36 (dd, J = 8.4, 1.8 Hz 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.21 - 7.18 (m, 1H), 7.15 (s, 2H), 7.09 - 7.03 (m, 3H), 6.27 (s, 1H), 6.01 (s, 1H) , 4.94 (dd, J = 12.6, 5.4 Hz, 1H), 3.96 (d, J = 11.4 Hz, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.81 (s, 4H), 3.74 - 3.68 ( m, 1H), 3.12 (t, J = 12.0 Hz, 1H), 3.06 - 3.01 (m, 2H), 2.88 (s, 3H), 2.77 - 2.70 (m, 2H), 2.57 - 2.52 (m, 3H) , 2.29 (s, 6H), 2.16 - 2.12 (m, 3H), 2.06 (t, J = 10.5 Hz, 2H), 1.88 - 1.73 (m, 8H), 1.25 - 1.22 (m, 2H). m/z 418.97 [M+2H] ²⁺ . Compound 142 ^1H NMR (600 MHz, CDCl ₃ ) δz 7.66 (dd, J = 8.4, 1.2 Hz, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.39 (d, J = 16.2 Hz, 1H) , 7.33 (d, J = 8.4 Hz, 1H), 7.17 - 7.14 (m, 3H), 7.04 (dd, J = 8.4, 3.6 Hz, 1H), 6.99 (d, J = 1.8 Hz, 1H), 6.68 ( dd, J = 8.4,1.8 Hz, 1H), 6.17 (s, 1H), 6.05 (s, 1H), 4.95 - 4.92 (m, 1H), 3.80 (s, 4H), 3.59 (t, J = 8.7 Hz) , 1H), 3.53 - 3.49 (m, 1H), 3.46 - 3.40 (m, 2H), 3.20 (dd, J = 9.6, 7.2 Hz, 1H), 3.05 - 3.03 (m, 1H), 2.95 (d, J = 8.4 Hz, 1H), 2.92 - 2.90 (m, 1H), 2.86 (s, 3H), 2.84 - 2.80 (m, 1H), 2.76 - 2.73 (m, 1H), 2.65 - 2.58 (m, 1H), 2.56 - 2.51 (m, 1H), 2.45 (dd, J = 12.0, 5.4 Hz, 1H), 2.39 - 2.34 (m, 2H), 2.27 (s, 6H), 2.23 - 2.19 (m, 1H), 2.17 - 2.14 (m, 1H), .2.09 (d, J = 11.4 Hz, 1H), 2.00 - 1.93 (m, 2H), 1.87 - 1.80 (m, 2H), 1.76 - 1.68 (m, 2H). m/z 411.93 [M+2H] ²⁺ . Compound 143 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.66 (dd, J = 8.4, 1.8 Hz, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 16.2 Hz, 1H) , 7.21 (s, 1H), 7.18 - 7.14 (m, 3H), 7.04 (dd, J = 7.8, 3.6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.68 (dd, J = 8.4 , 2.4 Hz, 1H), 6.19 (s, 1H), 6.06 (s, 1H), 4.96 - 4.92 (m, 1H), 3.80 (s, 3H), 3.75 (s, 1H), 3.59 (dd, J = 10.2, 7.2 Hz, 1H), 3.53 - 3.49 (m, 1H), 3.46 - 3.39 (m, 2H), 3.20 (dd, J = 10.2, 7.8 Hz, 1H), 3.06 - 3.02 (m, 1H), 2.94 (d, J = 12.6 Hz, 1H), 2.87 (s, 3H), 2.84 - 2.79 (m, 1H), 2.76 - 2.72 (m, 1H), 2.64 - 2.58 (m, 1H), 2.57 - 2.52 (m , 1H), 2.45 (dd, J = 12.0, 6.0 Hz, 1H), 2.38 - 2.34 (m, 2H), 2.28 (s, 6H), 2.23 - 2.20 (m, 1H), 2.17 - 2.14 (m, 1H) ), 2.16 - 2.08 (m, 1H), 2.00 - 1.93 (m, 2H), 1.87 - 1.81 (m, 3H), 1.78 - 1.72 (m, 2H). m/z 411.98 [M+2H] ²⁺ . Compound 144 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.28 (s, 1H), 8.09 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.47 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 7.19 (m, 3H), 7.10 (d, J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.71 (d, J = 8.5 Hz, 1H), 5.86 (s, 1H), 4.95 (m, 1H), 3.81 (s, 3H), 3.73 - 3.68 (m, 2H), 3.62 (m, 2H), 3.53 (m, 1H) ), 3.48 - 3.43 (m, 1H), 3.33 - 3.25 (m, 2H), 2.89 (m, 2H), 2.84 - 2.81 (m, 1H), 2.77 (m, 1H), 2.72 (m, 1H), 2.62 (m, 1H), 2.56 (m, 1H), 2.27 (s, 6H), 2.16 - 2.12 (m, 1H), 1.90 (m, 2H). m/z 739.43 [M+H] ⁺ . Compound 145 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 8.06 (s, 1H), 7.66 - 7.61 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.43 - 7.40 ( m, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.16 (m, 3H), 7.09 - 7.05 (m, 1H), 6.97 - 6.93 (m, 1H), 6.69 (dd, J = 8.5, 2.1 Hz, 1H), 5.85 (s, 1H), 4.93 (m, 1H), 3.79 (s, 3H), 3.72 - 3.55 (m, 4H), 3.54 - 3.48 (m, 1H), 3.44 (m) , 1H), 3.31 - 3.22 (m, 2H), 2.88 (m, 2H), 2.80 (m, 1H), 2.77 - 2.71 (m, 2H), 2.62 (m, 2H), 2.26 (s, 6H), 2.13 (m, 1H), 1.89 (m, 2H). m/z 739.45 [M+H] ⁺ . Compound 146 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.40 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 3.7 Hz) , 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.17 (t, J = 4.7 Hz, 1H), 7.16 - 7.12 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 7.03 (dd, J = 8.6, 2.3 Hz, 1H), 5.88 (s, 1H), 4.94 (m, 1H), 3.94 (d, J = 12.8 Hz, 2H) , 3.79 (s, 3H), 3.62 (s, 2H), 2.98 (t, J = 12.2 Hz, 2H), 2.91 - 2.89 (m, 1H), 2.89 - 2.86 (m, 2H), 2.84 - 2.78 (m , 2H), 2.76 - 2.72 (m, 3H), 2.58 - 2.55 (m, 2H), 2.27 (s, 6H), 2.13 (m, 1H), 1.85 (d, J = 12.1 Hz, 2H), 1.68 ( m, 2H), 1.35 (m, 2H). m/z 767.48 [M+H] ⁺ . Compound 147 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.42 - 7.39 (m, 2H), 7.33 (d, J = 2.0 Hz, 1H) , 7.18 - 7.14 (m, 3H), 7.09 (d, J = 5.4 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.52 (dd, J = 8.3, 2.1 Hz, 1H), 5.86 (s, 1H), 4.93 (m, 1H), 4.10 (t, J = 7.5 Hz, 2H), 3.89 (dd, J = 8.2, 5.4 Hz, 2H), 3.79 (s, 3H), 3.60 (s, 2H), 3.36 - 3.32 (m, 1H), 2.91 - 2.87 (m, 2H), 2.85 (m, 2H), 2.79 (m, 1H), 2.75 (d, J = 5.0 Hz, 1H), 2.70 (m, 2H), 2.37 (d, J = 7.2 Hz, 2H), 2.26 (s, 6H), 2.12 (m, 1H), 1.94 - 1.86 (m, 4H), 1.66 (m, 2H), 1.32 - 1.28 (m, 2H). m/z 808.49 [M+H] ⁺ . Compound 148 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 8.3, 2.0 Hz, 1H), 7.43 (s, 1H) , 7.32 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 7.17 - 7.11 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 5.95 (s, 1H), 4.92 (m, 1H), 3.78 (s, 3H), 3.71 (s, 2H), 3.66 (dd, J = 9.8, 2.2 Hz, 2H), 3.52 - 3.48 (m, 2H), 2.89 (m, 2H), 2.86 (m, 1H), 2.84 - 2.77 (m, 3H), 2.75 - 2.68 (m, 1H), 2.58 - 2.50 (m, 2H), 2.26 (s, 6H), 2.14 - 2.09 (m, 1H), 1.71 (s, 2H), 0.97 (m, 1H). m/z 751.48 [M+H] ⁺ . Compound 149 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.33 (d, J = 2.0 Hz, 1H) , 7.27 (d, J = 2.5 Hz, 1H), 7.18 - 7.10 (m, 4H), 7.07 - 7.00 (m, 2H), 5.91 (s, 1H), 4.93 (m, 1H), 3.94 (d, J = 12.9 Hz, 2H), 3.79 (s, 3H), 3.66 - 3.62 (m, 2H), 3.48 (d, J = 5.5 Hz, 2H), 3.19 - 3.13 (m, 1H), 3.02 - 2.97 (m, 2H), 2.96 - 2.92 (m, 2H), 2.91 - 2.89 (m, 1H), 2.87 - 2.83 (m, 2H), 2.82 - 2.79 (m, 1H), 2.76 - 2.68 (m, 2H), 2.58 ( t, J = 5.9 Hz, 2H), 2.44 (d, J = 6.8 Hz, 2H), 2.25 (s, 6H), 2.14 - 2.10 (m, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.34 - 1.27 (m, 2H). m/z 808.54 [M+H] ⁺ . Compound 150 ^1H NMR (600 MHz, CDCl ₃ ) δ 9.04 (s, 1H), 7.65 (dd, J = 8.4, 1.5 Hz, 1H), 7.53 (dd, J = 16.9, 7.9 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.28 - 7.26 (m, 1H), 7.18 - 7.13 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.95 (t , J = 2.1 Hz, 1H), 6.69 - 6.65 (m, 1H), 5.89 (d, J = 6.2 Hz, 1H), 4.95 - 4.91 (m, 1H), 3.79 (s, 3H), 3.69 - 3.60 ( m, 2H), 3.55 (dd, J = 10.1, 7.3 Hz, 1H), 3.50 - 3.45 (m, 1H), 3.43 - 3.36 (m, 3H), 3.23 - 3.11 (m, 2H), 2.99 (m, 2H), 2.93 - 2.78 (m, 5H), 2.76 - 2.69 (m, 1H), 2.65 - 2.52 (m, 4H), 2.45 (m, 1H), 2.27 (s, 6H), 2.23 - 2.18 (m, 1H), 2.16 - 2.11 (m, 1H). m/z 794.35 [M+H] ⁺ . Compound 151 ^1H NMR (600 MHz, CDCl ₃ ) δ 9.12 (s, 1H), 7.65 (dd, J = 8.4, 1.0 Hz, 1H), 7.53 (dd, J = 15.4, 8.7 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.44 - 7.40 (m, 1H), 7.28 (s, 1H), 7.20 - 7.12 (m, 3H), 7.05 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 2.0 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 5.92 (d, J = 5.9 Hz, 1H), 4.93 (m, 1H), 3.79 (s, 3H), 3.65 (m, 2H) ), 3.55 (dd, J = 10.0, 7.3 Hz, 1H), 3.48 (m, 1H), 3.43 - 3.37 (m, 3H), 3.22 - 3.12 (m, 2H), 3.00 (m, 2H), 2.91 - 2.80 (m, 5H), 2.75 - 2.69 (m, 1H), 2.61 - 2.51 (m, 4H), 2.45 (m, 1H), 2.27 (s, 6H), 2.23 - 2.17 (m, 1H), 2.13 ( dd, J = 9.0, 3.7 Hz, 1H). m/z 794.38 [M+H] ⁺ . Compound 152 ^1H NMR (400 MHz, CDCl ₃ ) δ 9.59 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 7.40 (s, 1H) , 7.32 (s, 2H), 7.14 (m, 3H), 7.04 (d, J = 8.3 Hz, 1H), 6.85 (d, J = 1.7 Hz, 1H), 6.46 (dd, J = 8.3, 2.0 Hz, 1H), 5.93 (s, 1H), 4.89 (m, 1H), 4.08 (m, 2H), 3.78 (s, 3H), 3.70 (m, 2H), 3.65 (m, 1H), 3.45 (s, 2H) ), 3.13 (m, 1H), 3.05 (m, 2H), 2.94 - 2.71 (m, 8H), 2.65 (m, 1H), 2.56 (t, J = 5.9 Hz, 2H), 2.25 (s, 6H) , 2.14 - 2.09 (m, 1H). m/z 780.33 [M+H] ⁺ . Compound 153 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.35 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 7.18 - 7.15 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 2.2 Hz, 1H) , 6.66 (dd, J = 8.5, 2.2 Hz, 1H), 5.92 (s, 1H), 4.93 (m, 1H), 3.79 (s, 3H), 3.62 (dd, J = 9.8, 2.7 Hz, 2H), 3.49 - 3.46 (m, 4H), 3.23 (s, 1H), 3.08 (s, 2H), 2.90 (dd, J = 4.0, 2.6 Hz, 1H), 2.86 (m, 4H), 2.82 - 2.78 (m, 1H), 2.76 - 2.69 (m, 1H), 2.58 (t, J = 5.9 Hz, 2H), 2.55 (s, 2H), 2.26 (s, 6H), 2.14 - 2.11 (m, 1H), 1.67 (s) , 2H), 0.81 - 0.78 (m, 1H). m/z 806.38 [M+H] ⁺ . Compound 154 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 8.37 (s, 1H), 7.85 (dd, J = 9.0, 2.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H) , 7.40 (s, 1H), 7.19 - 7.08 (m, 3H), 7.02 (s, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.71 - 6.66 (m, 2H), 5.87 (s, 1H) ), 4.94 (m, 1H), 3.80 - 3.71 (m, 3H), 3.55 - 3.49 (m, 4H), 3.47 (d, J = 22.3 Hz, 3H), 3.23 (dd, J = 9.6, 7.3 Hz, 1H), 2.96 - 2.79 (m, 3H), 2.76 - 2.66 (m, 2H), 2.65 - 2.60 (m, 2H), 2.58 - 2.52 (m, 2H), 2.45 (m, 2H), 2.34 - 2.20 ( m, 6H), 2.13 (m, 1H), 1.90 - 1.83 (m, 1H). m/z 769.44 [M+H] ⁺ . Compound 155 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.66 (dd, J = 8.4, 2.4 Hz, 1H) , 7.39 (d, J = 2.3 Hz, 1H), 7.15 (s, 3H), 6.96 (d, J = 11.7 Hz, 2H), 6.73 - 6.66 (m, 2H), 5.85 (s, 1H), 4.94 ( m, 1H), 3.76 (s, 3H), 3.52 (m, 4H), 3.50 (s, 3H), 3.25 - 3.20 (m, 1H), 2.86 (m, 3H), 2.77 - 2.68 (m, 2H) , 2.63 (s, 2H), 2.57 (s, 2H), 2.50 - 2.42 (m, 2H), 2.27 (d, J = 2.1 Hz, 6H), 2.17 - 2.10 (m, 1H), 1.90 - 1.83 (m , 1H). m/z 769.43 [M+H] ⁺ . Compound 156 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 8.21 (s, 1H), 7.88 - 7.82 (m, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.38 (s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.17 - 7.11 (m, 3H), 7.06 (dd, J = 8.6, 2.2 Hz, 1H), 6.97 (s, 1H), 6.68 (d, J = 9.1 Hz, 1H), 5.85 (s, 1H), 4.94 (m, 1H), 4.01 (d, J = 13.0 Hz, 2H), 3.76 (s, 3H), 3.51 (s, 4H), 3.02 (t , J = 11.6 Hz, 2H), 2.89 (dd, J = 16.8, 2.8 Hz, 1H), 2.84 - 2.79 (m, 2H), 2.76 (d, J = 5.2 Hz, 1H), 2.74 - 2.67 (m, 4H), 2.58 (s, 2H), 2.27 (s, 6H), 2.15 - 2.11 (m, 1H), 2.01 (m, 2H). m/z 769.45 [M+H] ⁺ . Compound 157 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.42 (d, J = 7.3 Hz, 2H), 7.84 (dd, J = 9.0, 2.7 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.9 Hz, 1H), 7.29 - 7.26 (m, 1H), 7.18 - 7.11 (m, 3H), 7.04 (dd, J = 8.6, 2.4 Hz, 1H), 6.98 (s, 1H), 6.68 (d, J = 9.1 Hz, 1H), 5.87 (s, 1H), 4.94 (m, 1H), 3.94 (d, J = 13.1 Hz, 2H), 3.75 (d, J = 9.9 Hz, 3H), 3.54 - 3.47 (m, 4H), 2.98 (m, 2H), 2.92 - 2.85 (m, 1H), 2.82 (m, 1H), 2.76 - 2.69 (m, 1H), 2.60 - 2.52 (m, 4H), 2.49 - 2.41 (m, 2H), 2.26 (s, 6H), 2.15 - 2.09 (m, 1H), 1.84 (d, J = 11.3 Hz, 2H), 1.65 - 1.61 (m, 1H), 1.53 (dd, J = 15.1, 7.0 Hz, 2H), 1.34 (m, 2H). m/z 797.47 [M+H] ⁺ . Compound 158 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.31 (s, 1H), 7.87 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 4.5 Hz, 1H), 7.15 (s, 3H), 6.98 (s, 1H), 6.81 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 7.4 Hz, 1H), 5.86 (s, 1H), 4.96 - 4.90 (m, 1H), 4.14 (s, 2H), 3.96 (d, J = 5.2 Hz, 2H), 3.77 (d, J = 3.1 Hz, 3H), 3.56 (s, 4H), 3.44 (s, 1H), 2.89 (d, J = 16.8 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.77 - 2.69 (m, 1H), 2.61 (dd , J = 15.4, 14.0 Hz, 4H), 2.27 (s, 6H), 2.15 (s, 1H). m/z 741.45 [M+H] ⁺ . Compound 159 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 8.43 (s, 1H), 7.86 (dd, J = 9.0, 2.7 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H) , 7.40 (s, 1H), 7.19 - 7.11 (m, 3H), 7.02 (s, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.68 (d, J = 9.1 Hz, 1H), 6.51 ( dd, J = 8.3, 2.1 Hz, 1H), 5.88 (s, 1H), 4.93 (m, 1H), 4.17 (t, J = 8.0 Hz, 2H), 3.76 (s, 3H), 3.74 (m, 2H) ), 3.54 - 3.47 (m, 4H), 3.11 - 3.05 (m, 1H), 2.91 - 2.86 (m, 1H), 2.84 - 2.78 (m, 1H), 2.76 - 2.69 (m, 3H), 2.64 - 2.55 (m, 4H), 2.26 (s, 6H), 2.15 - 2.10 (m, 1H). m/z 755.41 [M+H] ⁺ . Compound 160 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.84 (d, J = 21.0 Hz, 1H), 8.45 (s, 1H), 7.58 (d, J = 9.0 Hz 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.17 - 7.11 (m, 3H), 7.06 (dd, J = 8.4, 1.8 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H), 5.97 (s, 1H), 4.93 (dd, J = 12.6, 6.0 Hz, 1H), 3.93 (t, J = 8.7 Hz, 1H), 3.76 (s, 3H) ), 3.56 - 3.50 (m, 4H), 3.16 - 3.11 (m, 1H), 2.34 - 2.89 (m, 1H), 2.88 - 2.87 (m, 1H), 2.84 - 2.81 (m, 1H), 2.72 (m , 1H), 2.64 - 2.60 (m, 2H), 2.48 - 2.45 (m, 2H), 2.36 - 2.32 (m, 1H), 2.26 (s, 6H), 2.23 (dd, J = 12.6, 5.4 Hz, 1H ), 2.14 - 2.10 (m, 1H), 1.95 - 1.89 (m, 2H), 1.81 - 1.78 (m, 1H), 1.67 - 1.61 (m, 3H). m/z 783.48 [M+H] ⁺ . Compound 161 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.50 (d, J = 15.6 Hz, 1H), 8.43 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz) , 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.17 - 7.13 (m, 3H), 7.06 (d, J = 6.0 Hz, 1H), 6.68 (d, J = 9.0 Hz, 1H) , 5.90 (s, 1H), 4.93 (dd, J = 12.6, 5.4 Hz, 1H), 3.92 (s, 1H), 3.77 (s, 3H), 3.56 - 3.49 (m, 4H), 3.13 (t, J = 11.7 Hz, 1H), 2.94 - 2.87 (m, 2H), 2.82 (t, J = 12.6 Hz, 1H), 2.76 - 2.70 (m, 1H), 2.65 - 2.57 (m, 2H), .2.49 - 2.42 (m, 2H), 2.34 (t, J = 10.5 Hz, 1H), 2.26 (s, 6H), 2.16 - 2.10 (m, 1H), 1.95 - 1.89 (m, 2H), 1.81 - 1.75 (m, 1H) ), 1.67 - 1.62 (m, 1H), 1.58 (s, 3H). m/z 392.34 [M+2H] ²⁺ . Compound 162 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.55 (s, 1H), 8.37 (s, 1H), 8.01 - 7.94 (m, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.36 - 7.32 (m, 1H), 7.28 (s, 1H), 7.18 - 7.09 (m, 3H), 7.07 - 7.03 (m, 1H), 5.88 (s, 1H), 4.92 (m, 1H) , 3.96 (d, J = 12.7 Hz, 2H), 3.83 (s, 3H), 3.16 (s, 4H), 3.01 - 2.94 (m, 2H), 2.88 (m, 2H), 2.82 (m, 1H), 2.77 - 2.71 (m, 2H), 2.60 (s, 4H), 2.27 (s, 6H), 2.12 (m, 1H), 1.92 (m, 2H), 1.83 (s, 1H), 1.30 (d, J = 14.5 Hz, 2H). m/z 783.46 [M+H] ⁺ . Compound 163 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.9 Hz, 2H), 7.42 (s, 1H), 7.31 (d, J = 2.3 Hz, 1H), 7.19 - 7.14 (m, 3H), 7.07 (dd, J = 8.7, 2.3 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 5.87 (s, 1H), 5.00 - 4.95 (m, 1H), 3.98 (d, J = 12.9 Hz, 2H), 3.81 (s, 3H), 3.18 (s, 4H), 3.04 - 2.98 (m, 2H), 2.94 - 2.88 (m, 2H), 2.86 - 2.81 (m, 1H), 2.78 - 2.71 (m, 2H), 2.62 (s, 4H), 2.30 (s, 6H), 2.16 (m, 1H), 1.95 (d, J = 12.1 Hz, 2H), 1.86 (s, 1H), 1.33 (dd, J = 21.9, 11.7 Hz, 2H). m/z 782.47 [M+H] ⁺ . Compound 164 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.82 (d, J = 2.4 Hz, 2H), 8.07 (dd, J = 8.5, 2.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.18 - 7.13 (m, 4H), 7.05 (dd, J = 8.6, 2.3 Hz, 1H), 5.95 ( s, 1H), 4.94 (m, 1H), 3.96 (d, J = 12.9 Hz, 2H), 3.81 (s, 3H), 2.97 (m, 4H), 2.91 - 2.86 (m, 2H), 2.85 - 2.79 (m, 1H), 2.76 - 2.72 (m, 1H), 2.71 - 2.66 (m, 1H), 2.27 (s, 6H), 2.25 (s, 1H), 2.15 - 2.11 (m, 2H), 2.09 (s) , 2H), 1.93 (d, J = 10.7 Hz, 4H), 1.83 (s, 2H), 1.33 - 1.25 (m, 2H). m/z 782.42 [M+H] ⁺ . Compound 165 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.28 (d, J = 2.1 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.18 - 7.13 (m, 3H), 7.05 (dd, J = 8.6, 2.2 Hz, 1H), 5.86 (s, 1H), 4.94 (m, 1H), 3.96 (d, J = 12.8 Hz, 2H), 3.81 (s, 3H), 2.98 (m, 4H), 2.89 (m, 2H), 2.82 (m, 1H), 2.76 - 2.71 (m, 1H), 2.48 (s, 2H), 2.27 (s, 6H), 2.25 (s, 2H), 2.15 - 2.12 (m, 1H), 2.05 (m, 2H), 1.93 (d, J = 12.6 Hz, 2H), 1.82 (d, J = 11.0 Hz, 3H), 1.34 - 1.29 (m, 2H). m/z 781.48 [M+H] ⁺ . Compound 166 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.19 - 7.12 (m, 4H), 6.97 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.5, 2.2 Hz, 1H), 5.86 (s, 1H), 4.94 (m, 1H), 3.81 (s, 3H), 3.60 (dd, J = 9.9, 7.4 Hz, 1H), 3.54 - 3.47 (m, 2H), 3.42 (d, J = 9.8 Hz, 1H) ), 3.23 - 3.18 (m, 1H), 3.07 (d, J = 10.9 Hz, 1H), 2.99 (d, J = 10.8 Hz, 1H), 2.92 - 2.86 (m, 2H), 2.85 - 2.79 (m, 2H), 2.77 - 2.70 (m, 2H), 2.67 - 2.63 (m, 1H), 2.48 - 2.45 (m, 1H), 2.42 (d, J = 8.7 Hz, 1H), 2.27 (s, 6H), 2.16 - 2.12 (m, 1H), 2.06 (d, J = 2.4 Hz, 1H), 1.86 - 1.79 (m, 4H). m/z 767.32 [M+H] ⁺ . Compound 167 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.15 (m, 2H), 6.97 (d, J = 2.0 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 5.83 (s, 1H), 4.96 - 4.93 (m, 1H), 3.81 (s, 3H), 3.60 (s, 1H), 3.50 (d, J = 7.2 Hz, 1H), 3.42 (d, J = 9.3 Hz, 2H), 3.25 - 3.19 ( m, 1H), 3.07 (s, 1H), 2.98 (s, 1H), 2.92 - 2.86 (m, 2H), 2.83 (m, 2H), 2.76 - 2.70 (m, 2H), 2.66 (s, 1H) , 2.46 (s, 1H), 2.41 (s, 1H), 2.25 (s, 6H), 2.15 - 2.12 (m, 1H), 2.06 (s, 1H), 1.83 (s, 4H). m/z 767.34 [M+H] ⁺ . Compound 168 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.59 (d, J = 6.0 Hz, 2H), 7.42 (s, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 12.0 Hz, 2H), 7.17 - 7.14 (m, 3H), 7.07 (dd, J = 8.4, 2.4 Hz, 1H), 5.85 (s, 1 H), 4.95 (dd, J = 12.0, 6.0 Hz, 1H), 4.03 (d, J = 12.0 Hz, 2H), 3.81 (s, 3H), 3.08 (d, J = 6.0 Hz, 2H), 3.01 (t, J = 12.0 Hz, 2H), 2.9 (dt, J = 16.8, 3.3 Hz, 1H), 2.83 (td, J = 13.2, 4.8 Hz, 1H), 2.77 - 2.71 (m, 1H), 2.49 ( t, J = 12.0 Hz, 1H), 2.32 (t, J = 9.0 Hz, 2H), 2.27 (s, 6H), 2.17 - 2.12 (m, 1H), 2.0 (d, J = 11.4 Hz, 2H), 1.88 (d, J = 12.6 Hz, 2H), 1.80 - 1.74 (m, 2H), 1.71 - 1.67 (m, 3H). m/z 384.42 [M+2H] ²⁺ . Compound 169 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.17 - 7.13 (m, 3H), 7.12 (s, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 8.3, 2.1 Hz, 1H), 5.83 (s, 1H), 4.93 (m, 1H), 4.21 - 4.14 (m, 2H), 3.81 (s, 3H), 3.76 - 3.70 (m, 2H), 3.08 (s, 1H), 3.00 (s, 2H), 2.89 (m, 2H), 2.85 - 2.80 (m, 2H), 2.75 (m, 1H), 2.73 - 2.70 (m, 2H), 2.49 (m, 1H), 2.27 (s, 6H) ), 2.15 - 2.12 (m, 1H), 1.85 (d, J = 12.4 Hz, 2H), 1.79 (m, 2H). m/z 753.35 [M+H] ⁺ . Compound 170 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.41 (s, 1H), 7.22 - 7.18 (m, 2H), 7.15 (m, 3H), 6.67 (d, J = 8.9 Hz, 1H), 5.86 (s, 1H), 5.20 (m, 1H), 4.47 (d, J = 11.6 Hz, 2H), 4.30 (d, J = 16.2 Hz, 1H), 4.17 (d, J = 16.1 Hz, 1H), 3.81 (s, 3H), 3.02 (s, 2H), 2.95 (m, 2H), 2.90 ( s, 1H), 2.84 (m, 2H), 2.48 (s, 2H), 2.37 - 2.32 (m, 2H), 2.30 - 2.24 (s, 6H), 2.23 - 2.19 (m, 1H), 2.09 - 2.01 ( m, 3H), 1.91 (d, J = 13.1 Hz, 3H), 1.82 (s, 5H). m/z 768.40 [M+H] ⁺ . Compound 171 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.61 (s, 3H), 7.68 (d, J = 8.5 Hz, 1H), 7.41 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.16 (m, 3H), 7.05 (dd, J = 8.6, 2.3 Hz, 1H), 7.02 (s, 1H), 5.89 (s, 1H), 4.94 (m, 1H), 3.97 (d, J = 13.0 Hz, 2H), 3.80 (s, 4H), 3.76 (s, 3H), 2.99 (dd, J = 17.9, 7.4 Hz, 2H), 2.89 (m, 2H), 2.85 - 2.79 (m, 1H), 2.76 - 2.69 (m, 2H), 2.49 (s, 4H), 2.26 (d, J = 10.2 Hz, 6H), 2.16 - 2.11 (m, 1H), 1.93 (d, J = 13.0 Hz, 2H), 1.85 (s, 1H), 1.31 (m, 2H). m/z 784.37 [M+H] ⁺ . Compound 172 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 7.41 (s, 1H), 7.40 (s, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.18 - 7.13 (m, 3H), 7.06 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H) , 6.99 (d, J = 8.3 Hz, 1H), 5.83 (s, 1H), 4.94 (dd, J = 12.5, 5.4 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.80 (s, 3H), 3.59 (s, 2H), 3.00 (t, J = 11.7 Hz, 2H), 2.90 (t, J = 5.4 Hz, 2H), 2.89 - 2.87 (m, 1H), 2.85 - 2.79 (m, 1H) ), 2.74 - 2.69 (m, 3H), 2.39 (d, J = 6.9 Hz, 2H), 2.27 (s, 6H), 2.16 - 2.10 (m, 1H), 1.95 (d, J = 12.8 Hz, 2H) , 1.91 - 1.89 (m, 1H), 1.35 - 1.29 (m, 2H). m/z 753.34 [M+H] ⁺ . Compound 173 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.4, 1.8, 1H), 7.42 (s, 2H), 7.19 - 7.13 (m, 3H), 7.11 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.69 (dd, J = 8.5, 2.2 Hz) , 1H), 5.85 (s, 1H), 4.93 (dd, J = 12.5, 5.4 Hz, 1H), 3.80 (s, 3H), 3.68 (d, J = 14.4 Hz, 1H), 3.62 (s, 1H) , 3.60 (dd, J = 7.0, 2.7 Hz, 1H), 3.54 - 3.48 (m, 1H), 3.47 - 3.42 (m, 1H), 3.25 (dd, J = 9.9, 7.1 Hz, 1H), 2.94 - 2.91 (m, 2H), 2.91 - 2.89 (m, 1H), 2.88 - 2.86 (m, 1H), 2.82 (dd, J = 13.0, 4.3 Hz, 1H), 2.80 - 2.78 (m, 1H), 2.76 - 2.74 (m, 1H), 2.72 (dd, J = 5.1, 3.5 Hz, 1H), 2.62 - 2.54 (m, 2H), 2.27 (s, 6H), 2.24 - 2.22 (m, 1H), 2.15 - 2.10 (m , 1H), 1.93 - 1.85 (m, 1H). m/z 739.33 [M+H] ⁺ . Compound 174 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.42 (s, 2H), 7.17 - 7.13 (m, 3H), 6.99 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.69 (dd, J = 8.5, 2.2 Hz, 1H), 5.88 (s, 1H), 4.93 (dd, J = 12.5, 5.4 Hz, 1H), 3.80 (s, 3H), 3.68 (d, J = 14.4 Hz, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.51 ( dd, J = 10.2, 6.3 Hz, 1H), 3.47 - 3.40 (m, 1H), 3.46 - 3.42 (m, 1H), 3.25 (dd, J = 9.9, 7.1 Hz, 1H), 2.94 - 2.91 (m, 2H), 2.91 - 2.89 (m, 1H), 2.88 - 2.85 (m, 1H), 2.84 - 2.81 (m, 1H), 2.80 - 2.78 (m, 1H), 2.76 -2.74 (m, 1H), 2.73 - 2.71 (m, 1H), 2.62 - 2.54 (m, 2H), 2.27 (s, 6H), 2.25 - 2.22 (m, 1H), 2.15 - 2.09 (m, 1H), 1.92 - 1.86 (m, 1H). m/z 739.31 [M+H] ⁺ . Compound 175 ^1H NMR (600 MHz, CDCl ₃ ) δ 8.42 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.43 (s, 1H), 7.29 - 7.27 (m, 3H), 7.19 - 7.13 (m, 3H), 7.05 (dd, J = 8.6, 2.4 Hz, 1H), 5.85 (s, 1H), 4.94 (dd, J = 12.6, 5.4 Hz, 1H) ), 3.98 - 3.93 (m, 2H), 3.81 (s, 3H), 3.75 (t, J = 7.4 Hz, 2H), 3.69 - 3.64 (m, 1H), 3.13 (td, J = 7.2, 3.7 Hz, 2H), 2.98 (td, J = 13.0, 2.0 Hz, 2H), 2.92 - 2.88 (m, 1H), 2.86 - 2.80 (m, 1H), 2.77 - 2.70 (m, 1H), 2.42 (d, J = 6.7 Hz, 2H), 2.27 (s, 6H), 2.17 - 2.11 (m, 1H), 1.86 (d, J = 11.1 Hz, 2H), 1.68 - 1.64 (m, 1H), 1.39 - 1.30 (m, 2H) ). m/z 753.43 [M+H] ⁺ . Compound 176 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.66 (dd, J = 8.4, 2.0 Hz, 1H), 7.62 (dd, J = 8.5, 3.0 Hz, 2H), 7.43 (d, J = 1.2 Hz, 1H) , 7.28 - 7.26 (m, 2H), 7.19 - 7.14 (m, 3H), 6.96 (d, J = 2.2 Hz, 1H), 6.69 (dt, J = 8.5, 1.9 Hz, 1H), 5.83 (s, 1H) ), 4.94 (dd, J = 12.5, 5.4 Hz, 1H), 3.81 (s, 3H), 3.77 (t, J = 6.8 Hz, 2H), 3.73 - 3.67 (m, 1H), 3.58 (q, J = 8.6 Hz, 1H), 3.52 - 3.48 (m, 1H), 3.44 - 3.39 (m, 1H), 3.23 - 3.13 (m, 3H), 2.89 (dt, J = 9.6, 3.4 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.77 - 2.69 (m, 1H), 2.59 (t, J = 6.6 Hz, 2H), 2.48 - 2.40 (m, 1H), 2.27 (s, 6H), 2.25 - 2.20 (m, 1H) ), 2.16 - 2.10 (m, 1H), 1.86 - 1.79 (m, 1H). m/z 739.28 [M+H] ⁺ . Compound 177 ^1H NMR (600 MHz, CDCl ₃ ) δ 7.66 (dd, J = 8.4, 2.1 Hz, 1H), 7.62 (dd, J = 8.6, 3.0 Hz, 2H), 7.43 (d, J = 1.2 Hz, 1H) , 7.28 - 7.26 (m, 2H), 7.20 - 7.13 (m, 3H), 6.96 (d, J = 2.2 Hz, 1H), 6.69 (dt, J = 9.0, 2.1 Hz, 1H), 5.85 (s, 1H) ), 4.94 (dd, J = 12.5, 5.4 Hz, 1H), 3.81 (s, 3H), 3.78 (t, J = 6.8 Hz, 2H), 3.72 - 3.69 (m, 1H), 3.58 (q, J = 8.6 Hz, 1H), 3.52 - 3.47 (m, 1H), 3.44 - 3.39 (m, 1H), 3.23 - 3.14 (m, 3H), 2.92 - 2.86 (m, 1H), 2.85 - 2.80 (m, 1H) , 2.76 - 2.70 (m, 1H), 2.59 (t, J = 6.5 Hz, 2H), 2.46 - 2.41 (m, 1H), 2.27 (s, 6H), 2.25 - 2.19 (m, 1H), 2.17 - 2.11 (m, 1H), 1.87 - 1.80 (m, 1H). m/z 739.26 [M+H] ⁺ . Compound 178 ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.45 - 7.40 (m, 2H), 7.36 (s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.20 - 7.12 (m, 4H), 7.10 - 7.05 (m, 2H), 5.88 (s, 1H), 4.94 (m, 1H), 4.04 (m, 2H), 3.80 (s) , 3H), 3.68 (d, J = 14.9 Hz, 2H), 3.48 (s, 4H), 2.93 - 2.91 (m, 1H), 2.90 - 2.86 (m, 3H), 2.82 (m, 1H), 2.81 - 2.78 (m, 1H), 2.75 (m, 2H), 2.71 (m, 2H), 2.59 - 2.54 (m, 2H), 2.50 (m, 2H), 2.27 (s, 6H), 2.16 - 2.10 (m, 1H). m/z 798.41 [M+H] ⁺ . Compound 179 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.58 - 7.52 (m, 2H), 7.42 (s, 1H), 7.19 (s, 1H), 7.16 - 7.12 (m, 3H), 6.98 - 6.91 (m, 3H), 6.70 (dd, J = 8.5, 2.3 Hz, 1H), 5.93 (s, 1H), 4.94 (m, 1H), 3.78 (s, 3H), 3.63 - 3.56 (m, 1H), 3.54 - 3.48 (m, 1H), 3.42 (m, 1H), 3.25 - 3.12 (m, 5H), 2.87 (m, 2H), 2.78 (m) , 1H), 2.73 - 2.64 (m, 4H), 2.60 (m, 2H), 2.52 - 2.41 (m, 2H), 2.27 (s, 6H), 2.16 - 2.09 (m, 1H), 1.86 (m, 1H) ). m/z 768.43 [M+H] ⁺ . Compound 180 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.48 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.54 (m, 2H), 7.41 (s, 1H), 7.15 (m, 4H) , 6.97 - 6.91 (m, 3H), 6.70 (dd, J = 8.5, 2.2 Hz, 1H), 5.90 (s, 1H), 4.94 (m, 1H), 3.78 (s, 3H), 3.60 (m, 1H) ), 3.54 - 3.48 (m, 1H), 3.46 - 3.40 (m, 1H), 3.25 - 3.13 (m, 5H), 2.93 - 2.83 (m, 2H), 2.77 (m, 1H), 2.73 - 2.65 (m , 4H), 2.61 (m, 2H), 2.51 - 2.42 (m, 2H), 2.27 (s, 6H), 2.17 - 2.09 (m, 1H), 1.91 - 1.81 (m, 1H). m/z 768.43 [M+H] ⁺ . Compound 181 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 12.0 Hz, 2H), 7.40 (s, 1H), 7.16 - 7.14 (m, 3H), 7.04 (s, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 8.0, 2.0 Hz, 1H), 5.84 (s, 1H), 4.93 (dd, J = 12.0, 4.0 Hz, 1H), 4.17 (t, J = 8.0 Hz, 2H), 3.79 (s, 3H), 3.76 - 3.72 (m, 2H) ), 3.16 (t, J = 6.0 Hz, 4H), 3.10 - 3.04 (m 1H), 2.91 - 2.87 (m, 1H), 2.81 - 2.80 (m, 1H), 2.78 - 2.72 (m, 3H), 2.64 (t, J = 4.0 Hz, 4H), 2.27 (s, 6H), 2.15 - 2.11 (m, 1H). m/z 755.88 [M+H] ²⁺ . Compound 182 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.65 - 7.59 (m, 3H), 7.42 (s, 1H), 7.30 (s, 1H), 7.24 (s, 2H), 7.19 - 7.13 (m, 3H), 6.80 (d, J = 2.1 Hz, 1H), 6.51 (dd, J = 8.3, 1.9 Hz, 1H), 5.85 (s, 1H), 4.93 (m, 1H), 4.17 - 4.09 (m, 2H), 3.92 - 3.59 (m, 9H), 3.21 (s, 1H), 2.81 (m, 6H), 2.27 (s, 6H), 2.12 (m, 1H). m/z 725.41 [M+H] ⁺ . Compound 183 ^1H NMR (400 MHz, CDCl ₃ ) δ 7.97 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 7.16 - 7.12 (m, 3H), 6.99 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 8.4, 2.0 Hz, 1H), 5.80 (s, 1H), 4.93 (dd, J = 12.0, 4.8 Hz, 1H), 4.18 - 4.13 (m, 2H), 3.79 (s, 3H), 3.77 - 3.72 (m, 2H), 3.69 - 3.62 (m, 1H), 3.49 (m, 1H), 3.12 - 3.01 (m, 2H), 3.08 - 3.03 (m, 1H), 2.91 - 2.87 (m, 1H), 2.85 - 2.80 (m, 1H) , 2.78 - 2.74 (m, 1H), 2.72 - 2.67 (m, 3H), 2.63 (dd, J = 10.8, 3.2 Hz, 1H), 2.51 - 2.46 (m, 2H), 2.27 (s, 6H), 2.15 - 2.10 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H). m/z 768.46 [M+H] ⁺ . Compound 184 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 7.16 - 7.14 (m, 3H), 7.12 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 8.4, 2.0 Hz, 1H), 5.85 (s, 1H), 4.93 (dd, J = 12.4, 5.2 Hz, 1H), 4.18 - 4.13 (m, 2H), 3.79 (s, 3H), 3.77 - 3.73 (m, 2H), 3.69 - 3.62 (m, 1H), 3.12 - 3.01 (m, 2H), 3.08 - 3.03 (m, 1H), 2.91 - 2.87 (m, 1H), 2.85 - 2.80 (m, 1H), 2.78 - 2.74 (m, 1H), 2.72 - 2.67 (m, 3H), 2.63 (dd, J = 10.8, 3.2 Hz, 1H), 2.51 - 2.46 (m, 2H), 2.26 (s, 6H), 2.15 - 2.11 (m, 1H) , 1.03 (d, J = 6.4 Hz, 3H). m/z 768.44 [M+H] ⁺ . Compound 185 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (d, J = 4.8 Hz 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.16 - 7.12 (m, 3H), 7.00 (s, 1H), 6.92 (d, J = 5.6 Hz, 2H), 6.79 (s, 1H), 6.52 (dd, J = 8.4, 2.0 Hz, 1H) ), 5.82 (s, 1H), 4.93 (dd, J = 12.4, 5.2 Hz, 1H), 4.19 - 4.12 (m, 2H), 3.78 (s, 3H), 3.76 - 3.67 (m, 2H), 3.40 - 3.34 (m, 2H), 3.14 - 3.03 (m, 2H), 2.95 - 2.88 (m, 3H), 2.85 - 2.72 (m, 2H), 2.65 - 2.52 (m, 3H), 2.45 (t, J = 10.4 Hz, 1H), 2.26 (s, 6H), 2.18 - 2.10 (m, 1H), 1.16 (d, J = 5.2 Hz, 3H). m/z 768.43 [M+H] ⁺ Compound 186 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.19 (d, J = 6.4 Hz 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 7.16 - 7.12 (m, 3H), 7.04 (s, 1H), 6.92 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 6.52 (dd, J = 8.4, 1.6 Hz, 1H) ), 5.84 (s, 1H), 4.93 (dd, J = 12.0, 5.2 Hz, 1H), 4.20 - 4.13 (m, 2H), 3.78 (s, 3H), 3.77 - 3.74 (m, 1H), 3.70 - 3.67 (m, 1H), 3.40 - 3.34 (m, 2H), 3.14 - 3.06 (m, 2H), 2.96 - 2.88 (m, 3H), 2.85 - 2.72 (m, 2H), 2.65 - 2.59 (m, 2H) ), 2.57 - 2.52 (m, 1H), 2.45 (t, J = 9.8 Hz, 1H), 2.27 (s, 6H), 2.15 - 2.10 (m, 1H), 1.16 (d, J = 5.2 Hz, 3H) . m/z 768.44 [M+H] ⁺ Compound 187 ^1H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 6.9 Hz, 2H), 7.38 (s, 1H), 7.22 (s, 1H), 7.17 - 7.11 (m, 3H), 6.93 (d, J = 9.0 Hz, 2H), 6.24 (d, J = 8.6 Hz, 1H), 5.90 (s, 1H), 5.19 (m, 1H), 4.32 (d, J = 16.4 Hz, 1H), 4.25 (m, 2H), 4.19 (d, J = 16.4 Hz, 1H), 3.87 - 3.80 (m, 2H), 3.78 (s, 3H), 3.19 - 3.12 (m, 4H), 3.08 - 3.01 (m, 1H), 2.90 (m, 1H), 2.84 (m, 1H), 2.75 (d, J = 7.4 Hz, 2H), 2.67 - 2.60 (m, 4H), 2.36 - 2.29 (m, 1H), 2.27 (s, 6H), 2.24 - 2.17 (m, 1H). m/z 741.24 [M+H] ⁺ . Compound 188 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 12.0, 2H), 7.41 (s, 1H), 7.15 - 7.12 (m, 3H), 7.12 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.67 (d, J = 8.0 Hz, 1H), 5.90 (s, 1H), 5.21 (dd, J = 12.0, 4.0 Hz, 1H), 4.50 - 4.44 (m, 2H), 4.31 (d, J = 16.0 Hz, 1H), 4.17 (d, J = 16.0 Hz, 1H), 3.78 (s, 3H), 3.16 (t, J = 4.8, 4H), 2.99 - 2.92 (m, 2H), 2.90 (s, 1H), 2.86 - 2.81 (m, 1H), 2.59 (t, J = 4.8 Hz, 4H), 2.32 (dd , J = 12.8, 4.8 Hz, 1H), 2.27 (s, 6H), 2.24 - 2.17 (m, 2H), 1.90 (d, J = 12.0 Hz, 3H), 1.86 - 1.81 (m, 1H), 1.27 - 1.18 (m, 2H). m/z 770.42 [M+H] ²⁺ . Compound 189 LC/MS 832.3 [MH] / 834.3 [M+H]
^1H NMR (400 MHz, DMSO- d6 ) δ 10.77 (s, 1H) _, 9.87 (s, 1H), 9.54 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.77 (dd, J = 8.1, 2.3 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.53 ( s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.18-7.05 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 4.13-4.01 (m, 1H), 3.61 (s) , 3H), 3.54-3.49 (m, 2H), 3.10 (s, 2H), 2.92-2.82 (m, 2H), 2.76-2.72 (m, 2H), 2.69-2.60 (m, 4H), 2.57-2.54 (m, 4H), 2.48-2.37 (m, 2H), 2.36-2.28 (m, 2H), 2.20 (s, 6H), 2.17-2.11 (m, 1H), 1.91-1.82 (m, 2H), 1.79 -1.69 (m, 2H), 1.63 (s, 1H). Compound 190 LC/MS 721.33 [MH] / 723.15 [M+H]
^1H NMR (400 MHz, DMSO- d6 ) δ 10.76 (s, 1H), 9.66 (s, 1H), _8.81 (s, 1H), 8.34 (s, 1H), 8.14-7.96 (m, 3H), 7.74-7.56 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 7.15-7.02 (m, 4H), 4.64 (s, 2H), 4.06-3.98 (m, 1H), 3.70 (t, J = 5.6 Hz, 2H), 3.63 (s, 3H), 2.85-2.74 (m, 2H), 2.65-2.54 (m, 4H), 2.45-2.37 (m, 1H), 2.20 (s, 6H), 2.02 -1.78 (m, 2H). Compound 192 ^1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.85 (s, 1H), 9.67 (d, J = 10.2 Hz, 1H), 8.36 (d, J = 3.6 Hz, 1H), 8.12 ( s, 1H), 7.69 (d, J = 3.8 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.36-7.28 (m, 4H), 7.12-7.01 (m, 5H), 4.99-4.95 (m, 1H), 4.72 (s, 1H), 4.63 (s, 1H), 3.89-3.86 (m, 2H), 3.75-3.70 (m, 2H), 3.62 (s, 3H), 2.87-2.81 (m , 2H), 2.73-2.71 (m, 2H), 2.20 (s, 6H), 2.00-1.98 (m, 2H).
LC/MS (ESI) m/z [M+H]+: 739.09 Compound 193 ^1H NMR (500 MHz, DMSO) δ 11.09 (s, 1H), 9.86 (s, 1H), 9.58 (s, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.59-7.52 (m , 2H), 7.33-7.28 (m, 3H), 7.13-7.08 (m, 4H), 7.01-6.98 (m, 2H), 4.99-4.96 (m, 1H), 4.40-4.38 (m, 1H), 3.98 -3.96 (m, 1H), 3.75 (s, 2H), 3.61 (s, 3H), 3.51-3.50 (m, 2H), 3.18-3.16 (m, 1H), 3.05-3.00 (m, 1H), 2.90 -2.82 (m, 1H), 2.73-2.72 (m, 2H), 2.62-2.59 (m, 4H), 2.28-2.26 (m, 2H), 2.20 (s, 6H), 2.18-2.15 (m, 1H) , 2.06-1.98 (m, 2H), 1.88 (s, 1H), 1.75-1.69 (m, 2H).
LC/MS (ESI) m/z [M+H]+: 836.7 Compound 194 LC/MS (ESI) m/z [M+H]+: 714.6
^1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.74-7.69 (m, 1H), 8.37 (d, J = 3.2 Hz, 1H), 8.15 (s, 1H), 7.85-7.82 (m , 1H), 7.72-7.68 (m, 1H), 7.67-7.62 (m, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.39-7.36 (m, 1H), 7.15-7.09 (m, 4H) ), 5.28-5.24 (m, 2H), 5.15-5.10 (m, 1H), 4.70 (s, 1H), 4.61 (s, 1H), 3.70 (d, J = 5.6 Hz, 2H), 3.62 (s, 3H), 3.43 (s, 2H), 2.90-2.87 (m, 1H), 2.76-2.73 (m, 1H), 2.62-2.57 (m, 1H), 2.20 (s, 6H), 2.08-2.01 (m, 1H). Compound 195 LC/MS: 817.53 [M+H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H) _, 9.59 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.63-7.50 (m, 2H), 7.35-7.28 (m, 1H), 7.24 (d, J = 8.6 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.06 (d, J = 12.8 Hz, 2H), 3.58 (d, J = 29.9 Hz, 3H), 3.15-2.92 (m , 2H), 2.95-2.82 (m, 1H), 2.76 (s, 2H), 2.72-2.55 (m, 3H), 2.29 (d, J = 32.2 Hz, 3H), 2.01 (d, J = 15.0 Hz, 1H), 1.84 (d, J = 12.7 Hz, 1H), 1.26-1.17 (m, 1H). Compound 199 LCMS: 836.3 [M + H] ^+
1H NMR (500 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 7.63 (d, J = _8.6 Hz, 1H), 7.35 (s, 1H), 7.26 (s, 2H), 7.21-6.96 ( m, 5H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.07-3.79 (m, 5H), 3.62 (s, 1H), 3.00-2.69 (m, 6H), 2.66-2.58 (m, 2H), 2.37 (s, 2H), 2.25-2.13 (m, 6H), 2.05-1.96 (m, 1H), 1.82-1.41 (m, 4H), 1.24 (s, 2H), 1.08 (s, 2H) , 0.86 (s, 2H), 0.75 (s, 2H). compound 201 LC/MS: 703.31 [M + H] ^+
1H NMR (500 MHz, DMSO- d6 ) δ 11.02 (s, 1H), 9.59 (s, 1H), _8.35 (s, 2H), 8.11 (s, 1H), 7.62-7.51 (m, 2H), 7.23-7.06 (m, 3H), 7.01 (d, J = 8.5 Hz, 1H), 5.23 (s, 1H), 4.86 (dd, J = 12.8, 5.5 Hz, 1H), 3.61 (s, 3H), 3.53 (s, 2H), 3.09 (t, J = 12.5 Hz, 2H), 2.89-2.78 (m, 1H), 2.79-2.61 (m, 4H), 2.61-2.54 (m, 4H), 2.46-2.29 (m) , 3H), 2.20 (s, 6H), 2.03-1.77 (m, 2H), 1.23-1.13 (m, 2H). Compound 204 LCMS: 836.2 [M + H] ^+
1H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.55 (s, 1H), 8.34 (s, 1H), 8.13-8.01 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.63-7.49 (m, 2H), 7.30 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.16-7.06 (m, 3H), 7.01 (d, J = 8.5 Hz) , 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.01 (d, J = 13.1 Hz, 2H), 3.62 (s, 5H), 2.96 (t, J = 12.7 Hz, 2H), 2.92 -2.82 (m, 1H), 2.72 (s, 4H), 2.59 (s, 3H), 2.20 (s, 6H), 2.06-1.93 (m, 1H), 1.77-1.52 (m, 3H), 1.19-1.13 (m, 3H), 0.71-0.58 (m, 4H). Compound 205 LC/MS. 783.6 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.11 (s, 1H) _, 9.54 (s, 1H), 8.40 (d, J = 9.5 Hz, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 7.38-7.30 (m, 1H), 7.17-7.06 (m, 3H) ), 7.02-6.95 (m, 2H), 5.10 (dd, J = 12.7, 5.4 Hz, 1H), 4.64 (s, 2H), 3.62 (d, J = 8.1 Hz, 5H), 2.88 (d, J = 5.7 Hz, 2H), 2.69 (d, J = 14.9 Hz, 4H), 2.61 (s, 2H), 2.20 (s, 6H), 2.07-1.97 (m, 2H), 0.77 (s, 2H), 0.69 ( s, 2H). Compound 206 LCMS 894.4 [M+H].
^1H NMR (400 MHz, DMSO- d6 ) δ 9.81 (s, 1H) _, 9.66 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 8.14 ( s, 1H), 7.78 (s, 1H), 7.74-7.65 (m, 2H), 7.38 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H ), 7.16-7.02 (m, 3H), 5.70 (s, 2H), 5.26 (dd, J = 13.0, 5.4 Hz, 1H), 4.61 (d, J = 15.0 Hz, 1H), 4.35 (dd, J = 15.4, 7.5 Hz, 1H), 4.12 (d, J = 12.9 Hz, 2H), 3.64 (s, 3H), 3.41-3.30 (m, 2H), 3.28-3.15 (m, 4H), 3.15-2.98 (m , 5H), 2.98-2.84 (m, 3H), 2.76-2.59 (m, 3H), 2.20 (s, 6H), 2.10 (d, J = 8.7 Hz, 1H), 2.01-1.86 (m, 4H), 1.76-1.63 (m, 2H), 1.36-1.26 (m, 2H). Compound 207 LC/MS 881.1
^1H NMR (400 MHz, DMSO- d6 ) δ 9.56 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.66 (d, J = 8.5 Hz _, 1H), 7.61-7.48 ( m, 2H), 7.37-7.29 (m, 1H), 7.29-7.22 (m, 1H), 7.16-7.06 (m, 3H), 7.02 (d, J = 8.2 Hz, 1H), 5.64 (s, 2H) , 5.25 (dd, J = 13.1, 5.4 Hz, 1H), 4.06 (d, J = 12.7 Hz, 2H), 3.61 (s, 3H), 3.53 (s, 2H), 3.13-2.94 (m, 3H), 2.88-2.54 (m, 6H), 2.39-2.31 (m, 2H), 2.28 (t, J = 7.7 Hz, 2H), 2.20 (s, 6H), 2.13-2.03 (m, 1H), 2.02-1.93 ( m, 1H), 1.90-1.77 (m, 2H), 1.57-1.46 (m, 1H), 1.40 (q, J = 7.3 Hz, 2H), 1.23-1.12 (m, 2H), 0.85 (s, 3H) , 0.83 (s, 3H). Compound 208 LC/MS: 771.2 [M + H] ⁺ .
^1H NMR (400 MHz, DMSO- d6 ) δ 11.11 (s, 1H), 9.56 (s, 1H), _8.33 (s, 1H), 8.09 (s, 1H), 7.71 (d, J = 11.5 Hz, 1H), 7.57 (d, J = 15.1 Hz, 2H), 7.45 (d, J = 7.4 Hz, 1H), 7.11 (q, J = 5.3 Hz, 3H), 7.02 (d, J = 8.3 Hz, 1H) , 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 3.68-3.57 (m, 5H), 3.54 (s, 2H), 2.93 (t, J = 12.8 Hz, 3H), 2.76 (s, 2H), 2.66 (d, J = 6.0 Hz, 2H), 2.63-2.54 (m, 2H), 2.42-2.32 (m, 2H), 2.20 (s, 6H), 2.07-1.98 (m, 1H), 1.93-1.80 ( m, 3H), 1.37-1.27 (m, 2H). Compound 209 LCMS: 769.7 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 10.97 (s, 1H), 9.63 (s, 1H), 8.35 (d _, J = 6.5 Hz, 1H), 8.09 (s, 1H), 7.62 (d, J = 7.8 Hz, 3H), 7.49-7.28 (m, 2H), 7.18-7.02 (m, 4H), 5.08 (dd, J = 13.5, 5.0 Hz, 1H), 4.57 (d, J = 12.7 Hz, 1H) ), 4.28-4.06 (m, 2H), 3.83-3.44 (m, 5H), 3.22-3.07 (m, 1H), 3.03-2.65 (m, 7H), 2.63-2.56 (m, 2H), 2.42-2.27 (m, 2H), 2.27-2.13 (m, 7H), 2.06-1.90 (m, 1H), 1.82 (t, J = 14.8 Hz, 2H), 1.73-1.59 (m, 1H), 1.58-1.43 (m , 1H). Compound 210 LC/MS 882.1 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.11 (s, 1H), 9.55 (s, 1H), _8.33 (s, 1H), 8.09 (s, 1H), 7.72 (d, J = 11.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 7.18-7.05 (m, 3H), 7.01 (d, J = 8.4 Hz, 1H), 5.10 (dd, J = 12.8, 5.4 Hz, 1H), 4.40 (d, J = 12.6 Hz, 1H), 4.01 (d, J = 13.2 Hz, 1H), 3.72-3.57 (m, 5H) ), 3.53 (s, 2H), 3.11-2.82 (m, 6H), 2.75 (s, 2H), 2.70-2.55 (m, 5H), 2.32 (d, J = 7.5 Hz, 2H), 2.20 (s, 6H), 2.07-2.00 (m, 1H), 1.87-1.80 (m, 1H), 1.73 (s, 5H), 1.11-1.02 (m, 1H), 0.99-0.91 (m, 1H). Compound 211 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.09 (s, 1H), 9.97 (s, 1H), 9.82 (s, 1H), 8.40 (s, 1H), 8.18 ( _s , 1H), 7.78 ( s, 1H), 7.73-7.57 (m, 2H), 7.30-7.06 (m, 4H), 6.53 (s, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.61 (d, J = 16.0 Hz, 1H), 4.47-4.11 (m, 5H), 4.09-3.87 (m, 2H), 3.83-3.59 (m, 4H), 3.25-3.05 (m, 4H), 3.04-2.80 (m, 3H) , 2.72 (dd, J = 23.8, 11.4 Hz, 2H), 2.61 (s, 2H), 2.33-2.14 (m, 6H), 2.08-1.99 (m, 1H), 1.98-1.82 (m, 2H). Compound 217 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.10 (s, 1H) _, 9.72 (s, 1H), 8.73 (s, 1H), 8.62 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.7 Hz, 1H), 7.15 (q, J = 8.3 Hz, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.59 (d, J = 14.7 Hz, 1H), 4.26-4.14 (m, 1H), 4.03 (d, J = 12.9 Hz, 2H), 3.64 (s, 3H), 3.48-3.24 (m, 4H), 3.10 (q, J = 12.9, 12.1 Hz, 3H), 2.95-2.82 (m, 1H), 2.73 (d, J = 16.0 Hz, 1H) , 2.59 (d, J = 15.5 Hz, 2H), 2.05 (dd, J = 24.6, 11.9 Hz, 3H), 1.84 (s, 1H), 1.37 (dd, J = 28.9, 17.2 Hz, 3H).
LC/MS: 881.12 [M+H ⁺ ] Compound 218 ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.63 (s, 1H), 8.71 (d, J = 11.0 Hz, 1H), 8.65 (d, J = 9.2 Hz, 1H) , 7.77-7.50 (m, 5H), 7.32 (s, 1H), 7.23 (td, J = 8.3, 2.0 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H), 5.07 (dd, J = 12.9 , 5.4 Hz, 1H), 4.06 (d, J = 13.1 Hz, 2H), 3.64 (d, J = 8.6 Hz, 3H), 3.54 (s, 2H), 3.01 (t, J = 12.4 Hz, 2H), 2.97-2.81 (m, 2H), 2.76 (d, J = 6.0 Hz, 2H), 2.70-2.57 (m, 3H), 2.34 (d, J = 6.3 Hz, 2H), 2.01 (d, J = 13.0 Hz) , 2H), 1.84 (d, J = 13.0 Hz, 2H).
LC/MS: 878.22 [M+Na ⁺ ] Compound 219 ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.62 (s, 1H), 8.71 (d, J = 11.0 Hz, 1H), 8.57 (d, J = 8.3 Hz, 1H) , 7.98-7.86 (m, 1H), 7.72-7.51 (m, 3H), 7.32 (d, J = 2.3 Hz, 1H), 7.24 (dd, J = 8.7, 2.3 Hz, 1H), 7.09-7.01 (m , 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.06 (d, J = 13.0 Hz, 2H), 3.64 (d, J = 8.5 Hz, 3H), 3.54 (s, 1H), 3.01 (t, J = 12.4 Hz, 2H), 2.98-2.81 (m, 2H), 2.76 (s, 1H), 2.71-2.56 (m, 3H), 2.41-2.27 (m, 2H), 2.01 (d, J = 13.6 Hz, 2H), 1.84 (d, J = 13.0 Hz, 2H), 1.29-1.12 (m, 3H).
LC/MS: 883.15 [M+H ^- ] Compound 220 LC/MS 757.2 [M + H] ^+
1H NMR (400 MHz, Methanol- d ₄ ) δ 8.09 (s, 1H), 7.63-7.48 (m, 2H), 7.42 (d, J = 11.5 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.16 (s, 3H), 7.09 (d, J = 8.2 Hz, 1H), 5.13 (dd, J = 13.4, 5.1 Hz, 1H), 4.51-4.31 (m, 2H), 3.70 (s, 4H) ), 3.61 (d, J = 11.4 Hz, 2H), 2.98-2.75 (m, 7H), 2.49 (dd, J = 20.0, 6.0 Hz, 3H), 2.28 (s, 6H), 2.22-2.14 (m, 1H), 1.97 (d, J = 13.5 Hz, 3H), 1.50 (t, J = 11.9 Hz, 2H), 1.33 (d, J = 17.6 Hz, 2H). Compound 221 ^1H NMR (300 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 9.59 (s, 1H), 8.43 (d, J = 3.0 Hz, 1H), 8.32 (d, J = 3.1 Hz, 1H) , 8.06 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.57 (s, 2H), 7.32 (s, 1H), 7.24 (d, J = 8.7 Hz, 1H) , 7.04-7.02 (m, 1H), 7.00-6.96 (m, 1H), 5.07 (d, J = 12.1 Hz, 1H), 4.06 (d, J = 12.7 Hz, 2H), 3.58 (s, 3H), 3.34-3.01 (m, 2H), 2.97-2.67 (m, 5H), 2.37-2.07 (m, 6H), 2.01 (s, 2H), 1.93-1.71 (m, 2H), 1.22-1.18 (m, 2H) ).
LC/MS: 771.42 [M+H ⁺ ] Compound 222 ^1H NMR (500 MHz, DMSO- d6 ) δ 11.09 (s, 1H), 9.63 (s, 1H), _8.36 (s, 1H), 8.10 (s, 1H), 7.78-7.76 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.33 (s, 1H), 7.26-7.24 (m, 1H), 7.18-7.16 (m, 2H), 7.13-7.08 (m, 3H), 5.09-5.06 ( m, 1H), 4.08-4.04 (m, 1H), 3.61 (s, 3H), 3.12-3.07 (m, 1H), 3.02-2.97 (m, 2H), 2.61-2.55 (m, 3H), 2.33- 2.32 (m, 2H), 2.20 (s, 8H), 2.03-1.98 (m, 4H), 1.81-1.78 (m, 4H), 1.57-1.37 (m, 4H).
LC/MS (ESI) m/z [M+H]+: 809.50 Compound 225 ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.09 (s, 1H), 9.61 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H) , 8.34 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.52-7.48 (m, 1H), 7.37 (s, 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.15 (s, 1H), 7.13-7.10 (m, 2H), 5.10-5.06 (m, 1H), 4.17-4.14 (m, 1H), 3.60 (s, 3H), 3.51-3.49 (m, 4H), 3.13-3.07 (m, 2H), 2.93-2.84 (m, 2H), 2.73-2.63 (m, 6H), 2.57-2.55 (m, 2H), 2.20 ( s, 6H), 2.05-1.91 (m, 2H), 1.86-1.77 (m, 2H), 1.66-1.60 (m, 1H), 1.48-1.38 (m, 1H).
LC/MS (ESI) m/z [M+H]+: 810.51 Compound 226 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.09 (s, 1H), _9.85 (s, 1H), 8.74 (d, J = 4.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H) , 8.39 (s, 1H), 8.14-8.09 (m, 1H), 7.84-7.80 (m, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.51-7.48 (m, 1H), 7.38 (s) , 1H), 7.28 (d, J = 8.6 Hz, 1H), 7.23-7.18 (m, 1H), 7.14-7.09 (m, 1H), 5.10-5.06 (m, 1H), 4.17-4.14 (m, 1H) ), 3.62 (s, 3H), 3.51-3.49 (m, 4H), 3.06-3.00 (m, 2H), 2.93-2.84 (m, 2H), 2.67-2.60 (m, 6H), 2.57-2.53 (m , 2H), 2.20 (s, 6H), 2.04-1.94 (m, 2H), 1.80-1.74 (m, 2H), 1.70-1.67 (m, 1H), 1.52-1.47 (m, 1H).
LC/MS (ESI) m/z [M+H]+: 828.60. Compound 227 ^1H NMR (400 MHz, DMSO- d ₆ ) δ 11.08 (s, 1H), 9.85 (s, 1H), 8.39 (s, 1H), 8.14-8.09 (m, 1H), 7.84-7.81 (m, 1H) ), 7.65 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.25-7.19 (m, 2H), 7.14-7.07 (m, 3H), 5.09-5.04 (m, 1H), 4.60-4.57 (m, 1H), 4.07-4.04 (m, 3H), 3.63 (s, 3H), 3.18-3.10 (m, 1H), 3.03 -2.95 (m, 2H), 2.90-2.82 (m, 1H), 2.65-2.57 (m, 2H), 2.32 (d, J = 7.0 Hz, 2H), 2.20 (s, 6H), 2.03-2.00 (m , 2H), 1.81-1.78 (m, 4H), 1.62-1.53 (m, 1H), 1.49-1.40 (m, 1H), 1.26-1.24 (m, 4H).
LC/MS (ESI) m/z [M+H]+: 829.55 Compound 228 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H) _, 9.62 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.14-7.07 (m, 3H), 6.86 (d, J = 2.1 Hz, 1H), 6.73- 6.70 (m, 1H), 5.09-5.04 (m, 1H), 4.57-4.54 (m, 1H), 4.30-4.15 (m, 4H), 4.00-3.91 (m, 1H), 3.73 (d, J = 13.4 Hz, 1H), 3.61 (s, 3H), 3.16-3.10 (m, 1H), 2.85 (d, J = 5.6 Hz, 1H), 2.77 (s, 1H), 2.61-2.53 (m, 2H), 2.20 (s, 6H), 2.03-2.02 (m, 2H), 1.83-1.78 (m, 2H), 1.63-1.56 (m, 1H), 1.50-1.43 (m, 1H).
LC/MS (ESI) m/z [M+H]+: 767.51 Compound 229 ^1H NMR (500 MHz, DMSO- d6 ) δ 11.09 (s, 1H), 9.87 (s, 1H), _8.41 (s, 1H), 8.15 (s, 1H), 7.68-7.65 (m, 2H), 7.56-7.53 (m, 1H), 7.28-7.24(m, 1H), 7.14-7.09 (m, 3H), 6.86-6.84 (m, 1H), 6.73-6.68 (m, 1H), 5.08-5.05 (m , 1H), 4.58-4.56 (m, 1H), 4.27-4.20 (m, 4H), 4.11-4.08 (m, 1H), 3.97-3.91 (m, 1H), 3.76-3.70 (m, 1H), 3.63 (s, 3H), 2.8-2.87 (m, 1H), 2.86-2.85 (m, 1H), 2.61 (s, 1H), 2.57 (s, 1H), 2.21 (s, 6H), 2.05-1.97 (m , 4H), 1.78 (s, 2H).
LC/MS (ESI) m/z [M+H]+: 785.46 Compound 230 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 9.73 (s, 1H), _8.37 (s, 1H), 8.10 (d, J = 6.7 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.32 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H) , 7.14-7.09 (m, 3H), 6.09 (s, 1H), 5.09-5.04 (m, 1H), 4.24 (d, J = 5.8 Hz, 1H), 4.07-0.04 (m, 2H), 3.63 (s) , 3H), 3.08 (s, 2H), 3.02-2.93 (m, 3H), 2.90-2.85 (m, 1H), 2.64-2.60 (m, 4H), 2.28 (d, J = 7.0 Hz, 2H), 2.20 (s, 6H), 2.04-1.97 (m, 2H), 1.94-1.89 (m, 2H), 1.85-1.82 (m, 2H).
LC/MS (ESI) m/z [M+H] ⁺ : 779.46 Compound 231 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 8.98 (s, 1H), _8.28 (s, 1H), 8.10 (d, J = 4.2 Hz, 1H), 7.76-7.71 ( m, 1H), 7.67-7.65 (m, 1H), 7.48-7.44 (m, 1H), 7.32 (s, 1H), 7.25-7.20 (m, 1H), 7.13-7.05 (m, 4H), 5.09- 5.05 (m, 1H), 4.25-4.24 (m, 1H), 4.07-4.04 (m, 2H), 3.55 (s, 3H), 3.02-2.92 (m, 5H), 2.90-2.83 (m, 1H), 2.62-2.55 (m, 3H), 2.25-2.24 (m, 2H), 2.19 (s, 6H), 2.09-2.00 (m, 4H), 1.84-1.77 (m, 4H), 1.72-1.66 (m, 2H) ).
LC/MS (ESI) m/z [M+H] ⁺ : 799.51 Compound 232 LC/MS: 783.0 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 9.70 (d, J = 7.4 Hz, 1H), _8.36 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H) , 7.85-7.60 (m, 3H), 7.35 (s, 1H), 7.31-7.23 (m, 2H), 7.18 (d, J = 9.2 Hz, 1H), 7.15-7.06 (m, 3H), 5.33 (t) , J = 4.9 Hz, 1H), 5.27 (s, 1H), 5.16-5.01 (m, 1H), 4.31 (t, J = 6.0 Hz, 1H), 4.23-4.07 (m, 3H), 3.63 (d, J = 8.1 Hz, 3H), 3.22-3.08 (m, 2H), 3.00-2.80 (m, 3H), 2.64-2.54 (m, 2H), 2.20 (s, 6H), 2.05-1.98 (m, 2H) , 1.97-1.85 (m, 2H), 1.79-1.63 (m, 2H). Compound 233 LC/MS: 801.5 [M + H] ^+
1 H NMR (500 MHz, DMSO- d ₆ ) δ 11.13 (s, 1H), 9.70 (s, 1H), 8.37 (s, 0.6H), 8.35 (s, 0.4H), 8.12 (s, 1H), 7.78-7.70 (m, 2H), 7.68 (d, J = 2.2 Hz, 1H), 7.66-7.63 (m, 0.6H), 7.49-7.44 (m, 0.4H), 7.20-7.15 (m, 1H), 7.15-7.07 (m, 3H), 5.29 (s, 1H), 5.14-5.10 (m, 1H), 5.09 (s, 1H), 4.32 (t, J = 6.1 Hz, 1H), 4.14 (t, J = 6.0 Hz, 1H), 3.70 (t, J = 10.7 Hz, 2H), 3.63 (d, J = 4.9 Hz, 3H), 3.10 (q, J = 11.5 Hz, 2H), 2.98 - 2.85 (m, 3H) , 2.64-2.54 (m, 2H), 2.20 (d, J = 2.3 Hz, 6H), 2.10-1.96 (m, 4H), 1.75 (dd, J = 27.3, 12.7 Hz, 2H). Compound 234 LC/MS: 894.6 [M + H] ⁺ .
^1H NMR (500 MHz, DMSO- d6 ) δ 11.09 (s, 1H), 9.70 (d, J = 5.4 Hz, 1H), _8.36 (d, J = 8.9 Hz, 1H), 8.12 (s, 1H) , 7.80-7.70 (m, 1H), 7.66 (dt, J = 9.1, 4.3 Hz, 2H), 7.34 (d, J = 5.3 Hz, 1H), 7.29-7.21 (m, 1H), 7.17 (d, J = 10.0 Hz, 1H), 7.16-7.06 (m, 3H), 5.31-5.20 (m, 1H), 5.16-5.00 (m, 2H), 4.54-4.42 (m, 1H), 4.18-4.03 (m, 4H) ), 3.65-3.61 (m, 3H), 3.33-3.14 (m, 3H), 3.14-2.98 (m, 2H), 2.97-2.83 (m, 3H), 2.72-2.54 (m, 3H), 2.20 (s) , 7H), 2.08-1.95 (m, 1H), 1.90-1.49 (m, 8H). Compound 235 LC/MS: 840.6 [M + H] ⁺ .
^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 9.69 (d, J = 5.8 Hz, 1H), _8.35 (d, J = 6.3 Hz, 1H), 8.11 (s, 1H) , 7.78 (s, 0.4H), 7.72 (d, J = 8.4 Hz, 0.6H), 7.67 (s, 0.6H), 7.63 (d, J = 8.4 Hz, 0.4H), 7.57 (dd, J = 8.3 , 4.2 Hz, 1H), 7.26-6.95 (m, 7H), 5.27 (s, 1H), 5.13-4.98 (m, 2H), 4.60-4.24 (m, 3H), 4.24-3.93 (m, 5H), 3.63 (d, J = 7.7 Hz, 3H), 3.00-2.85 (m, 3H), 2.85-2.73 (m, 1H), 2.20 (s, 6H), 2.08-1.93 (m, 2H), 1.70 (s, 3H). Compound 236 LC/MS: 841.6 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.12 (s, 1H), _9.68 (d, J = 4.0 Hz, 1H), 8.35 (d, J = 7.3 Hz, 1H), 8.10 (d, J = 6.7 Hz, 1H), 7.83 (dd, J = 8.4, 3.8 Hz, 1H), 7.80-7.60 (m, 2H), 7.44 (d, J = 5.1 Hz, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.23-7.03 (m, 4H), 5.27 (s, 1H), 5.25-5.00 (m, 4H), 4.50-4.31 (m, 2H), 4.30-4.21 (m, 1H), 4.17-4.09 ( m, 1H), 3.92-3.80 (m, 1H), 3.63 (d, J = 5.9 Hz, 3H), 2.99-2.81 (m, 4H), 2.69-2.58 (m, 2H), 2.20 (s, 6H) , 2.11-1.83 (m, 3H), 1.77-1.61 (m, 3H). Compound 237 LC/MS: 739.6 [M + H] ^+
1 H NMR (400 MHz, Methanol- d ₄ ) δ 8.08 (s, 1H), 7.65 - 7.50 (m, 3H), 7.16 (s, 3H), 7.11 (d, J = 8.2 Hz, 1H), 6.73- 6.60 (m, 2H), 5.09 (dd, J = 13.3, 5.2 Hz, 1H), 4.44-4.33 (m, 2H), 3.81 (s, 2H), 3.69 (s, 3H), 3.66-3.48 (m, 3H), 3.46-3.40 (m, 1H), 3.09 (t, J = 8.8 Hz, 1H), 2.93 (d, J = 16.3 Hz, 4H), 2.85-2.68 (m, 3H), 2.53-2.36 (m) , 2H), 2.28 (s, 6H), 2.25-2.10 (m, 2H), 1.93-1.83 (m, 2H), 1.83-1.73 (m, 1H). Compound 238 LCMS: 683.33 MH, 685.35 M+H
^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 9.49 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.82-7.66 (m, 3H), 7.43 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.16-7.05 (m, 3H), 6.98 (d, J = 9.0 Hz, 2H), 5.09 (dd, J = 12.5, 5.4 Hz) , 1H), 3.68-3.56 (m, 4H), 3.68-3.56 (s, 3H) 3.28-3.18 (m, 4H), 3.01-2.79 (m, 1H), 2.65-2.55 (m, 1H), 2.20 ( s, 6H), 2.07-1.89 (m, 2H). Compound 239 LCMS: 786.4 M+H
^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.13 (s, 1H), 9.49 (s, 1H), 8.33-8.31 (m, 1H), 8.07 (s, 1H), 7.84-7.66 (m, 3H) ), 7.54 (d, J = 7.4 Hz, 1H), 7.17-7.07 (m, 3H), 6.99 (d, J = 8.9 Hz, 2H), 5.13 (dd, J = 12.9, 5.4 Hz, 1H), 3.60 (s, 3H), 3.45-3.39 (m, 4H), 3.30-3.21 (m, 4H), 2.99-2.81 (m, 1H), 2.69-2.55 (m, 2H), 2.20 (s, 6H), 2.14 -1.97 (m, 1H). Compound 240 LC/MS 929.7 [M + H] ^+
1H NMR (300 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 9.68 (s, 1H), 8.36 (s, 1H), 8.10 (d, J = 4.7 Hz, 1H), 7.83 - 7.58 ( m, 3H), 7.33 (s, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.19 - 6.95 (m, 4H), 5.07 (dd, J = 12.7, 5.4 Hz, 1H), 4.70 (d) , J = 19.4 Hz, 2H), 4.41 (d, J = 13.7 Hz, 1H), 4.07 (d, J = 12.5 Hz, 3H), 3.75 (s, 1H), 3.63 (s, 3H), 3.17 - 2.97 (m, 3H), 2.87 (d, J = 11.6 Hz, 3H), 2.58 (d, J = 16.0 Hz, 3H), 2.19 (d, J = 4.9 Hz, 6H), 2.08 - 1.92 (m, 2H) , 1.68 (s, 6H), 1.20 (d, J = 23.4 Hz, 4H). Compound 241 LC/MS 876.6 [M + H] ^+
1H NMR (300 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.68 (s, 1H), 8.36 (s, 1H), 8.10 (d, J = 4.3 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.05 (d, J = 38.4 Hz, 5H), 5.12 (d, J = 14.8 Hz, 3H), 4.70 (d, J = 18.6 Hz, 3H), 4.33 (d, J = 13.0 Hz, 1H), 3.80 (d, J = 30.9 Hz, 4H) , 3.63 (s, 3H), 2.84 (t, J = 14.3 Hz, 5H), 2.63 (s, 2H), 2.20 (s, 6H), 2.03 (dd, J = 20.1, 12.3 Hz, 2H), 1.77 ( s, 2H). Compound 243 ^1H NMR (400 MHz, Chloroform-d) δ 10.75-10.48 (m, 1H), 8.15 (s, 1H), 7.93-7.79 (m, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.65 (s, 0.6H), 7.55 (s, 0.4H), 7.46 (d, J = 7.0 Hz, 1H), 7.40-7.30 (m, 2H), 7.27-7.17 (m, 3H), 7.16-7.07 (m , 1H), 6.66 (s, 1H), 5.06-4.89 (m, 2H), 4.79 (s, 1H), 4.04 (s, 1H), 3.96-3.78 (m, 5H), 3.79-3.62 (m, 1H) ), 3.45 (t, J = 12.4 Hz, 2H), 3.03-2.69 (m, 5H), 2.56-2.35 (m, 2H), 2.30 (s, 6H), 2.21-2.04 (m, 3H). Compound 244 LC/MS: 803.6 [M + H] ^+
1H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 9.61 (s, 1H), 8.34 (s, 1H), 8.10 (s, 1H), 7.73 (d, J = 11.2 Hz, 1H), 7.69-7.57 (m, 2H), 7.53 (d, J = 7.3 Hz, 1H), 7.26-6.96 (m, 4H), 5.10 (dd, J = 12.7, 5.4 Hz, 1H), 4.89 (s) , 0.8H), 4.66 (s, 1.2H), 3.96 (s, 2H), 3.74 (s, 2H), 3.62 (s, 3H), 2.93-2.73 (m, 4H), 2.69-2.56 (m, 3H) ), 2.20 (s, 6H), 2.17-1.87 (m, 5H). Compound 245 LCMS: 786.4 M+H
^1H NMR (400 MHz, DMSO-d ₆ ) δ 10.98 (s, 1H), 9.43 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 11.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.10 (q, J = 5.5 Hz, 3H), 6.90 (d, J = 8.7 Hz, 2H) , 5.07 (dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.1 Hz, 1H), 4.24 (d, J = 17.0 Hz, 1H), 3.59 (s, 3H), 3.52-3.43 ( m, 2H), 3.16-3.05 (m, 5H), 2.98-2.84 (m, 2H), 2.81-2.71 (m, 2H), 2.65-2.55 (m, 2H), 2.43-2.31 (m, 2H), 2.30-2.23 (m, 2H), 2.20 (s, 6H), 2.03-1.93 (m, 2H), 1.89-1.81 (m, 2H), 1.79-1.64 (m, 2H). Compound 246 ^1H NMR (500 MHz, Chloroform-d) δ 10.76-10.39 (m, 1H), 8.22 (s, 1H), 7.88-7.82 (m, 0.5H), 7.71 (d, J = 8.2 Hz, 1H), 7.68-7.61 (m, 0.5H), 7.48 (d, J = 12.5 Hz, 1H), 7.31 (s, 1H), 7.27 (s, 1H), 7.25-7.13 (m, 4H), 7.09 (d, J = 8.6 Hz, 1H), 6.68 (s, 1H), 4.97 (dd, J = 12.3, 5.4 Hz, 1H), 4.91-4.84 (m, 1H), 4.74-4.63 (m, 1H), 4.55-4.46 ( m, 1H), 4.17-4.06 (m, 1H), 4.00 (d, J = 12.9 Hz, 2H), 3.92-3.85 (m, 2H), 3.82 (s, 3H), 3.62 (s, 0.7H), 3.52 (t, J = 12.6 Hz, 1.3H), 3.17-3.04 (m, 3H), 2.97-2.88 (m, 3H), 2.87-2.72 (m, 3H), 2.30 (s, 6H), 2.20-2.14 (m, 2H), 2.08 (d, J = 19.6 Hz, 2H), 1.96 (m, 1.98-1.93, 1H), 1.89 (m, 1.93-1.84, 2H). Compound 247 ¹ H NMR (500 MHz, Chloroform-d) δ 10.79 - 10.40 (m, 1H), 8.24 (s, 1H), 7.86 (s, 0.4H), 7.67 (d, J = 8.2 Hz, 1.6H), 7.53 -7.40 (m, 1H), 7.28-7.12 (m, 5H), 6.98 (s, 1H), 6.91-6.82 (m, 1H), 6.69 (s, 1H), 5.88 (s, 1H), 5.02-4.90 (m, 2H), 4.84 (d, J = 17.0 Hz, 1H), 4.72 (d, J = 17.4 Hz, 1H), 4.52 (s, 1H), 4.08 (s, 1H), 4.02 (s, 2H) , 3.98-3.70 (m, 6H), 3.54 (t, J = 12.6 Hz, 1H), 3.25 (s, 1H), 3.01-2.88 (m, 3H), 2.87-2.70 (m, 2H), 2.30 (s) , 6H), 2.19-2.10 (m, 3H). Compound 248 ^1H NMR (400 MHz, Chloroform-d) δ 8.44-8.18 (m, 1H), 7.83 (d, J = 8.4 Hz, 1.3H), 7.65 (d, J = 14.0 Hz, 0.7H), 7.50-7.36 (m, 2H), 7.35-7.29 (m, 2H), 7.27-7.09 (m, 4H), 6.65 (s, 1H), 4.98 (dd, J = 12.0, 5.2 Hz, 1H), 4.94-4.78 (m , 3.3H), 4.70 (d, J = 17.0 Hz, 0.7H), 4.43 (s, 1.3H), 4.07 (s, 0.7H), 3.96-3.77 (m, 5H), 3.55 (t, J = 12.7) Hz, 1H), 3.20 (t, J = 11.7 Hz, 1H), 3.04-2.88 (m, 3H), 2.88-2.72 (m, 2H), 2.29 (s, 6H), 2.15 (m, 2.21-2.00, 5H). Compound 250 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H), 9.70 (s, 1H), _8.39 (s, 1H), 8.11 (s, 1H), 7.91-7.86 (m, 1H), 7.76-7.72 (m, 1H), 7.67-7.65 (m, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.26-7.23 (m, 1H), 7.14-7.07 (m, 4H), 6.03 ( s, 1H), 5.09-5.05 (m, 1H), 4.08-4.04 (m, 2H), 3.62 (s, 3H), 3.10 (s, 2H), 3.02-3.00 (m, 2H), 2.92-2.82 ( m, 1H), 2.68-2.54 (m, 6H), 2.30-2.28 (m, 2H), 2.20 (s, 6H), 2.06-1.93 (m, 2H), 1.91-1.82 (m, 4H).
LC/MS (ESI) m/z [M+H] ⁺ : 797.48 Compound 253 LC/MS: 813 [M + H] ^+
1H NMR (400 MHz, Chloroform- d ) δ 10.50 (s, 1H), 8.27 (s, 1H), 7.80-7.60 (m, 4H), 7.37-7.31 (m, 1H), 7.26-7.16 (m, 5H), 7.13 (dd, J = 8.6, 2.3 Hz, 1.25H), 6.95 (s, 0.75H), 4.97 (dd, J = 12.2, 5.2 Hz, 1H), 4.83-4.52 (m, 2H), 3.94 -3.83 (m, 2H), 3.81 (s, 3H), 3.44 (t, J = 12.4 Hz, 2H), 3.27-3.10 (m, 1H), 2.96-2.70 (m, 5H), 2.57-2.33 (m , 1H), 2.30 (s, 6H), 2.21-2.09 (m, 3H), 1.98 (d, J = 13.5 Hz, 2H), 1.79-1.69 (m, 3H). Compound 254 LC/MS: 831.0 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.12 (s, 1H), 9.62 (s, 1H), 8.34 (d _, J = 11.0 Hz, 2H), 8.09 (s, 1H), 7.84-7.69 ( m, 3H), 7.54 (d, J = 7.3 Hz, 1H), 7.19 (d, J = 8.3 Hz, 2H), 7.14-7.07 (m, 2H), 5.12 (dd, J = 12.8, 5.4 Hz, 1H) ), 4.59 4.41 (m, 2H), 3.70-3.45 (m, 5H), 3.24 (t, J = 11.9 Hz, 2H), 2.98-2.70 (m, 3H), 2.65-2.55 (m, 2H), 2.39 -2.28 (m, 2H), 2.20 (s, 6H), 2.17-1.95 (m, 4H), 1.86 (d, J = 12.7 Hz, 2H), 1.64-1.47 (m, 2H). Compound 255 LC/MS: 799.0 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H) _, 9.63 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.73-7.60 (m, 3H), 7.56 (d, J = 7.7 Hz, 1H), 7.19-7.02 (m, 4H), 5.14 (dd, J = 13.3, 5.1 Hz, 1H), 4.87 (s) , 1H), 4.65 (s, 1H), 4.51 (d, J = 17.6 Hz, 1H), 4.38 (d, J = 17.5 Hz, 2H), 4.03-3.67 (m, 3H), 3.62 (s, 3H) , 3.51 (s, 1H), 3.23 (s, 1H), 3.02-2.86 (m, 2H), 2.82 (s, 2H), 2.70-2.57 (m, 2H), 2.47-2.36 (m, 1H), 2.20 (s, 6H), 2.14-2.07 (m, 1H), 2.05-1.92 (m, 2H). Compound 256 LC/MS: 796.6 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H) _, 9.42 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.62 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.18 - 7.01 (m, 3H), 6.89 (d, J = 8.9 Hz, 2H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.51 (d, J = 17.4 Hz, 2H), 4.38 (d, J = 17.7 Hz, 1H), 3.59 (s, 3H), 3.56-3.50 (m, 1H), 3.06 (s, 5H), 2.98-2.72 (m, 4H), 2.65-2.57 (m, 2H), 2.45-2.37 (m, 2H), 2.28-2.15 (m, 7H) ), 2.01 (dd, J = 15.4, 8.6 Hz, 1H), 1.95-1.60 (m, 4H), 1.12 (s, 2H). Compound 257 LC/MS 698.0 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H), 9.62 (s, 1H), _8.35 (s, 1H), 8.09 (s, 1H), 7.84-7.73 (m, 3H), 7.69 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.15-7.04 (m, 3H), 5.14 (dd, J = 13.2, 5.1 Hz) , 1H), 4.70-4.59 (m, 1H), 4.53 (d, J = 17.6 Hz, 1H), 4.39 (d, J = 17.6 Hz, 1H), 3.61 (s, 3H), 2.98-2.86 (m, 3H), 2.82-2.73 (m, 1H), 2.66-2.56 (m, 2H), 2.43-2.36 (m, 1H), 2.20 (s, 6H), 2.07-1.97 (m, 1H), 1.92-1.82 ( m, 1H), 1.65 (s, 3H). Compound 258 LC/MS: 767.2 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H) _, 9.54 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.54 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.16-7.05 (m, 3H), 7.01 (d, J = 8.3 Hz, 1H), 5.14 (dd, J = 13.2, 5.1 Hz, 1H), 4.51 (d, J = 17.2 Hz, 2H), 4.38 (d, J = 17.5 Hz, 1H), 3.61 (s, 3H), 3.53 (s, 2H), 3.16-2.99 (m, 2H), 2.99-2.79 (m, 3H), 2.74 (s, 2H), 2.70-2.57 (m, 4H), 2.36- 2.31 (m, 2H), 2.20 (s, 6H), 2.07-1.92 (m, 3H), 1.90-1.82 (m, 1H), 1.74-1.66 (m, 1H). Compound 259 LC/MS 832.6 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.01 (s, 1H) _, 9.66 (s, 1H), 8.35 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.63 (s, 2H), 7.50 (t, J = 9.5 Hz, 1H), 7.19-6.96 (m, 5H), 5.14 (dd, J = 13.2, 5.2 Hz, 1H) ), 4.69 (d, J = 25.4 Hz, 2H), 4.52 (d, J = 17.2 Hz, 2H), 4.38 (d, J = 17.5 Hz, 1H), 3.74 (s, 2H), 3.62 (s, 4H) ), 2.90 (dd, J = 30.9, 13.9 Hz, 4H), 2.65 (d, J = 18.6 Hz, 3H), 2.33 (s, 1H), 2.20 (s, 6H), 2.09-1.90 (m, 3H) , 1.55 (s, 2H). Compound 260 LC/MS 875.8 [M + H] ^+
1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), 9.66 (s, 1H), _8.36 (s, 1H), 8.10 (s, 1H), 7.77 (d, J = 20.1 Hz, 2H), 7.65-7.50 (m, 2H), 7.17-7.07 (m, 5H), 7.07-6.93 (m, 2H), 5.04 (dd, J = 12.8, 5.4 Hz, 1H), 4.82-4.55 (m, 3H), 4.41 (d, J = 12.7 Hz, 1H), 4.20-3.97 (m, 3H), 3.75 (s, 2H), 3.63 (d, J = 3.0 Hz, 3H), 3.20 (t, J = 12.4 Hz, 1H), 2.94-2.77 (m, 4H), 2.60 (s, 1H), 2.20 (s, 6H), 2.04-1.91 (m, 2H), 1.78 (s, 2H), 1.55 (d, J = 29.5 Hz, 1H), 1.42 (d, J = 15.3 Hz, 1H). Compound 261 LC/MS 903.8 [M + H] ^+
1H NMR (300 MHz, DMSO- d6 ) δ 11.07 (s, 1H) _, 9.63 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 7.17-7.09 (m, 4H), 7.09-7.01 (m, 2H), 6.93 (d, J = 9.8 Hz, 1H), 5.05 (dd, J = 12.7, 5.3 Hz, 1H), 4.41 (d, J = 13.2 Hz, 1H), 4.15 (s, 2H), 3.99 (s, 2H), 3.61 (d) , J = 1.3 Hz, 3H), 3.17 (d, J = 5.3 Hz, 2H), 2.98-2.68 (m, 6H), 2.61 (s, 1H), 2.20 (s, 6H), 2.09-1.91 (m, 3H), 1.89-1.70 (m, 4H), 1.58 (s, 3H). Compound 262 ^1H NMR (400 MHz, DMSO- d6 ) δ 9.62 (s, 1H) _, 8.74 (d, J = 4.4 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H) , 8.09 (s, 1H), 7.78 (s, 1H), 7.22-7.19 (m, 3H), 7.17-7.09 (m, 2H), 6.87-6.85 (m, 2H), 6.59 (d, J = 8.5 Hz , 1H), 5.46-5.42 (m, 1H), 4.84-4.74 (m, 2H), 4.60-4.57 (m, 1H), 4.15-4.11 (m, 1H), 3.73 (s, 3H), 3.61 (s) , 3H), 3.14-3.02 (m, 2H), 2.83-2.68 (m, 6H), 2.20 (s, 6H), 2.05-1.99 (m, 2H), 1.79-1.70 (m, 4H), 1.45-1.42 (m, 4H).
LC/MS (ESI) m/z [M+H] ⁺ : 796.42 Compound 263 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.08 (s, 1H) _, 9.73 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.92 (d, J = 7.0 Hz, 1H), 7.78-7.74 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.18-7.06 (m, 4H), 6.86-6.84 (m, 1H), 6.72-6.69 (m, 1H) , 6.09-6.06 (m, 1H), 5.09-5.04 (m, 1H), 4.31-4.25 (m, 2H), 4.21-4.14 (m, 3H), 4.10 (s, 1H), 4.04-3.97 (m, 1H), 3.75-3.73 (m, 1H), 3.63 (s, 3H), 3.58-3.55 (m, 1H), 3.13-3.07 (m, 1H), 2.93-2.82 (m, 1H), 2.63-2.53 ( m, 3H), 2.20 (s, 6H), 2.07-1.97 (m, 1H).
LC/MS (ESI) m/z [M+H] ⁺ : 783.57 Compound 264 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H), _9.63 (s, 1H), 8.35 (d, J = 3.0 Hz, 1H), 8.10 (d, J = 2.9 Hz, 1H) , 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.14-7.08 (m, 4H), 6.95-6.93 (m, 1H), 6.87-6.83 (m, 1H), 6.66-6.64 (m, 1H), 5.32-5.27 (m, 1H), 4.74 (s, 1H), 4.61 (s, 1H), 3.79-3.77 (m, 2H), 3.70-3.69 (m, 2H), 3.63 (s) , 3H), 3.32 (s, 3H), 2.94-2.80 (m, 4H), 2.78-2.68 (m, 4H), 2.20 (s, 6H), 2.02-1.96 (m, 1H), 1.77-1.73 (m , 4H).
LC/MS (ESI) m/z [M+H] ⁺ : 768.65 Compound 268 ^1H NMR (400 MHz, DMSO- d6 ) δ 11.07 (s, 1H) _, 9.95 (s, 1H), 8.35 (s, 1H), 8.27 (d, J = 9.8 Hz, 1H), 8.15 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.39-7.27 (m, 2H), 7.24 (dd, J = 8.9, 2.3 Hz, 1H), 7.10 (q, J = 5.2 Hz, 3H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.06 (d, J = 12.9 Hz, 2H), 3.59 (s, 3H), 3.51 (s, 4H), 2.97 (d, J = 12.3 Hz, 2H) ), 2.92-2.80 (m, 1H), 2.54 (s, 6H), 2.19 (s, 8H), 2.06-1.93 (m, 2H), 1.83 (d, J = 13.4 Hz, 2H), 1.18 (d, J = 12.5 Hz, 2H).
LC/MS (ESI) m/z [M+H] ⁺ : 784.59 Compound 272 LC/MS: 785.4 M+H
^1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) _, 9.60 (s, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 11.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.14-7.05 (m, 3H), 5.07 ( dd, J = 13.2, 5.1 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H), 4.24 (d, J = 17.1 Hz, 1H), 3.61 (s, 3H), 3.54-3.45 (m, 2H) ), 3.09-2.84 (m, 3H), 2.80-2.72 (m, 2H), 2.64-2.55 (m, 2H), 2.46-2.32 (m, 2H), 2.27-2.24 (m, 1H), 2.20 (s) , 6H), 2.05-1.91 (m, 3H), 1.88-1.80 (m, 2H), 1.80-1.58 (m, 5H), 1.39-1.27 (m, 2H).

<Experimental Example 1: Measurement of BTK protein degradation>

The synthesized compound is treated with TMD-8, RAMOS, or 293T BTK MUT (C481S) cells, and the amount of BTK protein present in the cells is measured using Western blotting detection. The protocol for the experiment conducted using TMD-8 cells is as follows.

[culture]

TMD-8 cells were resuspended in RPMI1640 MEDIUM (Hyclone, SH30027.01, 10% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02) media at 1×10 ⁶ /mL for 12 days. -Seed 1 mL each into the well plate.

[Compound treatment]

Process the 12-well plate as follows. Serially dilute the 10 mM stock 1/10 with DMSO (3 mL + 27 mL DMSO), treat the cells with the compound at a final concentration of 0.1, 1, 10 mM or 0.0001, 0.001, 0.01, 0.1 mM, and harvest after 24 hours. . In the negative control group, add DMSO diluted 1/10 to the media. (3 mL DMSO + 27 mL media)

[Harvest]

Pipette each well with a 1 mL pipette, collect in a 1.5 mL microtube, centrifuge (500 g, 5 min, 4℃) to remove the supernatant, wash with PBS, centrifuge again (500 g, 5 min, 4℃), and supernatant. Remove and collect pellets.

[Cell lysis and sample preparation]

Lysis buffer is prepared as follows. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1× Protease/Phosphatase Inhibitor (Cell signaling, 5872S) = Add 60-70 mL per well and leave on ice for 30 minutes. After (vortexing at 0 and 30 minutes respectively), sonication (10 seconds pulse, 30 seconds rest, 5 cycles, 70% amplification) is performed, centrifuge (15000g, 15 min, 4℃), and only the supernatant is picked and transferred to a new microtube. Dilute the sample by 1/2 with RIPA buffer in a 96-well plate, mix A:B = 50:1 with the BCA Protein Assay Kit (iNtRON, 21071), add 200 mL each, leave at 37°C for 30 minutes, and cool for 10 minutes. Afterwards, absorbance is measured at 562 nm using BioTek's SYNERGY H1 microplate reader. After making a sample by quantifying the protein using the measured value, it is boiled at 70°C for 10 minutes. The sample buffer used at this time is a mixture of NuPAGE or Bolt 4x sample buffer (Invitrogen) and each 10x sample reducing agent according to the gel to be used, and RIPA buffer is used for protein dilution.

[Western blotting detection method]

Load the same amount of sample into NuPAGE or Bolt Bis-tris 4-12% gradient gel and run (200 V, 35 minutes). Transfer to 0.2 mm NC membrane using Trans-blot Turbo (BIO-RAD). (1.3A constant, 25V limit, 15 minutes) Skim milk or Intercept Blocking Buffer (LI-COR, 927-60001): Block at room temperature for 1 hour with 0.1% TBST = 1:1. Anti BTK Rabbit (1:1,000 in 5% skim milk/0.2% TBST, size: 77 kDa, Cell signaling Technology) was reacted O/N at 4℃ or at room temperature for 2 hours, Anti GAPDH Rabbit (1:10,000) in 5% BSA/0.2% TBST, size: 36 kDa, GENETEX) and Anti β-actin mouse (1:10,000 in 5% BSA/0.2% TBST, RT, size: 43 kDa, GENETEX) at room temperature for 1 hour or React for 3 hours. Wash 3 times with 0.5% TBST for 5 minutes each and add secondary antibodies, Anti-Rabbit IgG (1:5,000 in 5% Skim milk/TBST, CST), IRDye® 800CW Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 5) % skim/TBST, RT 45 min), IRDye® 680RD Goat anti-Mouse IgG Secondary Antibody (1:10,000 in 5% skim/TBST, RT 45 min) is added in each case and reacted for 45 minutes on a rocker at room temperature. . Washed 5 times with 0.5% TBST for 5 minutes each and detected with LI-COR's Odyssey. At this time, BTK is detected using SuperSignal West Pico PLUS Chemiluminescent Substrate or SuperSignal West femto Maximum Sensitivity Substrate, and house-keeping genes are detected as is.

The BTK protein degradation activity of the compounds of the present invention is shown in Table 2 below. Depending on the concentration range of the compound showing 50% degradation of WT BTK protein and C481S BTK protein, +++ (0.0001 ~ 0.01 μM), ++ (0.01 ~ 1 μM), +(1~10 μM), -(>10 μM), and NT (not tested), and MT-802 (BTK degrader) was used as a comparison material for BTK protein degradation activity.

compound number WT BTK Degradation
(DC ₅₀ %) C481S BTK Degradation
(DC ₅₀ %) Compound 1 ++ - compound 2 +++ ++ Compound 3 +++ + Compound 4 ++ + Compound 5 ++ ++ Compound 6 ++ ++ Compound 7 +++ - Compound 8 +++ ++ Compound 9 ++ - Compound 10 ++ - Compound 11 +++ - Compound 12 ++ - Compound 13 +++ + Compound 14 +++ - Compound 15 +++ + Compound 16 +++ + Compound 17 +++ - Compound 18 +++ - Compound 19 ++ - Compound 20 +++ + Compound 21 +++ + Compound 22 +++ - Compound 23 +++ + Compound 24 +++ + Compound 25 +++ + Compound 26 +++ + Compound 27 +++ + Compound 28 +++ +++ Compound 29 +++ ++ Compound 30 +++ ++ Compound 31 +++ ++ Compound 32 ++ + Compound 33 ++ N.T. Compound 34 ++ N.T. Compound 35 +++ ++ Compound 36 +++ N.T. Compound 37 +++ +++ Compound 39 +++ N.T. Compound 40 +++ N.T. Compound 41 ++ N.T. Compound 42 +++ N.T. Compound 43 +++ N.T. Compound 44 +++ N.T. Compound 45 +++ N.T. Compound 46 ++ ++ Compound 47 +++ N.T. Compound 48 +++ N.T. Compound 49 ++ N.T. Compound 50 ++ N.T. Compound 51 +++ N.T. Compound 52 +++ N.T. Compound 53 +++ ++ Compound 54 +++ ++ Compound 55 +++ ++ Compound 56 ++ ++ Compound 57 +++ ++ Compound 58 +++ ++ Compound 59 +++ + Compound 60 +++ ++ Compound 61 +++ +++ Compound 62 +++ ++ Compound 63 +++ ++ Compound 64 +++ N.T. Compound 66 ++ N.T. Compound 67 ++ N.T. Compound 68 ++ N.T. Compound 69 ++ N.T. Compound 72 ++ N.T. Compound 73 ++ N.T. Compound 74 ++ N.T. Compound 75 ++ N.T. Compound 76 ++ N.T. Compound 80 +++ N.T. Compound 81 +++ N.T. Compound 82 +++ N.T. Compound 83 ++ N.T. Compound 84 +++ N.T. Compound 85 +++ +++ Compound 86 +++ N.T. Compound 88 +++ +++ Compound 90 ++ N.T. Compound 91 +++ N.T. Compound 92 +++ N.T. Compound 93 ++ N.T. Compound 94 ++ N.T. Compound 95 ++ N.T. Compound 96 +++ N.T. Compound 97 +++ N.T. Compound 98 +++ N.T. Compound 100 +++ N.T. compound 101 ++ N.T. Compound 102 ++ N.T. Compound 103 ++ N.T. Compound 104 +++ N.T. Compound 105 +++ N.T. Compound 106 ++ N.T. Compound 107 +++ N.T. Compound 108 +++ N.T. Compound 109 ++ N.T. Compound 110 +++ N.T. Compound 111 ++ N.T. Compound 112 + N.T. Compound 116 + N.T. Compound 117 + N.T. Compound 118 + N.T. Compound 121 ++ N.T. Compound 122 ++ N.T. Compound 123 ++ N.T. Compound 124 +++ N.T. Compound 125 +++ N.T. Compound 126 +++ N.T. Compound 127 +++ N.T. Compound 128 +++ N.T. Compound 129 +++ N.T. Compound 130 +++ N.T. Compound 131 +++ N.T. Compound 132 +++ N.T. Compound 133 +++ N.T. Compound 134 +++ N.T. Compound 135 +++ N.T. Compound 136 +++ N.T. Compound 137 +++ N.T. Compound 138 +++ N.T. Compound 139 +++ N.T. Compound 140 +++ N.T. Compound 141 +++ N.T. Compound 142 +++ N.T. Compound 143 +++ N.T. Compound 144 +++ +++ Compound 145 +++ N.T. Compound 146 +++ N.T. Compound 147 +++ N.T. Compound 148 +++ N.T. Compound 149 +++ +++ Compound 150 +++ N.T. Compound 151 +++ N.T. Compound 152 +++ N.T. Compound 153 +++ N.T. Compound 154 +++ N.T. Compound 155 +++ N.T. Compound 156 +++ N.T. Compound 157 +++ N.T. Compound 158 +++ N.T. Compound 159 +++ N.T. Compound 160 +++ N.T. Compound 161 +++ N.T. Compound 162 ++ N.T. Compound 163 +++ N.T. Compound 164 +++ N.T. Compound 165 +++ N.T. Compound 166 +++ N.T. Compound 167 +++ N.T. Compound 168 +++ N.T. Compound 169 +++ N.T. Compound 170 +++ N.T. Compound 171 +++ N.T. Compound 172 +++ N.T. Compound 173 +++ N.T. Compound 174 +++ N.T. Compound 175 +++ N.T. Compound 176 +++ N.T. Compound 177 +++ N.T. Compound 178 +++ N.T. Compound 179 +++ N.T. Compound 180 +++ N.T. Compound 181 +++ N.T. Compound 182 +++ N.T. Compound 183 +++ N.T. Compound 184 +++ N.T. Compound 185 +++ N.T. Compound 186 +++ N.T. Compound 187 +++ N.T. Compound 188 +++ N.T. Compound 192 ++ N.T. Compound 193 +++ N.T. Compound 194 ++ N.T. Compound 195 +++ N.T. Compound 199 ++ N.T. compound 201 +++ N.T. Compound 204 +++ N.T. Compound 205 ++ N.T. Compound 208 +++ N.T. Compound 209 +++ N.T. Compound 210 +++ N.T. Compound 211 +++ N.T. Compound 217 +++ N.T. Compound 218 +++ N.T. Compound 219 +++ N.T. Compound 220 +++ N.T. Compound 221 +++ N.T. Compound 222 +++ N.T. Compound 225 +++ N.T. Compound 226 +++ N.T. Compound 227 +++ N.T. Compound 228 +++ N.T. Compound 229 ++ N.T. Compound 230 +++ N.T. Compound 231 ++ N.T. Compound 232 +++ N.T. Compound 233 +++ N.T. Compound 234 +++ N.T. Compound 235 +++ N.T. Compound 236 +++ N.T. Compound 237 +++ N.T. Compound 238 +++ N.T. Compound 239 ++ N.T. Compound 240 +++ N.T. Compound 241 +++ N.T. Compound 243 +++ N.T. Compound 244 +++ N.T. Compound 245 +++ N.T. Compound 246 +++ N.T. Compound 247 +++ N.T. Compound 248 +++ N.T. Compound 250 +++ N.T. Compound 253 +++ N.T. Compound 254 ++ N.T. Compound 255 +++ N.T. Compound 256 +++ N.T. Compound 257 +++ N.T. Compound 258 +++ N.T. Compound 259 ++ N.T. Compound 260 +++ N.T. Compound 261 +++ N.T. Compound 262 +++ N.T. Compound 263 +++ N.T. Compound 264 +++ N.T. Compound 268 +++ N.T. Compound 272 +++ N.T. MT-802 (comparative compound) ++ +

As shown in Table 1, it can be seen that the compound according to the present invention has an excellent decomposition effect on Bruton's tyrosine kinase (BTK).

Therefore, the novel heterocyclic compound according to the present invention has an excellent decomposition effect on Bruton's tyrosine kinase (BTK), so it can be used to prevent cancer, autoimmune disease, and Parkinson's disease containing it as an active ingredient. Alternatively, it can be seen that it can be usefully used as a pharmaceutical composition for treatment.

<Formulation example 1. Preparation of powder>

A powder was prepared by mixing 2 g of Compound 28 of the present invention and 1 g of lactose and filling it in an airtight envelope.

<Formulation Example 2. Preparation of tablets>

Tablets were prepared by mixing 100 mg of Compound 28 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate and tableting according to a conventional tablet manufacturing method. .

<Formulation example 3. Preparation of capsule>

Mix 100 mg of Compound 28 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, then mix the above ingredients according to a typical capsule manufacturing method. Capsules were prepared by filling gelatin capsules.

<Formulation example 4. Preparation of pills>

After mixing 90 mg of Compound 28 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives that inhibit hygroscopicity, 100 mg of pills are administered according to a conventional method. made.

<Formulation Example 5. Preparation of injection>

After mixing 10 mg of Compound 28 of the present invention, an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjuster, the mixture was prepared with the above ingredients per 1 ampoule (2 mL) according to a conventional preparation method for injections.

Claims (16)

A bifunctional compound having the following formula (1), a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof;
[Formula 1]

In the above formula,
W is -NH-;
R ₁ is substituted or unsubstituted phenyl, substituted or unsubstituted indanyl, or substituted or unsubstituted heteroaryl,
The substituted phenyl, indanyl or heteroaryl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy , C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, or substituted or unsubstituted -NHC(O)phenyl,
In the substituted -NHC(O)phenyl, one or more hydrogens in phenyl are independently substituted with C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, or halogen;
R ₂ is -H, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl;
A is substituted or unsubstituted phenyl, substituted or unsubstituted heteroaryl, or formula 8,
In the substituted phenyl or heteroaryl, one or more hydrogens in the ring are independently substituted with C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy or halogen. ,
Formula 8 is as follows,
[Formula 8]

In the above formula 8,
R ^A is each independently -H, halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy,
p is each independently an integer selected from 0 to 2;
In addition, L is of the following formula 2,
[Formula 2]

In the above formula,
D is each independently a direct bond, -C(O)-, -O-, -NH-, -CH(OH)-, -C(O)NH-, -NHC(O)-, -NHC(O) CH ₂ O-, -NHC(O)CH ₂ NH-, -C(O)CH ₂ NH-, -C(=S)-, or -C(CN)=CH-;
E is each independently a direct bond, substituted or unsubstituted 3- to 12-membered carbocyclyl, substituted or unsubstituted heterocycle, substituted or unsubstituted 6- to 12-membered aryl, or substituted or unsubstituted It is heteroaryl,
The substituted carbocyclyl, heterocycle, aryl, or heteroaryl is one or more hydrogens in the ring independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C is substituted with ₁ -C ₆ alkoxy, -CN, -OH, or -NH ₂ ;
m is each independently an integer selected from 0 to 12;
In addition, B is selected from the following formulas 3, 4, 6, and 7,
[Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

In the above formula,
Z is -C(R ^A ) ₂ -, -C(O)-, -C(R ^A ) ₂ -C(R ^A ) ₂ -, -C(R ^A )=C(R ^A )-, -C (R ^A )=N-, -N=C(R ^A )-, or -N=N-;
Y is a direct bond, -C(R ^A ) ₂ -, -N(R ^A )-, -C(O)NH-, -SO ₂ NH-, or -O-;
X is each independently CH or N;
R ^A is each independently -H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy;
R is each independently -H, halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, -CN, -OH, or -NH ₂ and; and
q is an integer selected from 0 to 3; According to paragraph 1,
In Formula 1,
W, R ₁ , R ₂ and A are bifunctional compounds of Formula 1, a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein W, R 1 , R 2 and A are defined as follows;
In the above formula,
W is -NH-;
R ₁ is substituted or unsubstituted phenyl or substituted or unsubstituted indanyl,
As for the substituted phenyl or indanyl, one or more hydrogens in the ring are independently C ₁ -C ₆ alkyl, halogen, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ - C ₆ alkoxy, or substituted or unsubstituted -NHC(O)phenyl,
In the substituted -NHC(O)phenyl, one or more hydrogens in the phenyl are independently substituted with halo C ₁ -C ₆ alkyl;
R ₂ is H or C ₁ -C ₆ alkyl;
A is the formula 8 or 9 below,
[Formula 8]

[Formula 9]

In the above formula,
X is each independently CH or N;
R ^A is each independently -H, halogen, or C ₁ -C ₆ alkyl; and
p is an integer each independently selected from 0 to 2. According to paragraph 1,
In Formula 1,
L is a bifunctional compound of Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein L is defined as follows with respect to Formula 2;
In the above formula,
D is each independently a direct bond, -C(O)-, -O-, -NH-, -CH(OH)-, -C(O)NH-, -NHC(O)-, -NHC(O) CH ₂ O-, -NHC(O)CH ₂ NH-, -C(O)CH ₂ NH-, -C(=S)-, or -C(CN)=CH-;
m is each independently an integer selected from 0 to 12;
E is each independently a direct bond, phenyl, cyclopropyl, cyclohexyl, triazolyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, 1,2,3,6-tetrahydropyridinyl, selected from Formula 10 or 11 below,
In the substituted piperazinyl or piperidinyl or azetidinyl, one or more hydrogens in the ring may be independently substituted with a substituent selected from the group consisting of hydroxy, halogen, or C ₁ -C ₆ alkyl,
[Formula 10]

[Formula 11]

In the above formula,
p is each independently an integer selected from 0 to 2; and
r is an integer each independently selected from 1 to 2. According to paragraph 1,
In Formula 1,
B is a bifunctional compound selected from the following Formula 3, Formula 4, Formula 6, or Formula 7: Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof;
[Formula 3]

[Formula 4]

[Formula 6]

[Formula 7]

In the above formula,
X is each independently CH or N;
Y is a direct bond, -C(R ^A ) ₂ -, -N(R ^A )-, -C(O)NH-, or -SO ₂ NH-;
Z is -C(R ^A ) ₂ -, -C(O)-, or -N=N-;
R ^A is each independently -H, halogen, or C ₁ -C ₆ alkyl;
Each R is independently -H, halogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ alkoxy; and
q is an integer selected from 0 to 3; delete A compound characterized in that it is any one selected from the following compound group, or a pharmaceutically acceptable salt thereof;
4-((6-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-6-oxohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 1),
5-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 2),
4-((2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 3),
N-(2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 4),
N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-1-(2-(2,6-dioxopiperidine-3 -yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxamide (Compound 5),
N-(4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino )Ethoxy)ethoxy)ethoxy)ethoxy)phenyl)-4-(7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl)amino)-1- Methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1,1-dimethyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutane Amide (Compound 6),
4-((12-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-12-oxododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (compound 7),
5-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 8),
N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (Compound 9),
N-(14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (Compound 10),
tert- Butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-2-oxo-6,9,12, 15-Tetraoxa-3-azaheptadecane-17-oate (Compound 11),
N-(2-(2-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl )-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide (Compound 12),
4-((14-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d])pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)-14-oxo-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (compound 13),
tert- Butyl 2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)ethoxy)ethoxy ) Acetate (Compound 14),
5-((15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)amino)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 15),
N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetamide (Compound 16),
N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (Compound 17),
N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-(4-(2-(2,6-dioxopy) Peridin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 18),
N-(2-(2-(2-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy )Ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)acetamide (Compound 19),
N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (Compound 20),
N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-5-yl)piperidine-4-carboxamide (Compound 21),
N-(15-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinoline-2(1H)-yl)-15-oxo-3,6,9,12-tetraoxapentadecyl)-2-((2-(2,6-dioxopiperidine- 3-yl)-1,3-dioxoisoindolin-5-yl)amino)acetamide (Compound 22),
2-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)acetamide (Compound 23),
N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-4-yl)piperidine-4-carboxamide (Compound 24),
N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl)oxy)acetamide (Compound 25),
5-(4-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 26),
N-(2-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethoxy)ethyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoi Soindolin-5-yl)azetidine-3-carboxamide (Compound 27),
5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl) Isoindoline-1,3-dione (Compound 28),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dione (Compound 29),
5-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 30),
5-(4-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2 ,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 31),
5-(4-(2-((R)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 32),
5-(4-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2 -(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 33),
5-(2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperi Din-3-yl)isoindoline-1,3-dione (Compound 34),
5-((2-((S)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 35),
5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 36),
3-(6-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 37),
1-(5-(4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H )-dione (compound 38),
5-(4-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 39),
5-(4-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 40),
5-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) Benzyl) amino) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 41),
5-(4-(4-(((3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)benzyl)amino)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 42),
5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione (Compound 43),
5-(4-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidin-1-yl) -2-oxoethyl) piperazin-1-yl) -2- (2, 6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 44),
5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 45),
3-(6-((4-((7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)-4-oxobenzo[d][1,2,3]triazine -3(4H)-yl)piperidine-2,6-dione (Compound 46),
5-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- dione (compound 47),
3-(6-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][1, 2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 48),
5-(2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3- 1) Isoindoline-1,3-dione (Compound 49),
5-(3-((4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperi Din-3-yl)isoindoline-1,3-dione (Compound 50),
5-((2-(3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)azetidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 51),
3-(6-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 52),
3-(7-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H )-yl)piperidine-2,6-dione (Compound 53),
5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 54),
3-(6-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethoxy)-4-oxobenzo[d][1,2 ,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 55),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 56),
3-(6-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d])pyrimidine- 6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 57),
3-(6-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H) -I)piperidine-2,6-dione (Compound 58),
3-(5-(4-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H )-yl)piperidine-2,6-dione (Compound 59),
3-(7-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- I) amino) -1,2,3,4-tetrahydroisoquinoline-2-carbonyl) piperidine-1-carbonyl) piperidin-1-yl) -4-oxobenzo [d] [1 ,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 60),
3-(7-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 61),
3-(5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 62),
3-(7-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][ 1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 63),
3-(4-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)p Peridine-2,6-dione (Compound 64),
3-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 65),
5-(3-(7-((3-((2,6-dimethylphenyl))amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 66),
5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrrolidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) isoindoline-1,3-dione (compound 67),
3-(7-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-2-oxoethyl)amino)-4-oxobenzo[d][1 ,2,3]triazine-3(4H)-yl)piperidine-2,6-dione (Compound 68),
3-(7-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H) -1) Piperidine-2,6-dione (Compound 69),
5-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 70),
3-(7-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-4-oxobenzo[d][1,2,3]triazine-3(4H)-yl)piperidine-2,6-dione ( Compound 71),
5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 72),
5-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)iso indolin-2-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 73),
3-(7-(4-((5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)isoindolin-2-yl)methyl)piperidin-1-yl)-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)piperidin-2 ,6-dione (Compound 74),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 75),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-(2-methoxyethoxy)-2,6-dimethylphenyl) amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine- 1-yl) Isoindoline-1,3-dione (Compound 76),
5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-2'-(2,6 -dioxopiperidin-3-yl)-[2,5'-biisoindoline]-1',3'-dione (Compound 77),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1-isopropyl-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 78),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 79),
3-(5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-1-oxoisoindoline-2- 1) Piperidine-2,6-dione (Compound 80),
3-(5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 81 ),
5-(4-((7-((3-((2,6-dichlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 82),
5-(4-((7-((3-((2,4-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 83),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((1-methyl-3-(o-tolylamino)-1H-pyrazolo[3,4- d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (Compound 84 ),
5-(4-((7-((3-((2-chloro-6-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 85),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 86),
5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 87),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Compound 88),
5-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione ( Compound 89),
2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1,3 -dioxoisoindolin-5-yl)acetamide (Compound 90),
2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoi Soindolin-5-yl)acetamide (Compound 91),
4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4 -dihydroisoquinolin-2(1H)-yl)methyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine- 1-Carboxamide (Compound 92),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 93),
2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)acetamide (Compound 94),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 95),
7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(2-(2 ,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 96),
2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- dihydroisoquinolin-2(1H)-yl)-N-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)p Peridin-4-yl)acetamide (Compound 97),
3-(5-(((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 98),
7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-((2-( 2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 99),
N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxamide (Compound 100),
N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine-4- Carboxamide (Compound 101),
N4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-N1 -(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-1,4-dicarboxamide (Compound 102),
3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 103),
3-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione (Compound 104),
3-(5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 105),
3-(5-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (Compound 106),
(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl pivalate (Compound 107),
2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4- Dihydroisoquinolin-2(1H)-yl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetamide (Compound 108),
5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -Dione (Compound 109),
5-((2-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 110),
1-(5-(4-(2-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2, 4(1H,3H)-dione (Compound 111),
1-(5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2, 4(1H,3H)-dione (Compound 112),
N-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzamide (Compound 113),
N-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenethyl)-1 -(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)amino)-2-oxoethyl)piperidine-4- Carboxamide (Compound 114),
3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)piperazin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 115 ),
3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (compound 116),
3-(6-((1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-4-yl)oxy)-1-oxoisoindolin-2-yl)p Peridine-2,6-dione (Compound 117),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-methoxy-2-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 118),
5-(4-((7-((3-((2,3-dihydro-1H-inden-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl ) Isoindoline-1,3-dione (Compound 119),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((2-fluoro-4-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 120),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2-methylphenyl)amino)-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoindoline-1 ,3-dione (compound 121),
N-(4-((6-((2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperi din-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl )Amino)-3-methylphenyl)-3-(trifluoromethyl)benzamide (Compound 122),
5-((2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-Dihydroisoquinolin-2(1H)-yl)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 123) ,
5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-7-azaspiro[3.5]nonan-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Dolin-1,3-dione (Compound 124),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione (compound 125),
5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-3-oxopropyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso indoline-1,3-dione (compound 126),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-oxoethoxy)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 127),
5-(4-(((1r,4r)-4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyr midin-6-yl)amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclohexyl)oxy)piperidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 128),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 129),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoine Doline-1,3-dione (Compound 130),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)ethyl)-4-hydroxypiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 131),
3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4- b]pyridin-6-yl)piperidine-2,6-dione (Compound 132),
3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo [3,4-b]pyridin-6-yl)piperidine-2,6-dione (Compound 133),
5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 134),
5-(4-((1-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 135),
5-(4-((4-(3-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 136 ),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-Dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-N-(2,6-dioxopiperidin-3-yl)picolinamide (Compound 137) ,
5-(3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 138),
5-(4-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 139),
5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 140),
5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 141),
5-((R)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 142),
5-((S)-3-((4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioc Sopiperidin-3-yl)isoindoline-1,3-dione (Compound 143),
5-((R)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 144),
5-((S)-3-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 145),
5-(4-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 146),
5-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 147),
5-((1R,5S,6S)-6-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine -6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 148),
5-(4-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3 -1) Isoindoline-1,3-dione (Compound 149),
5-((R)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 150),
5-((S)-3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopy) Peridin-3-yl)isoindoline-1,3-dione (Compound 151),
5-(3-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3- 1) Isoindoline-1,3-dione (Compound 152),
5-((1R,5S,6S)-6-((3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d ]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)azetidin-1-yl)methyl)-3-azabicyclo[3.1.0]hexane-3- 1)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 153),
5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 154),
5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 155),
5-(4-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Pyridin-2-yl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 156),
5-(4-(2-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) pyridin-2-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (Compound 157),
5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 158 ),
5-(3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperazin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 159),
5-((R)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 160),
5-((S)-3-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 161),
5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-3-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 162),
5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 163 ),
5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridin-2-yl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 164),
5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (compound 165),
5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 166),
5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)piperidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 167),
5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) -[1,4'-bipiperidin]-1'-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 168),
5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 169 ),
3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine- 6-yl)piperidine-2,6-dione (Compound 170),
5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyrimidin-2-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 171),
5-(4-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 172),
5-((R)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 173),
5-((S)-3-((6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 174),
5-(4-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) azetidin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 175 ),
5-((R)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 176),
5-((S)-3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)azetidin-1-yl)methyl)pyrrolidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 177),
5-(4-(3-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinoline-2(1H)-yl)-2-hydroxypropyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Compound 178),
5-((R)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl) amino) phenyl) piperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- Dione (Compound 179),
5-((S)-3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl) amino) phenyl) piperazin-1-yl) methyl) pyrrolidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3- dione (compound 180),
5-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperazin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 181) ,
5-(3-((3-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) azetidin-1-yl) methyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 182) ,
5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 183),
5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-3-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 184),
5-(3-(((S)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 185),
5-(3-(((R)-4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine- 6-yl)amino)phenyl)-2-methylpiperazin-1-yl)methyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 186),
3-(2-(3-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)azetidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6- 1) Piperidine-2,6-dione (Compound 187),
3-(2-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6 -yl)piperidine-2,6-dione (Compound 188),
2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinoline-2(1H)-yl)methyl)piperidin-1-yl)-N-(3-(N-(2,6-dioxopiperidin-3-yl)sulfa Moyl)-4-methylphenyl)acetamide (Compound 189),
7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(3-(N -(2,6-dioxopiperidin-3-yl)sulfamoyl)-4-methylphenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (Compound 190),
3-(3-((3-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl)phenyl)amino)-2,5-dioxo-2,5-dihydro-1H-pyrrole -1-yl)piperidine-2,6-dione (Compound 192),
3-(3-((3-(2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d] pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)phenyl)amino)-2,5 -dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-2,6-dione (Compound 193),
5-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 ,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (compound 194),
5-(4-((7-((3-((2-bromo-6-methylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 195),
5-(4-(((1-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclopropyl)amino)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidine- 3-yl) Isoindoline-1,3-dione (Compound 199),
3-(3-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrole-1- 1) Piperidine-2,6-dione (Compound 201),
N-(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclopropyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperidine-4-carboxamide (Compound 204),
N-(1-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)cyclopropyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoine Dolin-5-yl)oxy)acetamide (Compound 205),
(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl piperidine-4-carboxylate bistrifluoroacetic acid (Compound 206),
(3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1,3-dioxoisoindolin-2-yl)-2,6-diox Sopiperidin-1-yl)methyl 4-methylpentanoate (Compound 207),
5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione (compound 208),
3-(5-(1-(2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)piperidin-4-yl)-1-oxoisoindolin-2-yl)piperidin-2,6- Dione (Compound 209),
5-(4-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione (Compound 210),
5-((2-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl )amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl)-6-fluoroisoindoline-1,3-dione (Compound 211),
5-(4-((7-((3-((2,6-dibromophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1 ,3-dione (compound 217),
5-(4-((7-((3-((2-bromo-6-chlorophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 218),
5-(4-((7-((3-((2-chloro-6-iodophenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline- 1,3-dione (Compound 219),
3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2 ,6-dione (compound 220),
2-(2,6-dioxopiperidin-3-yl)-5-(4-((7-((3-((4-fluoro-2,6-dimethylphenyl)amino)-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)isoine Dolin-1,3-dione (Compound 221),
5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidin-1-yl) -2-oxoethyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1 ,3-dione (compound 222),
5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidin-1-yl) -2-oxoethyl) piperazin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1, 3-dione (compound 225),
5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Compound 226),
5-(4-(2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- 1) Amino)-2-fluorophenyl)piperidin-1-yl)-2-oxoethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 227),
5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino ) Phenyl) piperidin-1-carbonyl) azetidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (Compound 228),
5-(3-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-2-fluorophenyl)piperidine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 229),
5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (compound 230),
5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3-fluorophenyl)piperidin-1-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1, 3-dione (compound 231),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3 -dione (compound 232),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline -1,3-dione (compound 233),
5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidine-1-carbonyl)piperidin-1-yl)-2-(2,6-dioxopiperidine -3-yl) Isoindoline-1,3-dione (Compound 234),
5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethyl)amino)-2-(2,6-dioxopiperidine -3-yl) isoindoline-1,3-dione (compound 235),
5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonothioyl)piperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxopiperidine-3 -1) Isoindoline-1,3-dione (Compound 236),
3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( Compound 237),
5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 238),
5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)phenyl) Piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline-1,3-dione (Compound 239),
(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindolin-5-yl) piperidine-4-carbonyl) piperidin-4-yl) acrylonitrile (Compound 240),
(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3- Dioxoisoindolin-5-yl)oxy)acetyl)piperidin-4-yl)acrylonitrile (Compound 241),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline -1,3-dione (Compound 243),
5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-1 ,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6- Fluoroisoindoline-1,3-dione (Compound 244),
3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione ( Compound 245),
5-(4-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carbonyl)piperidin-1-yl)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 246),
5-((2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethyl)amino)-2-(2,6- Dioxopiperidin-3-yl)isoindoline-1,3-dione (Compound 247),
5-(2-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidin-1-yl)-2-oxoethoxy)-2-(2,6-dioxophyll) Peridin-3-yl)isoindoline-1,3-dione (Compound 248),
5-(4-((4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-2-fluorophenyl)-3,6-dihydropyridin-1(2H)-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3- 1) Isoindoline-1,3-dione (Compound 250),
5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )phenyl)piperidin-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3- Dione (Compound 253),
5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )phenyl)piperidin-1-carbonyl)-4-fluoropiperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)-6-fluoroisoindoline- 1,3-dione (Compound 254),
3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-fluoropiperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2 ,6-dione (compound 255),
3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperazin-1-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 256),
3-(5-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )Phenyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 257),
3-(5-(4-((7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)piperidine-1-carbonyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 258),
(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-Tetrahydroisoquinoline-2-carbonyl)-3-(1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- Carbonyl)piperidin-4-yl)acrylonitrile (Compound 259),
(E)-2-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoine Dolin-5-yl)glycyl)piperidin-4-yl)acrylonitrile (Compound 260),
(E)-2-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) phenyl) piperidine-1-carbonyl)-3-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl ) Glycyl) piperidin-4-yl) acrylonitrile (Compound 261),
3-(5-(4-(4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6- yl) amino) phenyl) piperidine-1-carbonyl) piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1- 1) Piperidine-2,6-dione (Compound 262),
5-(3-(4-(5-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-2-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-carbonyl)azetidin-1-yl)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Compound 263),
3-(5-(4-(7-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino )-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d] Imidazol-1-yl)piperidine-2,6-dione (Compound 264),
5-(4-((4-(6-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl) Amino) pyridazin-3-yl) piperazin-1-yl) methyl) piperidin-1-yl) -2- (2,6-dioxopiperidin-3-yl) isoindoline-1,3 -dione (compound 268), and
3-(5-(4-((4-(4-((3-((2,6-dimethylphenyl)amino)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine-6 -yl)amino)phenyl)piperidin-1-yl)methyl)piperidin-1-yl)-6-fluoro-1-oxoisoindolin-2-yl)piperidin-2,6-dione (Compound 272). Cancer comprising a therapeutically effective amount of the bifunctional compound of any one of claims 1 to 4 and 6, a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition for the prevention or treatment of. In clause 7,
The compound is a pharmaceutical composition characterized in that it prevents or treats cancer by decomposing Bruton's tyrosine kinase (BTK). In clause 7,
A pharmaceutical composition, wherein the cancer is solid cancer or hematological cancer. According to clause 9,
The solid cancers include brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial tumor, ependymoma, brain stem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cavity cancer, nasopharyngeal cancer, salivary gland cancer, Hypopharyngeal cancer, thyroid cancer, oral cancer, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colon cancer. , anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, or skin cancer. Characterized pharmaceutical composition. According to clause 9,
A pharmaceutical composition, wherein the blood cancer is leukemia, malignant lymphoma, multiple myeloma, or aplastic anemia. A self-containing agent comprising a therapeutically effective amount of the bifunctional compound of any one of claims 1 to 4 and 6, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition for preventing or treating immune diseases. According to clause 12,
The compound is a pharmaceutical composition characterized in that it prevents or treats autoimmune diseases by decomposing Bruton's tyrosine kinase (BTK). According to clause 12,
The above autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, multiple sclerosis, Guillain-Barré syndrome, and acute disseminated disease. Encephalomyelitis, Addison's disease, myoclonus-myoclonus syndrome, ankylosing myelitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, chronic digestive disorder, Goodpasture syndrome, idiopathic thrombocytopenia purpura, optic neuritis, scleroderma, Primary biliary cirrhosis, Takayasu's arteritis, temporal arteritis, autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromuscular dystonia, scleroderma and vulva. A pharmaceutical composition selected from the group consisting of pain. Parkinson's disease comprising a therapeutically effective amount of the bifunctional compound of any one of claims 1 to 4 and 6, a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Pharmaceutical composition for the prevention or treatment of. According to clause 15,
The compound is a pharmaceutical composition characterized in that it prevents or treats Parkinson's disease by decomposing Bruton's tyrosine kinase (BTK).