EP300 / CBP regulator, and preparation method therefor and use thereof

Abstract

The present disclosure relates to an EP300 / CBP regulator as represented by formula (III), and a preparation method therefor and the use thereof. The structure of formula (III) is as follows.

Description

An EP300 / CBP regulator and its preparation method and use

[0001] This application requires the applicant to:

[0002] Priority benefit of the prior application PCT / CN2023 / 134158, filed with the State Intellectual Property Office of China on November 24, 2023, entitled “An EP300 / CBP Regulator and Uses Thereof”;

[0003] Priority benefit of the prior application PCT / CN2024 / 078870, filed with the State Intellectual Property Office of China on February 28, 2024, entitled “A Bridged EP300 / CBP Degrader, Preparation Method, and Use Thereof”;

[0004] The entirety of the prior application is incorporated into the present disclosure by reference. Technical Field

[0005] The present disclosure belongs to the field of medicine, and specifically relates to an EP300 / CBP regulator and its preparation method and use. Background Art

[0006] Histone acetyltransferases (HATs) and histone deacetylases (HDACs) influence histone acetylation. The recruitment and proper function of HATs and HDACs are key regulatory steps in gene expression and the cell cycle. Functional defects in these enzymes may lead to a variety of diseases, including cancer. The E1A-binding protein EP300 (EP300) and its closely related analog, the cAMP response element binding protein (CBP) binding protein, are ubiquitously expressed lysine acetyltransferases that transfer an acetyl group from acetyl-CoA to ε-N-acetylysine, thereby acetylating conserved lysine residues in histones.

[0007] EP300 / CBP is highly expressed and activated in a variety of tumors. EP300 / CBP is closely associated with a variety of neoplastic diseases and represents a promising target for cancer therapy. Accumulating evidence indicates that most oncogenic transcription factors, such as MYC, NF-κB, β-catenin, E2F1, and nuclear receptors, use EP300 and CBP as coactivators. Therefore, depletion of EP300 and / or CBP may affect tumor growth by impairing the function of these oncogenic transcription factors. Furthermore, EP300 has been reported to regulate immune cell function and is an important transcriptional coactivator of STAT and NF-κB family transcription factors. Consequently, modulators of EP300 / CBP are attracting increasing attention.

[0008] The bromodomain of EP300 / CBP is a domain of approximately 110 amino acids that can recognize acetylated lysine residues. Bromodomains are "readers" of lysine acetylation, responsible for transducing the signals carried by acetylated lysine residues and translating the signals into normal or abnormal phenotypes. The bromodomain of EP300 / CBP has a wide range of functions, ranging from histone acetyltransferase activity and chromatin remodeling to mediating transcriptional co-activation function. Currently, there is a lot of evidence that bromodomains play an important role in the malignant progression of tumors. Regulators targeting the characteristic bromodomain of EP300 / CBP have important development value and clinical significance in a variety of tumors. Summary of the Invention

[0009] To solve the problems existing in the prior art, in a first aspect, the present disclosure provides a compound represented by formula (III) and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt:

[0010] in,

[0011] represents an aromatic aryl group or heteroaryl group, or represents a non-aromatic heterocyclic group;

[0012] Ring A is selected from phenyl or 5-6 membered heteroaryl;

[0013] X is selected from NR1, or CH;

[0014] Y is selected from N or CH;

[0015] when When it is a single bond, U is selected from Z1; Z1 is selected from N or CH; and one of Y and Z1 is N;

[0016] when When it is a double bond, U is C;

[0017] Each R1 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more R1a: C 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R, C 6-14 Aryl, 5-14 membered heteroaryl; wherein R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C3-12 Cycloalkyl;

[0018] Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0019] Each R2 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1- 12 alkoxy;

[0020] Ra is selected from the group consisting of -link-E or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with 1, 2 or more Ra1: C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 1-12 alkyl;

[0021] Each Ra1 is the same or different and is independently selected from H, oxo (=O), halogen, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, C 2-12 Alkenyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 2-12 Alkenyl C(=O)-, C 2-12 Alkynyl C(=O)-, C 1- 12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C (= O) -, 5-14 membered heteroaryl C (= O) -, 3-14 membered heterocyclyl C (= O) -, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 2-12 Alkenyl S(=O)-, C 1-12Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 2- 12 Alkenyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 2-12 Alkenyl-C(=O)-NH-, C 2-12 Alkynyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH-, C 2-12 Alkenyl-S(=O)2-NH-;

[0022] Each Ra2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0023] R6 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R6a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl;

[0024] Each R6a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0025] R7 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R7a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl;

[0026] Each R7a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0027] Alternatively, R6 and R7 together with the atoms to which they are attached form the following group which is unsubstituted or optionally substituted with 1, 2 or more Rsa, Rc, Rd or Re: 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group; the 5-14 membered heteroaryl, 3-14 membered heterocyclic group contains at least one nitrogen atom;

[0028] Each Rsa is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more Rsb: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1- 12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0029] Each Rsb is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0030] Rb, Rc, Rd, Re, and Rz are the same or different and are independently selected from the following groups: C 6-14Aryl, 5-14 membered heteroaryl; or, two adjacent groups in Rb, Rc, Rd, Re, and Rz and the atoms to which they are attached form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rb2: C 6-14 Aryl, 5-14 membered heteroaryl;

[0031] Each Rb1 and Rb2 are the same or different and are independently selected from H, halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Rb3: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl; each Rb3 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0032] Alternatively, Rb and Rz together with the atoms to which they are attached form

[0033] Z2 is selected from CR3 or N;

[0034] R3 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl;

[0035] Each R3a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more R3b: C 1-12 Alkyl, C 1-12 Alkoxy, C1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1- 12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0036] Each R3b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0037] R4 is selected from -link-E group or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4a groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1- 12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl;

[0038] Each R4a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more R4b: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1- 12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0039] Each R4b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0040] At least one of Ra and R4 is a -link-E group, the -link-E group in Ra is -link1-E1, and the -link-E group in R4 is -link2-E2;

[0041] link1 and link2 are the same or different and are independently selected from -Cy1-L1-Cy2-L2-Q-;

[0042] Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, 5-14 membered heteroarylene;

[0043] Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene;

[0044] L1 is absent or selected from N(R L ), unsubstituted or optionally substituted by one, two or more R L1 Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkyleneoxy; R L Selected from H or C 1-12 alkyl;

[0045] L2 is absent or selected from unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C 1-12 Alkylene, (C 1-12 alkyleneoxy) t ; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0046] Q is absent or selected from O, N(R q ), ethynylene; R q Selected from H or C 1-12 alkyl;

[0047] R Cy1 、R Cy2 the same or different, independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 alkoxy;

[0048] R L1 、R L2the same or different, independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 alkoxy;

[0049] Cy1 end and The Q terminal is connected to E1 or E2;

[0050] E1 and E2 are the same or different and are independently selected from Ring G is selected from one, two or more R g Substituted 5-6 membered N-containing heterocyclic group; each R g the same or different, independently selected from H, oxo (=O), C 1-12 Alkyl or And ring G contains at least one R g1 Selected from H, hydroxyl C 1-12 Alkyl, (R g11 )(R g12 )-NC 1-12 Alkyl-C(O)OC 1-12 Alkyl; R g11 、R g12 The same or different, independently selected from H, C 1-12 alkyl; Indicates the junction site;

[0051] Each R5 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R5a: C 1-12 Alkyl, C 1-12 alkoxy;

[0052] Each R5a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0053] n is selected from 0, 1, 2;

[0054] m is selected from 0, 1, 2, 3;

[0055] p is selected from 0, 1, 2, 3, 4, 5;

[0056] q is selected from 0, 1, and 2.

[0057] According to an embodiment of the present invention, the compound represented by formula (III) has a structure represented by the following formula (I):

[0058] in,

[0059] represents an aromatic aryl group or heteroaryl group, or represents a non-aromatic heterocyclic group;

[0060] Ring A is selected from phenyl or 5-6 membered heteroaryl;

[0061] X is selected from NR1, or CH;

[0062] Y is selected from N or CH;

[0063] Z1 is selected from N, C or CH; and one of Y and Z1 is N;

[0064] Each R1 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more R1a: C 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R, C 6-14 Aryl, 5-14 membered heteroaryl; wherein R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 3-12 Cycloalkyl;

[0065] Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0066] Each R2 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1- 12 alkoxy;

[0067] Ra is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more Ra1 groups: C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 1-12 alkyl;

[0068] Each Ra1 is the same or different and is independently selected from H, oxo (=O), halogen, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: NH2, C 1-12 Alkyl, C 2-12Alkenyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, C 2-12 Alkenyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 2-12 Alkenyl C(=O)-, C 2-12 Alkynyl C(=O)-, C 1- 12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C (= O) -, 5-14 membered heteroaryl C (= O) -, 3-14 membered heterocyclyl C (= O) -, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 2-12 Alkenyl S(=O)-, C 1-12 Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 2- 12 Alkenyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 2-12 Alkenyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH-, C 2-12 Alkenyl-S(=O)2-NH-;

[0069] Each Ra2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0070] Rb, Rc, Rd, Re, and Rz are the same or different and are independently selected from the following groups: C 6-14 Aryl, 5-14 membered heteroaryl; or, two adjacent groups in Rb, Rc, Rd, Re, and Rz and the atoms to which they are attached form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rb2: C6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyl;

[0071] Each Rb1 and Rb2 are the same or different and are independently selected from H, halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Rb3: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl; each Rb3 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0072] n=0,1,2;

[0073] m=0, 1, 2, 3;

[0074] p=0, 1, 2, 3, 4, 5.

[0075] According to an embodiment of the present invention, Y is selected from N; Z is selected from C or CH;

[0076] According to an embodiment of the present invention, Y is selected from CH; Z is selected from N;

[0077] According to an embodiment of the present invention, ring A is selected from phenyl, pyrazolyl, imidazolyl;

[0078] According to an embodiment of the present invention, ring A is selected from

[0079] According to an embodiment of the present invention, is selected from phenyl or 5-6 membered heteroaryl; Indicates the junction site;

[0080] According to an embodiment of the present invention, Selected from tetrahydropyrrolyl, piperidinyl, phenyl;

[0081] According to an embodiment of the present invention, Selected from

[0082] According to an embodiment of the present invention, Selected from in, and connected.

[0083] According to an embodiment of the present invention, Selected from unsubstituted or optionally substituted by 1, 2 or more Rb1 or unsubstituted or optionally substituted with 1, 2 or more Rb2

[0084] According to an embodiment of the present invention, Selected from

[0085] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from -(C=O)C 1-6 Alkyl, -(C=O)-NH-C 1-6 Alkyl, C 1-6 alkyl-substituted 5-6 membered heteroaryl;

[0086] According to an embodiment of the present invention, each R1 is the same or different and is independently selected from -(C=O)CH3, -(C=O)-NH-CH3, According to an embodiment of the present invention, Ra is selected from the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra1: 3-8 membered heterocyclic group, C 3-8 Cycloalkyl;

[0087] According to an embodiment of the present invention, Ra is selected from the following groups which are unsubstituted or optionally substituted with 1, 2 or more Ra1: cyclohexyl, piperidinyl or piperazinyl.

[0088] According to an embodiment of the present invention, each Ra1 is the same or different and is independently selected from the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: 1-6 Alkyl, C 1-6 Alkyl C(=O)-, C 2-6 Alkenyl C(=O)-, C 2-6 Alkynyl C(=O)-, C 1-6 Alkyl-C(=O)-NH-, C 2-6 Alkenyl-C(=O)-NH-, C 2-6 Alkynyl-C(=O)-NH-, C 1-6 Alkyl-S(=O)2-, C 2-6 Alkenyl-S(=O)2-, C 1-6 Alkyl-S(=O)2-NH-, C 2-6Alkenyl-S(=O)2-NH-, 3-6 membered heterocyclic group;

[0089] According to an embodiment of the present invention, each Ra2 is the same or different and is independently selected from halogen, oxo (=O), (C 1-12 alkyl)2-NH-;

[0090] According to an embodiment of the present invention, each Ra1 is the same or different and is independently selected from methyl,

[0091] According to an embodiment of the present invention, each Rb is the same or different and is independently selected from oxo (=O), unsubstituted or optionally substituted by 1, 2 or more Rb1. 6-10 Aryl; or, two Rb and their respective attached groups form a C unsubstituted or optionally substituted by 1, 2 or more Rb2 6-10 aryl;

[0092] According to an embodiment of the present invention, each Rb is the same or different and is independently selected from oxo (=O), unsubstituted or phenyl optionally substituted by 1, 2 or more Rb1; or, two Rb and the group to which they are attached form a phenyl group which is unsubstituted or optionally substituted by 1, 2 or more Rb2;

[0093] According to an embodiment of the present invention, each Rb1 is the same or different and is independently selected from halogen, such as F;

[0094] According to an embodiment of the present invention, each Rb2 is the same or different and is independently selected from CN, halogenated C 1-6 Alkyl, C 3-6 Alkyl, C 1-6 Alkyl-5-6 membered heteroaryl;

[0095] According to an embodiment of the present invention, each Rb2 is the same or different and is independently selected from CN, difluoromethyl, cyclopropyl,

[0096] According to an embodiment of the present invention, the formula I is further selected from the following structures:

[0097] wherein ring A, R1, R2, Ra, Rb, m, and n are independently defined as described in the present invention; Rb 11 , Rb 12 are the same or different and independently have the meanings given above for Rb2.

[0098] According to an embodiment of the present invention, the formula I is further selected from the following structures:

[0099] wherein R1, Ra, and Rb1 independently have the definitions described in the present invention; Rb 11 , Rb 12 are the same or different and independently have the meanings given above for Rb2.

[0100] According to an embodiment of the present invention, the compound represented by formula (III) has a structure represented by the following formula (II):

[0101] in:

[0102] n=0,1,2;

[0103] m=0, 1, 2, 3;

[0104] p = 0, 1, 2, 3, 4, 5;

[0105] q = 0, 1, 2;

[0106] X1, X2, X3, X4 are the same or different and are independently selected from C or N;

[0107] Y is selected from C or N;

[0108] Z2 is selected from CR3 or N;

[0109] Each R1 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more R1a: C 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R;

[0110] The R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 3-12 Cycloalkyl;

[0111] Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0112] Each R2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0113] Ra is selected from -link-E groups or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with 1, 2 or more R a1 The following groups are substituted: C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 1-12 alkyl;

[0114] Each R a1 the same or different, independently selected from H, oxo (=O), halogen, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R a2 The following groups are substituted: NH2, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C (= O) -, 5-14 membered heteroaryl C (= O) -, 3-14 membered heterocyclyl C (= O) -, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 1-12 Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH--;

[0115] Each R a2 the same or different, independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino,;

[0116] R3 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3a: C 1-12Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl;

[0117] Each R3a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more R3b: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1- 12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0118] Each R3b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0119] R4 is selected from -link-E group or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4a groups: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1- 12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl;

[0120] Each R4a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more R4b: C1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1- 12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0121] Each R4b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino;

[0122] At least one of Ra and R4 is a -link-E group, the -link-E group in Ra is -link1-E1, and the -link-E group in R4 is -link2-E2;

[0123] link1 and link2 are the same or different and are independently selected from -Cy1-L1-Cy2-L2-Q-;

[0124] Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, 5-14 membered heteroarylene;

[0125] Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene;

[0126] L1 is absent or selected from N(R L ), unsubstituted or optionally substituted by one, two or more R L1 Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkyleneoxy; R L Selected from H or C 1-12 alkyl;

[0127] L2 is absent or selected from unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C 1-12 Alkylene, (C1-12 alkyleneoxy) t ; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0128] Q is absent or selected from O, N(R q ), ethynylene; R q Selected from H or C 1-12 alkyl;

[0129] R Cy1 、R Cy2 the same or different, independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 alkoxy;

[0130] R L1 、R L2 the same or different, independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 alkoxy;

[0131] Cy1 end and The Q terminal is connected to E1 or E2;

[0132] E1 and E2 are the same or different and are independently selected from Ring G is selected from one, two or more R g Substituted 5-6 membered N-containing heterocyclic group; each R g the same or different, independently selected from H, oxo (=O), C 1-12 Alkyl or And ring G contains at least one R g1 Selected from H, hydroxyl C 1-12 Alkyl, (R g11 )(R g12 )-NC 1-12 Alkyl-C(O)OC 1-12 Alkyl; R g11 、R g12 The same or different, independently selected from H, C 1-12 alkyl; Indicates the junction site;

[0133] Each R5 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R5a: C 1-12 Alkyl, C 1-12 alkoxy;

[0134] Each R5a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 alkoxy;

[0135] R6 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R6a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl;

[0136] Each R6a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0137] R7 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R7a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl;

[0138] Each R7a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0139] Or R6 and R7 together form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rsa: C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group; the 5-14 membered heteroaryl, 3-14 membered heterocyclic group contains at least one nitrogen atom;

[0140] Each Rsa is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted with 1, 2 or more Rsb: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl;

[0141] Each Rsb is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino.

[0142] In some embodiments, in formula (II), Partially selected from the following structures:

[0143] The structure has R1 and R2 substituents as defined above.

[0144] In some embodiments, each R1 is the same or different and is independently selected from oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, -(C=O)R; wherein R is selected from C 1-6 Alkyl, C 1-6 Alkoxy, NH2-, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl;

[0145] In some embodiments, R1 is a substituent on the ring N atom, for example, (* represents the R1 substitution position).

[0146] In some embodiments, R1 is -(C=O)CH3, -C(=O)OCH3, -C(=O)NH-CH3;

[0147] In some embodiments, Ra is selected from -link1-E1 group or 5-8 membered heterocyclic group; the 5-8 membered heterocyclic group is, for example

[0148] In some embodiments, R3 is selected from halogenated C 1-6 alkyl;

[0149] In some embodiments, R3 is selected from -CHF2.

[0150] In some embodiments, R4 is selected from -link2-E2 group or 5-6 membered heteroaryl (eg, pyrazolyl) which is unsubstituted or optionally substituted with one, two or more R4a; each R4a is the same or different and is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R4 is

[0151] In some embodiments, R6 and R7 together form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rsa: 5-6 membered heterocyclyl, C 6-10 Aryl, such as piperidinyl or phenyl.

[0152] In some embodiments, R6 and R7 together form the following structure which is unsubstituted or optionally substituted with 1, 2 or more Rsa:

[0153] In some embodiments, in formula (II), Partially selected from the following structures:

[0154] In some embodiments, Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted following groups: 5-8 membered heterocyclylene, C 3-8 Cycloalkylene, 5-10 membered heteroarylene;

[0155] In some embodiments, Cy1 is selected from piperidinylene, cyclohexylene, pyridinylene; for example

[0156] In some embodiments, Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted following groups: 5-8 membered heterocyclylene, C 3-8 Cycloalkylene, C 6-10Arylene, 5-10 membered heteroarylene;

[0157] In some embodiments, Cy2 is absent or selected from piperidinylene, morpholinylene, piperazinylene, phenylene, pyridinylene, triazolylene; for example

[0158] In some embodiments, L1 is absent or selected from unsubstituted or optionally substituted with one, two or more R L1 Substituted C 1-10 alkylene;

[0159] In some embodiments, L1 is absent or selected from NH, N(CH3), methylene, ethylene,

[0160] In some embodiments, L2 is absent or selected from C 1-6 Alkylene, (C 1-6 alkyleneoxy) t ; t is selected from 1, 2, 3, 4;

[0161] In some embodiments, L2 is absent or selected from methylene, ethylene, propylene, ethyleneoxy,

[0162] In some embodiments, Q is absent or selected from O, NH, and ethynylene.

[0163] In some embodiments, link1 and link2 are the same or different and are independently selected from

[0164] In some embodiments, ring G is selected from the group consisting of g Substituted tetrahydropyrrolyl, imidazolidinyl; e.g.

[0165] In some embodiments, ring G is selected from

[0166] In some embodiments, each R g the same or different, independently selected from H, oxo (=O), C 1-6 Alkyl or

[0167] In some embodiments, R g1 Selected from H, hydroxyl C 1-6 Alkyl, (C 1-6Alkyl)(C 1-6 Alkyl)-NC 1-6 Alkylene-C(O)OC 1-6 Alkylene, H2N-C 1-6 Alkylene-C(O)OC 1-6 alkylene;

[0168] In some embodiments, R g1 Selected from H, hydroxymethyl,

[0169] In some embodiments, E1 and E2 are the same or different and are independently selected from:

[0170] In some embodiments, E1 and E2 are the same or different and are independently selected from:

[0171] In some embodiments, the formula (III) is further selected from the following structures:

[0172] wherein R1, R2, Ra, R4, R5, R6, R7, X1, X2, X3, X4, Y, Z2, m, n, and q have the definitions described in the present invention.

[0173] In some embodiments, the formula (III) is further selected from the following structures:

[0174] wherein R1, R2, Ra, R4, R5, X1, X2, X3, X4, lm, n, p, and q have the definitions described in the present invention.

[0175] In some embodiments, the formula (III) is further selected from the following structures:

[0176] Among them, R1, R2, Ra, R4, R5, R6, R7, X1, X2, X3, X4, Y, Z2, link1, link2, E1, E2, m, n, p, and q have the definitions described in the present invention.

[0177] In some embodiments, exemplary specific compounds of the compound represented by formula (III) are as follows:

[0178] In some embodiments, exemplary specific compounds of the compound represented by formula (III) are as follows:

[0179] In another aspect, the present disclosure further provides a pharmaceutical composition comprising a compound represented by Formula III and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts.

[0180] In another aspect, the present disclosure also provides the use of a compound represented by Formula III and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts, and pharmaceutical compositions containing the same, in the preparation of drugs for preventing and / or treating diseases or conditions mediated by EP300 and / or CBP.

[0181] According to an embodiment of the present invention, the prevention and / or treatment of diseases or conditions mediated by EP300 and / or CBP is achieved by degrading EP300 and / or CBP proteins using the compound represented by Formula III and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing the same.

[0182] In another aspect, the present disclosure also provides a method for preventing and / or treating diseases or conditions mediated by EP300 and / or CBP, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula III and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions comprising the same.

[0183] The diseases or conditions mediated by EP300 and / or CBP described in the present disclosure are selected from cancer, heart disease, metabolic disease, inflammatory disease, fibrotic disease and viral infection. The cancer includes, but is not limited to, prostate cancer, breast cancer, bladder cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, ovarian cancer, cervical cancer, bladder cancer, laryngeal cancer, multiple myeloma, liver cancer, lymphoma and leukemia. Prostate cancer can be, for example, castration-resistant prostate cancer (CRPC). Lung cancer can be, for example, non-small cell lung cancer or small cell lung cancer. The lymphoma can be selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, etc.

[0184] The compounds of the present disclosure may be used in combination with other drugs or other therapies.

[0185] In some embodiments, the compounds described hereinabove are used in combination with radiation therapy.

[0186] In some embodiments, the present invention further provides the compound for use in combination with an immunomodulatory agent for treating diseases or disorders mediated by EP300 and / or CBP (eg, multiple myeloma).

[0187] In some embodiments, the immunomodulators include tumor necrosis factor; interferon alpha, beta, and gamma; IL-2 and other cytokines; F42K and other cytokine analogs; or MIP-1, MIP-1β, MCP-1, RANTES, and other chemokines.

[0188] In some embodiments, the compounds described hereinabove are used in combination with a second therapeutic agent, which may be selected from drugs conventionally used to treat cancer, heart disease, metabolic disease, inflammatory disease, fibrotic disease, and viral infection. In some embodiments, the class of the second therapeutic agent may include androgen receptor antagonists, such as enzalutamide, and inhibitors of CYP17A1 (17α-hydroxylase / C17,20 lyase), such as abiraterone; cytotoxic chemotherapy agents, such as docetaxel; therapeutic agents used to treat lung cancer include cytotoxic chemotherapy agents, such as cisplatin, carboplatin, and docetaxel; therapeutic agents used to treat bladder cancer include cytotoxic chemotherapy agents, such as gemcitabine, cisplatin, or immunotherapy, such as Bacillus Calmette-Guérin (BCG). The second therapeutic agent may also be selected from immune checkpoint inhibitors, such as pembrolizumab, nivolumab, atezolizumab, ipilimumab; PARP (poly ADP ribose polymerase) inhibitors such as olaparib; and CDK4 / 6 (cyclin-dependent kinase 4 and 6) inhibitors. In some embodiments, the second therapeutic agent may be selected from a combination therapy with a KRAS inhibitor, for the treatment of various tumors such as lung cancer, colorectal cancer, pancreatic cancer, liver cancer, and hematologic malignancies.

[0189] Therefore, the present disclosure provides a combination composition comprising a compound represented by Formula III and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof and a second therapeutic agent;

[0190] The present disclosure also provides a method for the combined prevention and / or treatment of diseases or conditions mediated by EP300 and / or CBP, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula III and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof, and a second therapeutic agent.

[0191] Pharmaceutically acceptable salts of the compounds of the present disclosure may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0192] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0193] Compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure. The names of compounds named in a single manner do not exclude any tautomers.

[0194] The present disclosure also includes isotopically labeled compounds of the present disclosure having the same structure as described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0195] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to be deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium or more. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0196] As used herein, the term "EP300 and / or CBP-mediated disease or condition" refers to a disease or condition in which the biological function of EP300, CBP, or both EP300 and CBP affects the development and / or course of the disease or condition, and / or in which regulation of EP300, CBP, or both EP300 and CBP alters the development, course, and / or symptoms. Diseases or conditions mediated by EP300 or CBP include those in which EP300 inhibition, CBP inhibition, or both EP300 and CBP inhibition provide a therapeutic benefit, e.g., treatment with an EP300 or CBP inhibitor (including a compound described herein) provides a therapeutic benefit to a subject having the disease or condition or at risk of the disease or condition. Diseases or conditions mediated by EP300 or CBP are intended to include cancers with a loss of function mutation of CBP or EP300, or cancers in which EP300 or CBP is activated. Diseases or conditions mediated by EP300 or CBP are also intended to include cancers that express the androgen receptor.

[0197] The "therapeutically effective amount" of the present disclosure refers to the amount of an active compound or drug that elicits a biological or medical response in a tissue, system, animal, individual or human that is sought by a researcher, veterinarian, physician or other clinician, and includes one or more of the following: (1) preventing disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) inhibiting disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) alleviating disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. With respect to a drug or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments. Beneficial effects

[0198] The present disclosure provides a class of novel compounds having a structure represented by formula (III), which have good EP300 / CBP regulating activity (eg, inhibitory or degradation activity) and pharmaceutical prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0199] FIG1 is a degradation experiment of the target protein P300 by the compounds of the present invention.

[0200] FIG2 is an experiment showing the degradation of target proteins and corresponding downstream proteins by the compounds of the present invention.

[0201] Definitions and Explanations of Terms

[0202] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0203] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0204] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12), preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6Alkyl). Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof. Alkyl groups can be substituted or unsubstituted.

[0205] The term "alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (C 2-12 Alkenyl), more preferably "C 2-8 Alkenyl". "C 2-8 "Alkenyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, e.g. 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3It is understood that when the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl But-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0206] The term "alkynyl" is understood to mean preferably a linear or branched monovalent hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms (C 2-12 Alkynyl), for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., "C 2-8 alkynyl”), having 2, 3, 4, 5, or 6 carbon atoms (i.e., “C 2-6 Alkynyl”), having 2 or 3 carbon atoms (“C 2-3The alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, In some embodiments, the alkynyl group is ethynyl, prop-1-ynyl or prop-2-ynyl.

[0207] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be substituted or unsubstituted.

[0208] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, preferably containing 3 to 12 or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0209] The term " spiroalkyl " refers to a polycyclic group sharing a carbon atom (claiming spiral atom) between each monocycle in the system, which can contain one or more double bonds. Preferably, it is 6 to 12 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiral atoms between the rings, spiroalkyl is divided into single spiroalkyl, double spiroalkyl or multiple spiroalkyl, preferably single spiroalkyl and double spiroalkyl. More preferably, it is 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl. Non-limiting examples of spiroalkyl include:

[0210] The term " fused cycloalkyl " refers to a full carbon polycyclic group that each ring in the system shares a pair of carbon atoms adjacent to other rings in the system, wherein one or more rings can contain one or more double bonds.Preferably 6 to 12 members, more preferably 7 to 10 members (such as 7,8,9 or 10 members).Can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number forming ring, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 members, 3 yuan / 5 members, 3 yuan / 6 members, 4 yuan / 4 members, 4 yuan / 5 members, 4 yuan / 6 members, 5 yuan / 4 members, 5 yuan / 5 members, 5 yuan / 6 members, 6 yuan / 3 members, 6 yuan / 4 members, 6 yuan / 5 members and 6 yuan / 6 members of the bicyclic alkyl.The limiting examples of fused cycloalkyl include:

[0211] The term "bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 12 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0212] The cycloalkyl ring includes a cycloalkyl group as described herein (including monocyclic, spirocyclic, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples of which include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.

[0213] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 14 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) of which 1 to 4 (e.g., 1, 2, 3 and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8) of which 1 to 3 (e.g., 1, 2 and 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms of which 1 to 3 are heteroatoms; and most preferably, it contains 5 or 6 ring atoms of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclyls.

[0214] The term "spiro heterocyclic radical" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between each monocyclic ring in the system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It can contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of shared spiral atoms between the rings, the spiral heterocyclic radical is divided into a monospiro heterocyclic radical, a dispiro heterocyclic radical or a polyspiro heterocyclic radical, preferably a monospiro heterocyclic radical and a dispiro heterocyclic radical. It is more preferably a 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or a 5 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples of spiro heterocyclic radicals include:

[0215] The term "fused heterocyclic radical" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of atoms adjacent to other rings in the system, and one or more rings can contain one or more double bonds, wherein one or more annular atoms are heteroatoms selected from nitrogen, oxygen and sulphur, and the sulphur can be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining annular atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radicals, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan and 6 yuan / 6 yuan bicyclic fused heterocyclic radicals. The limiting examples of fused heterocyclic radicals include:

[0216] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, and which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, wherein the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0217] The heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0218] The heterocyclic group may be substituted or unsubstituted.

[0219] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0220] Aryl groups can be substituted or unsubstituted.

[0221] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5-membered or 6-membered, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0222] Heteroaryl groups can be substituted or unsubstituted.

[0223] Those skilled in the art will appreciate that the cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent, i.e., "divalent cycloalkyl," "divalent heterocyclyl," "arylene," and "heteroarylene." Those skilled in the art will appreciate that when a linking group is clearly required in a compound structure, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linking alkylene or arylene group, respectively. Therefore, when used as a linking group, "alkyl" and "alkylene" have equivalent definitions, e.g., "alkyl" and "alkylene" have equivalent definitions, and "aryl" and "arylene" have equivalent definitions.

[0224] The term "halogen" refers to F, Cl, Br or I.

[0225] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0226] The term "more" includes 3, 4, 5 and more.

[0227] Pharmaceutically acceptable salts of the compounds of the present disclosure may be inorganic or organic salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form internal salts.

[0228] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0229] Compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure. The names of compounds named in a single manner do not exclude any tautomers.

[0230] The present disclosure also includes isotopically labeled compounds of the present disclosure having the same structure as described herein, but with one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N.15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.

[0231] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to be deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium or more. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to the relevant literature. In preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used, or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0232] As used herein, the term "modulator" refers to a compound that alters (ie, increases or decreases) the activity of a target biomolecule, such as an enzyme. Generally, a modulator will be a small molecule.

[0233] The term "modulate" refers to the ability of a compound to increase or decrease the function and / or expression of a target (such as EP300 or CBP), wherein such function may include transcriptional regulatory activity and / or binding. Modulation can be performed in vitro or in vivo. As described herein, modulation includes direct or indirect inhibition, antagonism, partial antagonism, degradation, activation, excitement or partial excitement of a function or feature associated with EP300 or CBP, and / or direct or indirect upregulation or downregulation of expression of EP300 or CBP. In another embodiment, modulation is direct. An inhibitor or antagonist or degrader is a compound that (e.g., in combination with) partially or completely blocks stimulation, reduces, prevents, inhibits, delays activation, inactivates, passivates or downregulates signal transduction. An activator or agonist is a compound that (e.g., in combination with) stimulates, increases, opens, activates, promotes, enhances activation, activates, sensitizes or upregulates signal transduction. Therefore, "EP300&CBP modulator" can further cover "EP300&CBP inhibitor", "EP300&CBP degrader" and "EP300&CBP agonist".

[0234] As used herein, the term "EP300 and / or CBP-mediated disease or condition" refers to a disease or condition in which the biological function of EP300, CBP, or both EP300 and CBP affects the development and / or course of the disease or condition, and / or in which regulation of EP300, CBP, or both EP300 and CBP alters the development, course, and / or symptoms. Diseases or conditions mediated by EP300 or CBP include those in which EP300 inhibition, CBP inhibition, or both EP300 and CBP inhibition provide a therapeutic benefit, e.g., treatment with an EP300 or CBP inhibitor (including a compound described herein) provides a therapeutic benefit to a subject having the disease or condition or at risk of the disease or condition. Diseases or conditions mediated by EP300 or CBP are intended to include cancers with loss of function mutations of EP300 or CBP, or cancers in which EP300 or CBP activation is present. Diseases or conditions mediated by EP300 or CBP are also intended to include cancers that express the androgen receptor.

[0235] The "therapeutically effective amount" of the present disclosure refers to the amount of an active compound or drug that elicits a biological or medical response in a tissue, system, animal, individual or human that is sought by a researcher, veterinarian, physician or other clinician, and includes one or more of the following: (1) preventing disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) inhibiting disease: for example, inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) alleviating disease: for example, alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. With respect to a drug or pharmacologically active agent, a "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments. DETAILED DESCRIPTION

[0236] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0237] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0238] Example 1-1

[0239] Synthesis of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0240] To a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (18 g, 98.2 mmol, 1 eq) in DCM (180 ml) was added NBS (17.5 g, 98.2 mmol, 1 eq) at 0 ° C. The mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched by adding glacial H2O (200 mL) and extracted with DCM (150 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 10%) to give 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (16 g, 61.1 mmol, 62.1% yield) as a yellow solid.

[0241] MS(ESI):C 10 H 11 F2N; found 262.6 (M+H) + .

[0242] 1 H NMR (400MHz, CDCl3) δ = 7.18 (s, 1H), 7.04 (s, 1H), 6.63 (s, 1H), 4.09-3.82 (m, 1H), 3.28-3.18 (m, 2H), 2.66 (br t, J = 6.3Hz, 2H), 1.88-1.79 (m, 2H)

[0243] A mixture of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (11 g, 41.9 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dihydrobenzofuran-2-yl)pyrazole (8.7 g, 41.9 mmol, 1 eq), cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (3.0 g, 4.2 mmol, 0.1 eq), K2CO3 (11.6 g, 83.9 mmol, 2 eq) in dioxane (80 mL) and H2O (20 mL) was stirred at 110° C. under N2 for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 40%) to give 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (compound int-1, 10 g, 37.9 mmol, 90.5% yield) as a brown solid.

[0244] MS(ESI):C 14 H 15 F2N3; found 263.9 (M+H) + .

[0245] 1 H NMR (400MHz, DMSO-d6)δ=7.68(s,1H),7.43(s,1H),6.90(s,1H),6.73(s,1H),6.01(s,1H),3.84(s,3H),3.24-3.14(m,2H),2.68(br t,J=6.0Hz,2H),1.79(quin,J=5.9Hz,2H)

[0246] Example 1-2

[0247] To a solution of 5-chloro-2-methylbenzoic acid (50 g, 293.1 mmol, 1 eq) in concentrated sulfuric acid (350 mL) was added dropwise a solution of NIS (76 g, 331 mmol, 98% purity, 1.13 eq) in sulfuric acid (30 mL) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction was poured into ice water (500 mL) and stirred for 30 minutes, then filtered to provide 5-chloro-3-iodo-2-methylbenzoic acid (68.5 g, 231 mmol, 78.8% yield) as a brown solid.

[0248] MS(ESI):C8H6ClIO2; found 294.8(MH) + .

[0249] To 5-chloro-3-iodo-2-methylbenzoic acid (68.5g, 231mmol, 1eq) in MeOH (350mL) solution, add concentrated H SO (12mL).The mixture was stirred at 60 ℃ for 16 hours.The reaction mixture was concentrated under reduced pressure.Residue was diluted with DCM (300mL), and the organic phase merged was washed with NaHCO aqueous solution (200mL) and salt solution (200mL).Use anhydrous Na SO Drying, filter and vacuum concentration to obtain yellow oily 5-chloro-3-iodo-2-methylbenzoic acid methyl ester (58.5g, 188.4mmol, 81.5% yield).

[0250] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.98 (d, J = 2.0Hz, 1H), 7.76 (d, J = 1.8Hz, 1H), 3.92 (s, 4H), 2.64 (s, 3H).

[0251] To the CCl of 5-chloro-3-iodo-2-methylbenzoic acid methyl ester (55g, 177.12mmol, 1eq) (350ml) solution, add NBS (33g, 185.41mmol, 1.05eq) and BPO (4.5g, 18.58mmol, 1e-1eq).Mixture was stirred 17 hours at 80 ℃.Filter reaction mixture and concentrate under reduced pressure.Resistates obtains colorless oily 2-(bromomethyl)-5-chloro-3-iodobenzoic acid methyl ester (40g, 103.1mmol, 57% productive rate) by column chromatography eluting (petroleum ether / ethyl acetate=100 / 0 to 10 / 1).

[0252] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.97 (d, J = 2.2Hz, 1H), 7.84 (d, J = 2.2Hz, 1H), 5.01 (s, 2H), 3.89 (s, 3H).

[0253] Methyl 2-(bromomethyl)-5-chloro-3-iodobenzoate (40 g, 102.5 mmol, 1 eq) was added to a NH3 / MeOH (150 ml) solution. The mixture was stirred at 60°C for 2.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was washed three times with EA (150 mL) to give 6-chloro-4-iodoisoindole-1-one (20.6 g, 70.4 mmol, 68.5% yield) as a white solid.

[0254] MS(ESI):C8H6ClINO; found 295.8(M+H) + .

[0255] 1 H NMR (400MHz, DMSO-d6) δ = 8.96 (br s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 4.18 (s, 2H)

[0256] To a solution of 6-chloro-4-iodoisoindole-1-one (17 g, 57.92 mmol, 1 eq) in DCM (150 mL) was added DIBALH (1 M, 202.73 mL, 3.5 eq) dropwise at 0 ° C under nitrogen. The mixture was stirred at 45 ° C for 54 hours. The reaction mixture was quenched by adding 15% NaOH 100 mL at 0 ° C, then filtered and washed with EtOAc. The filtrate was washed with brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-10% MeOH / DCM eluent) to give 6-chloro-4-iodo-2,3-dihydro-1H-isoindole hydrochloride (5.5 g, 19.6 mmol, 33.9%) as a brown solid.

[0257] 1 H NMR (400MHz, DMSO-d6) δ = 7.64 (s, 1H), 7.37 (s, 1H), 4.20 (s, 2H), 3.93 (s, 2H).

[0258] At 25 ° C, NaHCO3 (9.17 g, 0.109 mol) and Boc2O (8.74 g, 0.0400 mol) were added to a solution of 6-chloro-4-iodo-2,3-dihydro-1H-isoindole hydrochloride (11.5 g, 0.0364 mol) in THF (220 mL) and H2O (109 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 0%-5% EtOAc in PE to give tert-butyl (6-chloro-4-iodo-1,3-dihydroisoindole-2-yl) formate (9.90 g, 70% yield) as a white solid. LC-MS: (ESI)m / z[m+H-56]+234.0.

[0259] To a solution of 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (14.0 g, 0.0532 mol) and tert-butyl (6-chloro-4-iodo-1,3-dihydroisoindol-2-yl)carboxylate (24.3 g, 0.0638 mol) in 1,4-dioxane (1.0 L) was added BuONa (15.3 g, 0.160 mol) and XPhos Pd G3 (4.50 g, 0.00530 mol) at 25 ° C. The reaction mixture was heated to 90 ° C. and stirred under N2 for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was added to water (500 mL). The aqueous phase was extracted with ethyl acetate (200 mL×3). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with THF in PE from 0% to 25% to give tert-butyl {6-chloro-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}carboxylate (22.3 g, 80% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 515.2.

[0260] 1 H NMR (400MHz, DMSO-d6) δ7.76(s,1H),7.50(s,1H),7.32(m,2H),7.16(s,1H),6.78(t,J=55.2Hz,1H),6.42(d,J=10 .0Hz,1H),4.63(s,2H),4.36–4.19(m,2H),3.86(s,3H),3.55(s,2H),2.87(s,2H),1.99(s,2H),1.49–1.33(m,9H).

[0261] To a solution of tert-butyl 6-chloro-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindoline-2-carboxylate (700 mg, 1.36 mmol) in dioxane (5.0 mL) and H O (0.5 ml) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-ol (609.2 mg, 2.72 mmol), K CO (563.6 mg, 4.08 mmol) and XPhos Pd G (114.9 mg, 0.14 mmol). The mixture was then stirred at 100° C. for 2 hours. LCMS showed that the starting material was consumed and the desired product was detected. The residue was purified by flash column chromatography eluting with EtOAc in PE from 0-50% and then with MeOH in DCM from 0-5% to give tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohex-1-en-1-yl)isoindoline-2-carboxylate as a yellow solid.

[0262] To a solution of tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohex-1-en-1-yl)isoindoline-2-carboxylate (700 mg, 1.21 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was concentrated under reduced pressure to afford 4-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohex-3-en-1-ol (600 mg, 98% yield) as a yellow solid.

[0263] To a solution of 4-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohex-3-en-1-ol (600 mg, 1.3 mmol) in DCM (4.0 mL) was added 25% TEA (382.2 mg, 3.8 mmol) and acetyl chloride (197.7 mg, 2.5 mmol). The reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×3) and dried over anhydrous NaSO. The residue was purified by flash column chromatography eluting with EtOAc in PE from 0-50% and then by flash column chromatography eluting with methanol in DCM from 0-5% to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohex-1-en-1-yl)isoindolin-2-yl)ethan-1-one as a yellow solid (600 mg, 92% yield).

[0264] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohex-1-en-1-yl)isoindolin-2-yl)ethan-1-one (600 mg, 1.2 mmol) in THF (4.0 mL) at 25° C. under H2 atmosphere (15 PSI) was added Pd / C (60% in oil) (123.1 mg, 1.2 mol). After filtration, the filtrate was concentrated under reduced pressure to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohexyl)isoindolin-2-yl)ethan-1-one (600 mg, 99% yield) as a yellow solid.

[0265] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohexyl)isoindolin-2-yl)ethan-1-one (130 mg, 0.25 mmol) in DCM (2.0 mL) was added DessMartin (158.9 mg, 0.37 mmol) at 25°C. The mixture was then stirred at 25°C for 2 hours. The mixture was quenched by the addition of saturated aqueous NaHCO3 (20 mL) and extracted with DCM (3×20 mL). The combined organic layers were dried over Na2SO4. After filtration, the filtrate was purified by flash column chromatography eluting with EtOAc in PE from 0% to 50%, and then by flash column chromatography eluting with methanol in dichloromethane from 0% to 5% to give 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexan-1-one as a white solid (100 mg, 77% yield).

[0266] To a solution of 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexan-1-one (200 mg, 0.39 mmol) in MeOH (3.0 mL) was added ammonium carbonate (74.1 mg, 0.77 mmol) at 25° C. The mixture was stirred at 25° C. for 1 hour. NaCNBH 3 (48.5 mg, 0.77 mmol) was then added to the mixture. The mixture was stirred at 25° C. for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The crude product was purified by preparative HPLC eluting with CH3CN in 0.1% FA / water from 38% to 45% in 8 min to give 1-(6-(4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-2-yl)ethan-1-one (30.4 mg, 15% yield) as a white solid.

[0267] To a solution of 1-(6-(4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-2-yl)ethan-1-one (215 mg, 0.414 mmol) and Boc2O (181 mg, 0.828 mol) in DCM (6 mL) was added TEA (41.9 mg, 1.24 mmol) at 25°C. The reaction mixture was stirred at 25°C under N2 for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by SFC (Daicel CHIRALCEL IB-N, 250 mm×30 mm ID, 10 μm; mobile phase CO2 / MeOH [0.2% NH3 (7 M The mixture was stirred for 2 h in 4% CO 2 0 ℃ for 1 h (4 h) to give tert-butyl ((1s,4s)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)carbamate (37.2 mg, 14.5% yield) and tert-butyl ((1r,4r)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)carbamate (105.3 mg, 41%) as a white solid.

[0268] To a solution of tert-butyl (1s,4s)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)carbamate (37.2 mg, 0.0601 mmol) in dioxane (5 mL) was added HCl in dioxane (4N, 5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The aqueous solution was dried by freeze drying to give 28.5 mg (84%) of 1-(6-((1s,4s)-4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-2-yl)ethan-1-one hydrochloride as a white solid.

[0269] To a solution of tert-butyl (1r,4r)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)carbamate (105.3 mg, 0.170 mmol) in dioxane (5 mL) was added HCl in dioxane (4N, 5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The aqueous solution was dried by freeze drying to give 1-(6-((1r,4r)-4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-2-yl)ethan-1-one hydrochloride (93.2 mg, 98% yield) as a white solid.

[0270] Example 1-3 (Synthesis of 1338)

[0271] To a solution of 1-(6-((1r,4r)-4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-isoindolin-2-yl)-1-one (20.0 mg, 0.0385 mmol) in DCM (3.0 mL) was added TEA (11.7 mg, 0.116 mmol) and acryloyl chloride (6.97 mg, 0.0770 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (30% to 50% in 8 min with CH3CN) to give N-(((1r,4r)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)acrylamide (compound 1338, 11.2 mg, 50% yield) as a yellow solid.

[0272] 1H NMR (400MHz, DMSO-d6) δ8.06–7.98(m,1H),7.75(s,1H),7.49(s,1H),7.21–7.09(m,3H),6.74(t,J=55. 2Hz,1H),6.46–6.36(m,1H),6.27–6.16(m,1H),6.12–6.02(m,1H),5.61–5.50(m,1H),4.91–4.80(m,1H) ),4.75–4.50(m,2H),4.34–4.20(m,1H),3.86(s,3H),3.75–3.63(m,1H),3.61–3.50(m,2H),2.93–2.84 (m,2H),2.59–2.53(m,1H),2.08–1.97(m,5H),1.95–1.80(m,4H),1.65–1.50(m,2H),1.40–1.25(m,2H).

[0273] Example 1-4 (Synthesis of 1344)

[0274] To a solution of tert-butyl {6-chloro-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}carboxylate (2 g, 0.0039 mol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2 g, 0.0058 mol) in THF / H2O (33 ml) was added XPhosPdG3 (0.33 g, 0.0003 mol) and K3PO4 (2.5 g, 0.012 mol). The mixture was stirred at 60°C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 50% over 15 minutes, to provide tert-butyl 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindoline-2-carboxylate (2.6 g, 95% yield) as a yellow solid. LCMS: m / z [m+H]+ 696.3.

[0275] A solution of tert-butyl 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindoline-2-carboxylate (2.6 g, 0.0037 mol) in DCM / TFA (20 ml) was stirred at 25° C. for 0.1 hour. The mixture was concentrated under reduced pressure to give benzyl 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (2.2 g, 95% yield) as a yellow solid. LCMS: m / z [m+H]+ 596.3.

[0276] To a solution of 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (2.2 g, 0.0037 mol) and TEA (3.7 g, 0.037 mol) in DCM (20 ml) was added acetyl chloride (1.5 g, 0.019 mol). The mixture was stirred at 25 ° C for 0.1 hour, LCMS showed that the raw material was consumed and the required MS was detected. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 80% with EtOAc / petroleum ether and EtOAc in 15 minutes to give compound 4 (2.3 g, 92% yield) as a yellow solid. MS: m / z[M+H]+596.2.

[0277] To a solution of benzyl 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.3 g, 0.0036 mol) in MeOH (20 ml) was added Pd / C (0.77 g, 0.0072 mol). The mixture was stirred at 25° C. for 12 hours, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC, eluting with 0-100% CH3CN in water over 15 minutes to afford 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (compound 5, 1.4 g, 72% yield) as a white solid. LCMS: m / z [m+H]+ 506.3.

[0278] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (100 mg, 0.20 mmol) and TEA (40 mg, 0.40 mmol) in DCM (2 ml) was added 2-chloroethanesulfonyl chloride (39 mg, 0.24 mmol). The mixture was stirred at 25° C. for 0.1 hour. The mixture was concentrated under reduced pressure and purified by prep-HPLC, eluting with 45% to 75% CHCN in water over 8 minutes, to afford 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(vinylsulfonyl)piperidin-4-yl)isoindol-2-yl)ethan-1-one (1344 mg, 33 mg, 27% yield) as a white solid. MS: m / z [M+H]+ 596.2. 1 H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.49(s,1H),7.19-7.12(m,3H),6.89– 6.59(m,2H),6.40(d,J=27.6Hz,1H),6.20–6.08(m,2H),4.86(s,1H),4.63(d ,J=18.4Hz,2H),4.28(s,1H),3.85(s,3H),3.72–3.50(m,4H),2.87(s,2H), 2.79–2.63(m,3H),2.07–1.95(m,5H),1.88-1.85(m,2H),1.71-1.64(m,2H).

[0279] Example 1-5 (Synthesis of 1391)

[0280] To a solution of tert-butyl 6-chloro-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-carboxylate (600 mg, 1.2 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 2.3 mmol) in THF / H2O (30 mL) was added XPhos Pd G3 (197 mg, 0.23 mmol) and K3PO4 (742 mg, 3.5 mmol). The mixture was stirred at 60°C for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 30% over 20 minutes to give tert-butyl 6-{1-[(benzyloxy)carbonyl]-3,6-dihydro-2H-pyridin-4-yl}-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-carboxylate (480 mg, 53% yield) as a yellow gum.

[0281] A mixture of tert-butyl 6-{1-[(benzyloxy)carbonyl]-3,6-dihydro-2H-pyridin-4-yl}-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-carboxylate (500 mg, 0.72 mmol) in DCM / TFA = 2:1 (30 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-1H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-3,6-dibenzylhydro-2H-pyridine-1-carboxylate (450 mg, 95% yield) as a yellow gum.

[0282] To a solution of benzyl 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (450 mg, 0.76 mmol) and TEA (382 mg, 3.8 mmol) in DCM (20 mL) was added N-methylcarbamoyl chloride (106 mg, 1.1 mmol). The mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 70% in 12 minutes to give benzyl 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-(methylcarbamoyl)-1,3-dihydroisoindol-5-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 91% yield) as a yellow gum.

[0283] To a mixture of benzyl 4-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-(methylcarbamoyl)-1,3-dihydroisoindol-5-yl}-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.77 mmol) in MeOH (10 mL) was added Pd / C (408 mg, 3.8 mmol). The mixture was stirred at 25° C. under H 2 for 3 hours. The mixture was filtered and concentrated under reduced pressure to afford 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(piperidin-4-yl)-1,3-dihydroisoindole-2-carboxamide (350 mg, 79% yield) as a yellow gum.

[0284] To a solution of 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(piperidin-4-yl)-1,3-dihydroisoindole-2-carboxamide (100 mg, 0.19 mmol) and TEA (58.32 mg, 0.57 mmol) in DCM (5 ml) was added 2-chloroethanesulfonyl chloride (46.98 mg, 0.28 mmol) The mixture was stirred at 25° C. for 30 minutes. The mixture was concentrated under reduced pressure and the residue was purified by pre-HPLC eluting with 45% to 65% CH3CN in CH3CN over 18 minutes to give 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-(vinylsulfonyl)piperidin-4-yl)isoindoline-2-carboxamide (25.8 mg, 20.93% yield) as a yellow solid.

[0285] 1H NMR (400MHz, DMSO) δ7.74(s,1H),7.49(s,1H),7.37–7.05(m,3H),6.96–6.55(m,2H),6.39–6.21(m,2H),6.19–6.07(m,2H),4.61(d,J=9. 2Hz,2H),4.30(s,2H),3.86(s,3H),3.82–3.50(m,4H),2.90(d,J=20.6Hz,2H),2.77–2.54(m,6H),2.16–1.82(m,4H),1.76–1.62(m,2H).

[0286] Example 1-6 (Synthesis of 1345)

[0287] To a solution of 1-(6-((1s,4s)-4-aminocyclohexyl)-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-2-yl)ethan-1-one (15.0 mg, 0.0289 mmol) in DCM (3.0 mL) was added TEA (8.77 mg, 0.0867 mmol) and ethylenesulfonyl chloride (7.32 mg, 0.0578 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 10 minutes. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (30% to 50% CH3CN over 8 minutes) to give N-((1s,4s)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)ethylenesulfonamide (3.40 mg, 19% yield) as a white solid.

[0288] 1 H NMR (400MHz, DMSO-d6) δ7.78–7.70(m,1H),7.55–7.43(m,2H),7.25–7.15(m,2H),7.15–7.08(m ,1H),6.92–6.58(m,2H),6.43–6.34(m,1H),6.08–6.00(m,1H),5.99–5.88(m,1H),5.00–4.81(m ,1H),4.79–4.50(m,2H),4.40–4.15(m,1H),3.86(s,3H),3.62–3.50(m,2H),3.49–3.43(m,1H), 2.93–2.84(m,2H),2.58–2.54(m,1H),2.07–1.97(m,5H),1.91–1.70(m,4H),1.69–1.48(m,4H).

[0289] Example 1-7 (Synthesis of 1366 and 1367)

[0290] A solution of 8-bromo-6-chloroisoquinoline (8.6 g, 35.46 mmol) in AcOH (80 mL) was cooled to 0° C., and then NaBH 4 (2.68 g, 70.93 mmol) was added portionwise, and the mixture was stirred at 25° C. for 0.5 hours. The mixture was poured into H 2 O to quench the reaction, and then the pH was adjusted to 8 with NH 4 Cl, and the mixture was extracted with EtOAc (200 ml) to give Compound 2 (8.48 g, 34.40 mmol, 97.0% yield, crude product) as a yellow solid, which was confirmed by HNMR.

[0291] 1 H NMR (400MHz, CD3Cl) δ7.42(s,1H),7.09(s,1H),4.00(s,2H),3.15-3.18(m,2H),2.85-2.88(m,2H).

[0292] To a solution of 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline (8.48 g, 34.40 mmol) in DCM (100 mL) was added TEA (6.96 g, 68.79 mmol) and Boc2O (11.26 g, 51.60 mmol). The mixture was stirred at 25 ° C for 12 hours. The mixture was washed with brine (50 mL x 2) to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to give tert-butyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.7 g, 19.33 mmol, 56.2% yield) as a yellow oil, which was confirmed by nuclear magnetic resonance.

[0293] 1 H NMR (400MHz, CD3Cl) δ7.42(s,1H),7.10(s,1H),4.49(s,2H),3.61-3.63(m,2H),2.80-2.82(m,2H),1.50(s,9H).

[0294] A mixture of tert-butyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (29.3 g, 84.52 mmol, 29.3 mg, 84.52 mmol), 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,3,4-tetrahydroquinoline (13.35 g, 50.71 mmol), tBuONa (24.37 g, 253.57 mmol), CPHOS PD G3 (6.82 g, 8.45 mmol) and dioxane (300 mL) was degassed and replaced with N2 three times, and then the mixture was stirred at 100° C. under N2 for 2 hours. The mixture was extracted with EtOAc (200 ml) to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to give tert-butyl 6-chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (22.6 g, 42.72 mmol, 50.5%) as a yellow oil.

[0295] LCMS(ESI+):m / z 529.3(M+H)+,Rt:2.38min.

[0296] To a solution of tert-butyl 6-chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.00 g, 3.80 mmol) and 2-{1,4-dioxaspiro[4.5]dec-7-en-8-yl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.52 g, 5.70 mmol) in THF (20 mL) and H2O was added K3PO4 (2.42 g, 11.4 mmol) and XPhos Pd G3 (0.320 g, 0.380 mmol) (2.0 mL) at 25° C. The reaction mixture was stirred at 60° C. under nitrogen for 2 hours. The mixture was quenched with water (50 mL) and then extracted with ethyl acetate (80 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with THF in PE from 0% to 50% to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-yl)-6-(1,4-dioxaspiro[4.5]dec-7-ene-8-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (2.00 g, 79% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 633.3.

[0297] To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.00 g, 3.20 mmol) in MeOH (20 mL) was added Pd / C (0.680 g, 6.40 mmol). The mixture was stirred under H2 balloon pressure at 25°C for 48 hours, filtered to remove the solid, and concentrated to afford tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.70 g, 78% yield) as a white solid. LC-MS: (ESI) m / z [M+H]+ 635.3.

[0298] To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1,4-dioxaspiro[4.5]dec-8-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (1.90 g, 3.00 mmol) in DCM (8.0 mL) was added TFA (8.0 mL) at 25°C. The reaction mixture was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure to give 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclohexanone (1.40 g, crude) as a yellow solid, which was used directly in the next step without further purification. LC-MS:(ESI)m / z[M+H] + 491.3.

[0299] To a solution of 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)cyclohexanone (1.40 g, 29.0 mmol) and N-methylcarbamoyl chloride (0.680 g, 7.25 mmol) in DCM (14 mL) was added TEA (0.880 g, 8.70 mol) at 25 ° C. The reaction mixture was stirred at 25 ° C for 10 minutes. The mixture was quenched with water (50 mL) and then extracted with DCM (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in DCM from 0% to 4% to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(4-oxocyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (1.30 g, 72% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 548.2.

[0300] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(4-oxocyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (1.10 g, 2.00 mmol) in MeOH (20 mL) was added NH4Cl (0.320 g, 6.00 mmol) and NaCNBH3 (0.380 g, 6.00 mmol) at 25°C. The reaction mixture was stirred at 25°C for 16 hours, quenched with water (50 mL), and then extracted with ethyl acetate (50 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The reaction mixture was concentrated under reduced pressure and purified by reverse phase chromatography (ACN water (0.1% FA)); from 5% to 35%) to give 6-(4-aminocyclohexyl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (0.462 g, 40% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 549.2.

[0301] To a solution of 6-(4-aminocyclohexyl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (100 mg, 0.182 mmol) in DCM (6.0 mL) was added 2-chloroethanesulfonyl chloride (44.6 mg, 0.273 mmol) and TEA (55.3 mg, 0.547 mmol). The reaction mixture was stirred at 25° C. for 10 minutes. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated. The residue was purified by Prep HPLC (column: -Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O, 45-75% MeCN in 0.1% FA / water, 30 mL / min) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-((1s,4s)-4-(vinylsulfonamido)cyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (8.20 mg, 7% yield) as a white solid.

[0302] Simultaneously, 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-((1r,4r)-4-(vinylsulfonamido)cyclohexyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (26.3 mg, 22% yield) was obtained as a white solid.

[0303] Example 1-8 (Synthesis of 1346)

[0304] To a solution of tert-butyl 6-chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.567 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (292 mg, 0.851 mol) in THF (10 mL) and H2O (1.0 mL) was added K3PO4 (360 mg, 1.70 mmol) and XPhos-Pd G3 (47.9 mg, 0.0567 mmol) at 25° C. The reaction mixture was stirred at 60° C. under N2 for 2 hours. The mixture was quenched with water (100 mL) and then extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol in DCM from 0% to 5% to give 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (308 mg, 77% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 710.3.

[0305] To a solution of tert-butyl 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (308 mg, 0.434 mmol) in DCM (3.0 mL) was added TFA (3.0 mL) at 25 °C. The reaction mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure to give benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (270 mg, crude product) as a brown oil. It was used directly in the next step without further purification. LC-MS: (ESI) m / z [M+H] + 610.4.

[0306] To a solution of benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (265 mg, 0.435 mmol) in DCM (8.0 mL) was added TEA (132 mg, 0.869 mmol) at 25 °C. The reaction mixture was stirred at 25°C for 10 minutes and then concentrated under reduced pressure to give benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a white solid (260 mg, 85% yield). LC-MS: (ESI) m / z [M+H] + 627.3.

[0307] To a solution of benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.390 mmol) in MeOH (10 mL) was added Pd / C (41.5 mg, 0.390 mol). The mixture was stirred under H2 balloon pressure at 25°C for 16 hours, filtered to remove solids, and concentrated to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (160 mg, 73% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 535.3.

[0308] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (20.0 mg, 0.0374 mmol) in DCM (3.0 mL) was added TEA (11.4 mg, 0.112 mmol) and prop-2-enoyl chloride (6.77 mg, 0.0748 mmol) at 25 °C. The reaction mixture was stirred at 25°C for 30 minutes and then concentrated under reduced pressure. The residue was purified by Prep-HPLC (CH3CN from 30% to 50% in 8 minutes) to give 6-(1-acryloylpiperidin-4-yl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (compound 1346, 3.40 mg, 15% yield) as a white solid.

[0309] 1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.47(s,1H),7.10–7.00(m,3H),6.86–6.77(m,1H),6.70–6.54( m,1H),6.51–6.44(m,1H),6.17(s,1H),6.13–6.05(m,1H),5.69–5.62(m,1H),4.60–4.50(m,1H),4.4 6–4.37(m,2H),4.18–4.06(m,3H),3.86(s,3H),3.20–3.02(m,2H),2.94–2.74(m,6H),2.72–2.63(m, 2H),2.55–2.53(m,3H),2.53–2.52(m,1H),2.12–1.97(m,2H),1.85–1.75(m,2H),1.58–1.39(m,2H). 19 F NMR(400MHz,DMSO-d6)δ-108.048.LC-MS:m / z[M-40+H] + 549.3.

[0310] Example 1-9 (Synthesis of 1369)

[0311] At 25 ° C, to a solution of tert-butyl 3-iodo-1H, 4H, 6H, 7H-pyrazolo [4,3-c] pyridine-5-carboxylate (1000 mg, 2.86 mmol) in DMF (20 mL) were added benzyl 4-(methylsulfonyloxy) piperidine-1-carboxylate (1032 mg, 3.29 mmol) and potassium carbonate (1187 mg, 8.59 mmol). After addition, the mixture was stirred at 100 ° C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phase was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0% to 90% over 15 minutes to give tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (700 mg, 40% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ7.50–7.35(m,5H),5.10(s,2H),4.31–4.29(m,2H),4.15–4.10(m,4H),3.61–3. 58(m,2H),3.02–2.98(m,2H),2.75–2.70(m,2H),1.84–1.75(m,4H),1.42(s,9H).LC-MS:(ESI)m / z[M+H] + 567.1.

[0312] Tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-iodo-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 2.64 mmol), 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (836 mg, 3.17 mmol), X-phos-Pd G3 (224 mg, 0.26 mmol) and t-BuONa (763 mg, 7.94 mmol) in 1,4-dioxane (20 mL) were heated at 110 ° C for 16 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was diluted with H2O (50 mL), extracted with EtOAc (50 mL×3), washed with brine (50 mL), and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give the crude product. The residue was purified by flash chromatography (eluent: MeOH in DCM = 0-10%) to give tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 19% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 702.2.

[0313] To a solution of tert-butyl 1-(1-((benzyloxy)carbonyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (400 mg, 0.57 mmol) in DCM (4 mL) was added TFA (4 mL) at 25 °C. The mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure to give benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (300 mg, 78% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 602.3.

[0314] To a solution of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (300 mg, 0.49 mmol) in DCM (5 mL) was added N-methylcarbamoyl chloride (69 mg, 0.74 mmol) and TEA (151 mg, 1.49 mmol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 90% over 15 minutes to give benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-5-(methylcarbamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (250 mg, 68% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 659.3.

[0315] To a stirred solution of benzyl 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-5-(methylcarbamoyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)piperidine-1-carboxylate (120 mg, 0.18 mmol) in EtOH (3 mL) was added Pd / C (19 mg, 10% by weight, 0.18 mmol) followed by 1,4-dioxane / HCl (0.3 mL). The reaction mixture was stirred at 25° C. under a hydrogen atmosphere (balloon) for 5 hours. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (80 mg, 75% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 525.3.

[0316] To a solution of 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (50 mg, 0.09 mmol) in DCM (1 mL) was added 2-chloroethanesulfonyl chloride (23 mg, 0.14 mmol) and DIEA (12 mg, 0.09 mmol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase column (eluent ACN in H2O = 22-60%, 0.1% FA) to give 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(1-(ethylenesulfonyl)piperidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (compound 1369, 7 mg, 11% yield) as a white solid.

[0317] 1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.50(s,1H),7.10(s,1H),6.93–6.65(m,3H),6.54–6.52(m,1H),6.18–6.11(m,2H),4.25–4.2 3(m,1H),4.03(s,2H),3.85(s,3H),3.61–3.55(m,6H),2.95–2.75(m,4H),2.75–2.33(m,2H),2.51–2.50(m,3H),2.01–1.95(m,6H). 19 F NMR(400MHz,DMSO-d6)δppm-108.18.LC-MS:(ESI)m / z[M+H] + 615.3.

[0318] Example 1-10 (Synthesis of 1377)

[0319] To a solution of 3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(piperidin-4-yl)-4H,6H,7Hpyrazolo[4,3-c]pyridine-5-carboxamide (20 mg, 0.03 mmol) in DCM (1 mL) was added 2-chloroacetyl chloride (8 mg, 0.07 mmol) and DIEA (14 mg, 0.11 mmol) at 25° C. After addition, the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The reaction mixture was purified by preparative HPLC (0% to 100% CH3CN over 10 min) to give 1-(1-(2-chloroacetyl)piperidin-4-yl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (4.2 mg, 16% yield) as a white solid.

[0320] 1 H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.49(s,1H),7.09(s,1H),6.92–6.64(m,2H),6.56–6.55(m,1H),4.50–4.27(m ,5H),4.01–3.88(m,2H),3.86(s,3H),3.58–3.56(m,2H),2.83–2.74(m,6H),2.55–2.50(m,3H),2.03–1.76(m,6H).

[0321] Example 1-11 (Synthesis of 1378)

[0322] To a solution of 7-bromo-1,2,3,4-tetrahydroquinoline (2.0 g, 0.0094 mol), cyclopropylboranediol (1.2 g, 0.014 mol) and K 3 PO 4 (6.0 g, 0.028 mol) in toluene / H 2 O (55 mL) were added Pd (OAc) 2 (0.21 g, 0.0009 mol) and Pcy 3 (0.4 g, 0.0014 mol). Under nitrogen protection, the mixture was stirred at 110 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0 to 10% in 15 minutes to give 7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.05 g, 62% yield) as a yellow solid.

[0323] To a solution of 7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.09 g, 0.0063 mol) in CAN (40 mL) was added N-bromosuccinimide (1.12 g, 0.0063 mol) at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc / petroleum ether and EtOAc from 0 to 10% over 20 minutes to give 6-bromo-7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.1 g, 68% yield) as a yellow liquid.

[0324] To a solution of 6-bromo-7-cyclopropyl-1,2,3,4-tetrahydroquinoline (500 mg, 1.98 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (619 mg, 2.97 mmol) in dioxane / H2O (11 mL) was added K2CO3 (822 mg, 5.95 mmol) and Pd(dppf)Cl2 (145 mg, 0.20 mmol). The mixture was stirred at 90°C for 3 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0 to 20% over 15 minutes to give 7-cyclopropyl-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (380 mg, 76% yield) as a yellow gum.

[0325] To a solution of benzyl 4-{5-[(tert-butoxy)carbonyl]-3-iodo-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (1020 mg, 1.80 mmol) and 7-cyclopropyl-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (380 mg, 1.50 mmol) in 1,4-dioxane (20 mL) was added Ruphos Pd G4 (255 mg, 0.30 mmol) and t-BuONa (432 mg, 4.50 mmol). The mixture was stirred at 80 ° C for 4 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 80% in 20 minutes to give benzyl 4-{5-[(tert-butoxy)carbonyl]-3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (580 mg, 53% yield) as a yellow solid.

[0326] A mixture of benzyl 4-{5-[(tert-butoxy)carbonyl]-3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (100 mg, 0.14 mmol) in DCM / TFA (4 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give 4-{3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,5H,6H pyridin-1-yl}piperidine-1-carboxylate (80 mg, 94% yield) as a yellow gum.

[0327] To a solution of benzyl 4-{3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (80 mg, 0.14 mmol) and TEA (68 mg, 0.68 mmol) in DCM (2 mL) was added N-methylcarbamoyl chloride (38 mg, 0.41 mmol). The mixture was stirred at 25 ° C for 1 hour. LCMS showed that the starting material had been consumed and the desired mass was detected. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with THF / petroleum ether and THF from 0 to 100% in 15 minutes to give benzyl 4-{3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-5-(methylcarbamoyl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (80 mg, 87% yield) as a yellow solid.

[0328] To a solution of benzyl 4-{3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-5-(methylcarbamoyl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (90 mg, 0.1387 mmol) and Pd / C (29.52 mg, 0.2774 mmol) in ethanol (5 mL) was added HCl in dioxane (0.1 mL). The mixture was stirred at 25° C. for 2 hours. LCMS showed that the starting material had been consumed, and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give 3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (70 mg, 98% yield) as a yellow gum.

[0329] To a solution of 3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (70 mg, 0.14 mmol) and TEA (83 mg, 0.82 mmol) in DCM (3 mL) was added 2-chloroethanesulfonyl chloride (44 mg, 0.27 mmol). The mixture was stirred at 25 ° C for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC eluting with 43% to 53% CH3CN in CH3CN in 10 min to give 3-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[1-(ethylenesulfonyl)piperidin-4-yl]-N-methyl-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (12 mg, 12% yield) as a grey solid.

[0330] 1 H NMR(400MHz,dmso-d6)δ7.88(s,1H),7.65(s,1H),6.99(s,1H),6.99-6.84(m, 1H),6.24–6.08(m,3H),5.58-5.24(m,1H),4.26–4.17(m,1H),3.97(s,2H),3.8 7(s,3H),3.67–3.57(m,4H),3.55–3.50(m,2H),2.90–2.81(m,3H),2.78–2.69 (m,4H),2.54(s,3H),2.01–1.84(m,7H),0.84–0.73(m,2H),0.41–0.31(m,2H).

[0331] Example 1-12 (Synthesis of 1379)

[0332] To a solution of 7-bromo-1,2,3,4-tetrahydroquinoline (2.3 g, 0.011 mol) and potassium ferricyanide (II) (2.3 g, 0.0054 mol) in 1,4-dioxane / H2O=1:1 (8 mL) was added XPhos (0.51 g, 0.0010 mol), XPhos Pd G3 (0.9 g, 0.001 mol) and palladium diacetate (7.3 g, 0.032 mol). Under nitrogen, the mixture was stirred at 110 ° for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0 to 10% in 20 minutes to give 1,2,3,4-tetrahydroquinoline-7-carbonitrile (1.3 g, 71% yield) as a yellow solid.

[0333] To a solution of 1,2,3,4-tetrahydroquinoline-7-carbonitrile (1.3 g, 0.0079 mol) in DCM (50 mL) was added N-bromosuccinimide (1.4 g, 0.0079 mol) at 0 ° C. The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue was eluted with 0 to 10% EtOAc / petroleum ether and EtOAc on silica gel chromatography over 20 minutes to give 6-bromo-1,2,3,4-tetrahydroquinoline-7-carbonitrile (0.4 g, 22% yield) as a yellow solid.

[0334] To a solution of 6-bromo-1,2,3,4-tetrahydroquinoline-7-carbonitrile (340 mg, 1.43 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (418 mg, 2.01 mmol) in 1,4-dioxane / H2O (22 mL) was added K2CO3 (595 mg, 4.30 mmol) and Pd(dppf)Cl2 DCM (234 mg, 0.29 mmol). The mixture was stirred at 90 ° C for 3 hours. The mixture was concentrated under reduced pressure. The residue was chromatographed on silica gel using EtOAc / petroleum ether and 0 to 50% EtOAc over 20 minutes to give 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-7-carbonitrile (270 mg, 79% yield) as a white solid.

[0335] To a solution of 4-{5-[(tert-butoxy)carbonyl]-3-iodo-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylic acid benzyl ester (742 mg, 1.31 mmol) and 6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-7-carbonitrile (250 mg, 1.05 mmol) in 1,4-dioxane (25 mL) was added t-BuONa (377 mg, 3.93 mmol) and Ruphos Pd G4 (223 mg, 0.26 mmol). The mixture was stirred at 80 ° C for 6 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 80% in 20 minutes to give benzyl 4-{5-[(tert-butoxy)carbonyl]-3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (320 mg, 34% yield) as a yellow solid.

[0336] A mixture of benzyl 4-{5-[(tert-butoxy)carbonyl]-3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (100 mg, 0.15 mmol) in DCM / TFA (2 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give 4-{3-[7-cyano-6-(1-ethylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,5H,6H-,7H-pyrazolo-4,3-c>pyridin-1-yl}piperidine-1-carboxylate (80 mg, 89% yield) as a yellow gum.

[0337] To a solution of benzyl 4-{3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (80 mg, 0.14 mmol) and TEA (70 mg, 0.69 mmol) in DCM (2 mL) was added N-methylcarbamoyl chloride (39 mg, 0.42 mmol). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with THF / petroleum ether and THF from 0 to 100% in 20 minutes to give benzyl 4-{3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-5-(methylcarbamoyl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (70 mg, 76% yield) as a yellow solid.

[0338] To a solution of benzyl 4-{3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-5-(methylcarbamoyl)-4H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}piperidine-1-carboxylate (50 mg, 0.079 mmol) in ethanol (5 mL) was added Pd / C (25 mg, 0.24 mmol). The mixture was stirred at 25 ° C for 3 hours. The mixture was filtered and concentrated under reduced pressure to give 3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (40 mg, 96% yield) as a yellow solid.

[0339] To a solution of 3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-1-(piperidin-4-yl)-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (40 mg, 0.080 mmol) and TEA (41 mg, 0.40 mmol) in DCM (5 mL) was added 2-chloroethanesulfonyl chloride (26 mg, 0.16 mmol). The mixture was stirred at 25 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC eluting with 40% to 50% aqueous CH3CN and CH3CN over 10 minutes to give 3-[7-cyano-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1-[1-(ethylenesulfonyl)piperidin-4-yl]-N-methyl-4H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxamide (40 mg, 80% yield) as a yellow solid.

[0340] 1H NMR(400MHz,dmso-d6)δ8.04(s,1H),7.77(s,1H),7.33(s,1H),6.87-6.82(m,1H),6.67(s,1H),6.53(d,J=4.8Hz,1H),6.16-6.09(m,2H),4.2 6–4.16(m,1H),4.01(d,J=9.6Hz,2H),3.86(s,3H),3.59-3.52(m,6H), 2.85(d,J=5.6Hz,4H),2.70(s,2H),2.53(d,J=4.8Hz,3H),1.95(s,6H).

[0341] Example 1-13 (Synthesis of 1374 and 1375)

[0342] At 25 ° C, TEA (6.38 g, 63.21 mmol) and MsCl (4.34 g, 37.92 mmol) were added to a DCM (50 mL) solution of 1,4-dioxyaspirino [4.5] decan-8-ol (2 g, 12.64 mmol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give 1,4-dioxyaspirino [4.5] decan-8-yl methanesulfonate (2 g, 63% yield) as a yellow solid.

[0343] To a solution of tert-butyl 3-iodo-1H, 4H, 6H, 7H pyrazolo[4,3-c]pyridine-5-carboxylate (2.0 g, 5.72 mmol) in DMF (20 mL) was added Cs2CO3 (5.59 g, 17.18 mmol) and 1,4-dioxaspiro[4.5]decane-8-yl methanesulfonate (1.75 g, 7.44 mmol) at 25 ° C. After addition, the mixture was stirred at 100 ° C for 8 hours. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give tert-butyl 3-iodo-1-(1,4-dioxaspirino[4.5]dec-8-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.5 g, 50% yield) as a yellow solid.

[0344] A mixture of tert-butyl 3-iodo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.2 g, 2.45 mmol), RuPhosPdG4 (208 mg, 0.24 mmol), 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (645 mg, 2.45 mmol) and t-BuONa (706 mg, 7.35 mmol) in dioxane (20 mL) was stirred at 25 ° C under nitrogen. The mixture was heated to 100 ° C and stirred at this temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether from 0 to 80% EtOAc in 15 minutes to give tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1,4-dioxaspirino[4.5]dec-8-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (0.8 g, 45% yield) as a yellow solid.

[0345] To a solution of tert-butyl 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(1,4-dioxaspirino[4.5]dec-8-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (100 mg, 0.16 mmol) in DCM (2 mL) was added TFA (1 mL) at 25° C. After addition, the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% over 15 minutes to give 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexan-1-one (70 mg, 81% yield) as a yellow solid.

[0346] To a solution of 4-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazino[4,3-c]pyridin-1-yl)cyclohexan-1-one (270 mg, 0.56 mmol) in DCM (5 mL) was added DIEA (217 mg, 1.6857 mmol) and N-methylcarbamoyl chloride (78 mg, 0.84 mmol) at 25° C. After the addition, the mixture was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(4-oxocyclohexyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (230 mg, 68% yield) as a yellow solid.

[0347] To a solution of 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-(4-oxocyclohexyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (300 mg, 0.55 mmol) in methanol (5 mL) was added NH4Cl (149 mg, 2.79 mmol) and NaCNBH3 (175 mg, 2.79 mmol) at 25°C. After the addition, the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give 1-(4-aminocyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (200 mg, 59% yield) as a yellow solid.

[0348] To a solution of 1-(4-aminocyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (60 mg, 0.11 mmol) in DCM (2 mL) was added DIEA (43 mg, 0.34 mmol) and 2-chloroethanesulfonyl chloride (36 mg, 0.22 mmol) at 25° C. After the addition, the mixture was stirred at 25° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure. The reaction mixture was purified by preparative HPLC (0% to 80% CH3CN over 10 min) to give 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-1-((1r,4r)-4-(vinylsulfonyl)cyclohexyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (3 mg, 4% yield) and 3-(7-(1s,4s)-4-(vinylsulfonyl)cyclohexyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (1.5 mg, 2% yield) as white solids.

[0349] 1374:1H NMR(400MHz,DMSO-d6)δ7.74(s,1H),7.50(s,1H),7.37(s,1H),7.09(s,1H),6.79–6.64(m,3H),6.53(s,1H),6.06–5.92(m,2H),4.00– 3.98(m,3H),3.86(s,3H),3.55–3.52(m,2H),3.01(s,1H),2.88–2.71(m,4H),2.55–2.50(m,3H),2.01–1.82(m,8H),1.45–1.24(m,4H).

[0350] 1375:1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.50(s,1H),7.33(s,1H),7.09(s,1H),6.72–6.65(m,3H),6.53(s,1H),6.05–5.94(m,2H),4.06–4.00(m,3 H),3.86(s,3H),3.58–3.55(m,2H),3.33(s,1H),2.71–2.67(m,4H),2.5 5–2.50(m,3H),2.12–1.85(m,6H),1.70–1.65(m,4H),1.24–1.23(m,2H).

[0351] Example 1-14 (Synthesis of 1383)

[0352] A solution of 1-(4-aminocyclohexyl)-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-4H,6H,7H pyrazolo[4,3-c]pyridine-5-carboxamide (40 mg, 0.074 mmol) and furan-2,5-dione (15 mg, 0.15 mmol) in DCM (2 mL) was stirred at 40 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue and sodium acetate (6 mg, 0.074 mmol) were added to acetic anhydride (2 mL). The mixture was stirred at 100 ° C for 2 hours. The mixture was purified by pre-HPLC eluting with 50% to 80% aqueous CH3CN and CH3CN over 10 minutes to give 3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-((1r,4r)-4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)cyclohexyl)-N-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxamide (5 mg, 10% yield) as a yellow solid.

[0353] 1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.50(s,1H),7.09(s,1H),6.99(s,2H),6.92(s ,0.25H),6.80(d,J=13.6Hz,1.5H),6.64(s,0.25H),6.54(d,J=4.4Hz,1H),4.01(s,2 H),3.86(s,3H),3.59(d,J=5.2Hz,4H),2.84(s,2H),2.76(s,2H),2.54(d,J=4.8Hz, 4H), 2.20 (d, J = 12.4Hz, 1H), 1.96-1.86 (m, 7H), 1.74 (d, J = 10.4Hz, 2H), 1.23 (s, 2H).

[0354] Example 1-15 (Synthesis of 1387 and 1388)

[0355] To a solution of 4-{3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-1-yl}cyclohexan-1-one (900 mg, 1.87 mmol) in DCM (20 mL) was added DIEA (726 mg, 5.61 mmol) and acetyl chloride (220 mg, 2.81 mmol) at 25° C. After addition, the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexan-1-one (900 mg, 82% yield) as a yellow solid.

[0356] To a solution of 4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazino[4,3-c]pyridin-1-yl)cyclohexan-1-one (400 mg, 0.76 mmol) in methanol (10 mL) was added NH4Cl (204 mg, 3.82 mmol) and sodium cyanoborohydride (240 mg, 3.82 mmol) at 25°C. After the addition, the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether and EtOAc from 0 to 90% in 15 minutes to give 1-(1-(4-aminocyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (200 mg, 47% yield) as a yellow solid.

[0357] To a solution of 1-(1-(4-aminocyclohexyl)-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one (200 mg, 0.38 mmol) in DCM (5 mL) was added DIEA (148 mg, 1.14 mmol) and 2-chloroethanesulfonyl chloride (80 mg, 0.49 mmol) at 25° C. After the addition, the mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (10% to 70% in 10 min using CH3CN) to give N-((1r,4r)-4-(5-acetyl-3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)ethylenesulfonamide (24 mg, 9% yield) and N-(1s,4s)-4-(5-acetyl-3-2H)-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)ethylenesulfonamide (12 mg, 4% yield) as white solids.

[0358] 1387:1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.36(s,1H),7.30(s,1H),7.09(s,1H),6.79–6.64(m,3H),6.07–6.03(m,1H),5.95–5.92(m,1H),4.25–4.11 (m,2H),4.01(s,1H),3.86(s,3H),3.74–3.65(m,2H),3.55–3.50(m,2H) ,3.01(s,1H),2.80–2.73(m,4H),2.07–1.80(m,11H),1.45–1.42(m,2H).

[0359] 1388:1H NMR(400MHz,DMSO-d6)δ7.75(s,1H),7.50(s,1H),7.33(s,1H),7.10(s,1H),6.73–6.66(m,3H),6.05–5.94(m,2H),4.15–4.10(m ,3H),3.86(s,3H),3.75–3.62(m,4H),3.33(s,1H),2.84–2.72(m,4H),2.10–2.07(m,4H),1.97–1.86(m,5H),1.70–1.65(m,4H).

[0360] Example 1-16 (Synthesis of 1384)

[0361] To a DCM (2 mL) solution of 1-[6-(4-aminocyclohexyl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl] ketene (40 mg, 0.077 mmol) and furan-2,5-dione (15 mg, 0.15 mmol) was added. The mixture was stirred at 40 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue and sodium acetate (19 mg, 0.23 mmol) were added to acetic anhydride (2 mL). The mixture was stirred at 100 ° C for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC using aqueous CH3CN eluting with 57% to 70% CH3CN over 9 minutes to afford 1-((1s,4s)-4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)-1H-pyrrole-2,5-dione as a yellow solid (3.8 mg, 8% yield).

[0362] 1H NMR (400MHz, DMSO-d6) δ7.74(d,J=3.6Hz,1H),7.49(s,1H),7.30(d,J=10.4Hz,1H),7.24(d,J=9.6Hz,1H) ,7.13(s,1H),6.92(d,J=3.6Hz,2H),6.86(s,0.25H),6.72(s,0.5H),6.58(s,0.25H),6.45(d,J=26.4Hz,1 H),4.89(s,1H),4.66(d,J=18.4Hz,2H),4.31(s,1H),3.96-9-3.92(m,1H),3.86(s,3H),3.60(d,J=5.6Hz, 2H),3.03(s,1H),2.89(s,2H),2.22(d,J=10.4Hz,2H),2.13–1.98(m,7H),1.87–1.76(m,2H),1.51(s,2H).

[0363] Example 1-17 (Synthesis of 1385)

[0364] A solution of 1-[6-(4-aminocyclohexyl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl] ketene (50 mg, 0.096 mmol) and furan-2,5-dione (9 mg, 0.096 mol) in DCM (2 mL) was stirred at 40 ° C for 1 hour. The mixture was concentrated under reduced pressure. The residue and sodium acetate (6 mg, 0.067 mmol) were added to acetic anhydride (2 mL). The mixture was stirred at 140 ° C for 2 hours. The mixture was purified by pre-HPLC eluting with 50% to 80% aqueous CH3CN and CH3CN over 10 minutes to give 1-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}cyclohexyl)pyrrole-2,5-dione (12 mg, 21% yield) as a white solid.

[0365] 1H NMR (400MHz, DMSO-d6) δ7.75(s,1H),7.49(s,1H),7.20-7.15(m,2H),7.12(s,1H),6.98(d,J=2.8 Hz,2H),6.87-6.60(m,1H),6.41(d,J=27.6Hz,1H),4.85(s,1H),4.64-4.60(m,2H),4.27(s,1H), 3.98–3.90(m,1H),3.87(d,J=10.4Hz,3H),3.61–3.50(m,2H),2.88(s,2H),2.20–2.09(m,2H),2. 05–1.95(m,5H),1.90(d,J=8.4Hz,2H),1.77–1.66(m,2H),1.65–1.55(m,2H),1.25-1.20(m,1H).

[0366] Example 1-18 (Synthesis of 1370)

[0367] To a solution of 4-bromo-1-fluoro-2-nitrobenzene (3.00 g, 0.0136 mol) and (3,5-dimethyl-1,2-oxazol-4-yl)boryl alkynediol (2.30 g, 0.0163 mol) in 1,4-dioxane (30 mL) and H₂O (6.0 mL) was added K₂CO₃ (5.64 g, 0.0408 mol) and Pd(dppf)Cl₂˙DCM (1.11 g, 0.00136 mol). The reaction mixture was stirred at 90°C under N₂ for 16 hours. The mixture was quenched with water (50 mL) and then extracted with ethyl acetate (80 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with THF in PE from 0% to 30% to give 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.70 g, 81% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 273.1.

[0368] At 25 ℃, to 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.50g, 0.0106mol) and N-(4-aminocyclohexyl) tert-butyl carbamate (2.50g, 0.0116mol) in ACN (50mL) solution, add K CO (3.66g, 0.0265mol).The reaction mixture was stirred at 80 ℃ for 3 hours.The mixture was quenched with water (50mL), then extracted with ethyl acetate (80mL x 2).The organic phase merged was dried over sodium sulfate and filtered.The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in petroleum from 0% to 25% to give tert-butyl ((1r,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexyl)carbamate (3.90 g, 81% yield) as a red solid. LC-MS: (ESI) m / z [M+H] + 431.2.

[0369] To a solution of tert-butyl ((1r, 4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)cyclohexyl)carbamate (1.80 g, 0.00420 mol) in THF (36 mL) and H2O (36 mL) was added Na2S2O3 (9.13 g, 0.0462 mol) and ammonium hydroxide (10.8 g, 0.0924 mol). The reaction mixture was stirred at 25 ° C. under N2 for 3 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in petroleum from 0% to 50% to give tert-butyl ((1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexyl)carbamate (1.40 g, 78% yield) as a red solid. LC-MS: (ESI) m / z [M+H] + 401.2.

[0370] To a solution of (2S)-6-oxopiperidine-2-carboxylic acid (0.550 g, 3.85 mmol) in DMF (14 mL) were added HATU (1.46 g, 3.85 mmol), tert-butyl ((1r,4r)-4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)cyclohexyl)carbamate (1.40 g, 3.50 mmol), and TEA (0.530 g, 5.25 mmol). The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was added to water (50 mL), the aqueous phase was extracted with ethyl acetate (60 mL x 2), and the combined organic phases were washed with aqueous NaCl (20 mL x 3) and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in DCM from 0% to 6% to give tert-butyl ((1S,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidine-2-carboxamido)phenyl)amino)cyclohexyl)carbamate (1.80 g, 94% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 526.3.

[0371] To a solution of tert-butyl ((1S,4r)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidine-2-carboxamido)phenyl)amino)cyclohexyl)carbamate (1.60 g, 0.00300 mol) in DCM (8.0 mL) was added TFA (8.0 mL) at 25°C. The reaction mixture was stirred at 25°C for 30 minutes. The filtrate was concentrated under reduced pressure to give (S)-N-(2-((((1r,4S)-4-aminocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide (1.20 g, crude), which was used directly in the next step as a yellow oil without further purification. LC-MS: (ESI) m / z [M+H] + 426.2.

[0372] (S)-N-(2-((((1r,4S)-4-aminocyclohexyl)amino)-5-(3,5-dimethylisoxazol-4-yl)phenyl)-6-oxopiperidine-2-carboxamide (1.20 g, 0.00280 mol) was dissolved in AcOH (12 mL) at 25°C. The reaction mixture was stirred at 65°C for 72 hours, then concentrated under reduced pressure and purified by reverse phase chromatography (ACN-water (0.1% NH3HCO3)); from 5% to 25%) to afford (S)-6-(1-((1r,4S)-4-aminocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (0.860 g, 71% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 408.2.

[0373] To a solution of (S)-6-(1-((1r, 4S)-4-aminocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (131 mg, 0.322 mmol) in DCM (6.0 mL) was added 2-chloroethanesulfonyl chloride (78.6 mg, 0.482 mmol) and TEA (97.6 mg, 0.965 mmol). The reaction mixture was stirred at 25 ° C for 30 minutes. LCMS showed that the starting material was consumed and the desired compound was detected. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in DCM from 0% to 25% to afford N-((1S,4r)-4-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidin-2-yl)-1H-benzimidazol-1-yl)cyclohexyl)ethanesulfonamide (80.0 mg, 45% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 498.2.

[0374] DBU (25.4 mg, 0.161 mmol) was added to a solution of N-((1S, 4r)-4-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidin-2-yl)-1H-benzimidazol-1-yl)cyclohexyl)ethanesulfonamide (80.0 mg, 0.161 mmol) in DCM (14 mL) and stirred for 10 minutes. CU-TMEDA catalyst (14.9 mg, 0.0322 mmol) was added, sonicated and stirred for 10 minutes. (3,4-difluorophenyl)borylene diol (25.4 mg, 0.161 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep HPLC (column: -Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O, 45-75% MeCN in 0.1% FA / water, 30 mL / min) to give N-((1S,4r)-4-(2-((S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl)ethanesulfonamide (compound 1370, 10.0 mg, 10% yield) as a white solid.

[0375] 1 H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.4Hz,1H),7.69(d,J=1.4Hz,1H),7.46(d,J=6.8Hz,1H), 7.42–7.29(m,2H),7.16–7.10(m,1H),7.10–7.01(m,1H),6.83–6.74(m,1H),6.09(d,J=16.4H z,1H),5.97(d,J=10.0Hz,1H),5.83–5.73(m,1H),4.40–4.25(m,1H),3.36–3.33(m,1H),2.6 4–2.52(m,2H),2.45–2.12(m,10H),2.04–1.89(m,4H),1.84–1.74(m,2H),1.58–1.46(m,2H). 19 F NMR(400MHz,DMSO-d6)δ-137.907,-140.684.LC-MS:(ESI)m / z[M+H] + 610.2.

[0376] Example 1-19 (Synthesis of 1371)

[0377] To a solution of (S)-6-(1-((1r, 4S)-4-aminocyclohexyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (220 mg, 0.540 mmol) in DCM (8.0 mL) was added propenyl chloride (73.3 mg, 0.810 mmol) and TEA (164 mg, 1.62 mmol) at 25 ° C. The reaction mixture was stirred at 25 ° C for 10 minutes. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 6% to give N-((1S,4r)-4-(5-(3,5-dimethylisoxazol-4-yl)-2-((S)-6-oxopiperidin-2-yl)-1H-benzo[d]imidazol-1-yl)cyclohexyl)acrylamide (180 mg, 71% yield) as a white solid.

[0378] DBU (58.0 mg, 0.381 mmol) was added to a DCM (6.0 mL) solution of N-{4-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-2-[(2S)-6-oxopiperidin-2-yl]-1,3-benzodiazol-1-yl]cyclohexyl}prop-2-eneamide (80.0 mg, 0.173 mmol) and stirred for 10 minutes. CU-TMEDA CATALYST (16.1 mg, 0.0346 mmol) was added, sonicated and stirred for 10 minutes, (3,4-difluorophenyl)boronic acid diol (30.1 mg, 0.191 mmol) was added, and the reaction was stirred at 25 ° C for 16 hours. LCMS showed that the starting material was consumed and the desired compound was detected. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatographic column: -Xbridge-C18 150x 19mm, 5um mobile phase: ACN-H2O, 45-75% MeCN in 0.1% FA / water, 30mL / min) to give a white solid N-(4-{2-[(2S)-1-(3,4-difluorophenyl)-6-oxopiperidin-2-yl]-5-(3,5-dimethyl-1,2-oxazol-4-yl)-1,3-benzodiazol-1-yl}cyclohexyl)prop-2-enamide (13.2 mg, 13% yield).

[0379] 1H NMR (400MHz, DMSO-d6) δ8.05(d,J=7.6Hz,1H),7.89(d,J=8.5Hz,1H),7.70(d,J=1.4Hz,1H), 7.44–7.28(m,2H),7.15(dd,J=8.5,1.6Hz,1H),7.07–6.99(m,1H),6.32–6.21(m,1H),6.16–6 .06(m,1H),5.82–5.71(m,1H),5.64–5.56(m,1H),4.42–4.26(m,1H),3.96–3.80(m,1H),2.6 1–2.55(m,2H),2.46–2.15(m,10H),2.09–1.88(m,4H),1.85–1.72(m,2H),1.52–1.39(m,2H).

[0380] Example 1-20 (Synthesis of 1373)

[0381] At 25 ° C, to 4-bromo-1-fluoro-2-nitrobenzene (3.00g, 0.0136mol) and (3,5-dimethyl-1,2-oxazol-4-yl) borane (2.30g, 0.01mol) in 1,4-dioxane (30mL) and H2O (6.0mL) solution, K2CO3 (5.64g, 0.0408mol) and Pd (dppf) Cl2DCM (1.11g, 0.00136mol) were added. The reaction mixture was stirred at 90 ° C under N2 for 16 hours. The mixture was quenched with water (50mL) and extracted with ethyl acetate (80mL x 2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 30% THF in PE to afford 4-(4-fluoro-3-nitrophenyl)-3,5-dimethylisoxazole (2.70 g, 81% yield) as a white solid.

[0382] At 25 ℃, to 4-(4-fluoro-3-nitrophenyl)-3,5-dimethyl-1,2-oxazole (1.32g, 0.00560mol) and 4-aminopiperidine-1-tert-butyl formate (1.35g, 0.00672mol) in ACN (12mL) solution, KCO (1.93g, 0.0140mol) was added. The reaction mixture was stirred at 80 ℃ for 16 hours. The mixture was quenched with water (50mL) and then extracted with ethyl acetate (80mL x 2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in petroleum from 0% to 25% to give tert-butyl 4-((4-(3,5-dimethylisoxazol-4-yl)-2-nitrophenyl)amino)piperidine-1-carboxylate (2.00 g, 82% yield) as a red solid.

[0383] At 25 ℃, to 4-{[4-(3,5-dimethyl-1,2-oxazol-4-yl)-2-nitrophenyl] amino} piperidine-1-carboxylic acid tert-butyl ester (1.90g, 0.00460mol) in THF (38mL) and H2O (38mL) solution, Na2S2O3 (10.0g, 0.0506mol) and ammonium hydroxide (11.8g, 0.101mol) were added. The reaction mixture was stirred at 25 ℃ under N2 for 3 hours. The mixture was quenched with water (50mL) and extracted with ethyl acetate (60mL x2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc in petroleum from 0% to 50% to give tert-butyl 4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidine-1-carboxylate (1.30 g, 72% yield) as a red solid.

[0384] To a solution of (2S)-6-oxopiperidine-2-carboxylic acid (530 mg, 3.70 mmol) in DMF (13 mL) was added HATU (1407 mg, 3.70 mmol), tert-butyl 4-((2-amino-4-(3,5-dimethylisoxazol-4-yl)phenyl)amino)piperidine-1-carboxylate (1300 mg, 3.36 mmol), and TEA (511 mg, 5.05 mmol) at 25°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was added to water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with aqueous NaCl (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0% to 6% MeOH in DCM to give (S)-tert-butyl 4-(((4-(3,5-dimethylisoxazol-4-yl)-2-(6-oxopiperidine-2-carboxamido)phenyl)amino)piperidine-1-carboxylate (1300 mg, 94% yield) as a white solid.

[0385] To a solution of tert-butyl (S)-4-((4-(3,5-dimethylisoxazol-4-yl)-2-(6-oxopiperidine-2-carboxamido)phenyl)amino)piperidine-1-carboxylate (1.30 g, 0.00250 mol) in DCM (8 mL) was added TFA (8 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 30 min. The filtrate was concentrated under reduced pressure to give (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-4-ylamino)phenyl)-6-oxopiperidine-2-carboxamide (1.00 g, crude) as a yellow oil, which was used in the next step without further purification.

[0386] To a solution of (S)-N-(5-(3,5-dimethylisoxazol-4-yl)-2-(piperidin-4-ylamino)phenyl)-6-oxopiperidine-2-carboxamide (1.00 g, 0.00240 mol) in AcOH (8 mL) was added at 25°C. The reaction mixture was stirred at 65°C for 72 hours. The reaction was concentrated under reduced pressure and purified by reverse phase chromatography (ACN-Water (0.1% NH3HCO3); 5% to 25%) to give (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (0.580 g, 54% yield) as a white solid.

[0387] At 25 ° C, to a solution of (S) -6- (5- (3,5- dimethylisoxazol-4-yl) -1- (piperidin-4-yl) -1H- benzo [d] imidazoles -2-yl) piperidin-2-one (300 mg, 0.762 mmol) in DCM (6.0 mL) was added 2- chloroethanesulfonyl chloride (186 mg, 1.14 mmol) and TEA (231 mg, 2.29 mmol). The reaction mixture was stirred at 25 ° C for 30 minutes. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (30 mL x2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 25% to give (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(vinylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (90.0 mg, 23% yield) as a white solid.

[0388] DBU (62.3 mg, 0.409 mmol) was added to a solution of (S)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(vinylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (90.0 mg, 0.186 mmol) in DCM (6.0 mL) and stirred for 10 minutes. CU-TMEDA CATALYST (34.6 mg, 0.0744 mmol) was added, sonicated and stirred for 10 minutes, and (3,4-difluorophenyl)boranediol (58.8 mg, 0.372 mmol) was added. The reaction was stirred at 25 ° C for 16 hours. The mixture was quenched with water (20 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: -Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O, 45-75% MeCN in 0.1% FA / water, 30 mL / min) to give (S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(vinylsulfonyl)piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one (9.20 mg, 10% yield) as a white solid.

[0389] 1H NMR(400MHz, DMSO-d6)δ7.72(s,1H),7.68(d,J=8.4Hz,1H),7.41–7.28(m,2H),7.25–7.16(m,1H),7.07–7.01(m,1H),7.01–6.88(m 1H),6.31–6.10(m,2H),5.58–5.69(m,1H),4.64–4.51(m,1H),3.77–3.64(m,2H ),2.94–2.83(m,2H),2.58–2.54(m,2H),2.46–2.14(m,10H),2.09–1.76(m,4H).

[0390] The following compounds were prepared by the methods of Reference Examples 1-1 to 1-20:

[0391] Example 2-1

[0392] To a solution of 7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (18 g, 98.2 mmol, 1 eq) in DCM (180 ml) at 0°C was added NBS (17.5 g, 98.2 mmol, 1 eq). The mixture was stirred at 25°C for 16 hours, quenched with H2O (200 mL), extracted with DCM (150 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 10%) to give 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (16 g, 61.1 mmol, 62.1% yield) as a yellow solid.

[0393] MS (ESI): 262.6 (M+H) + .

[0394] 1 H NMR (400MHz, CDCl3) δ = 7.18 (s, 1H), 7.04 (s, 1H), 6.63 (s, 1H), 4.09-3.82 (m, 1H), 3.28-3.18 (m, 2H), 2.66 (br t, J = 6.3Hz, 2H), 1.88-1.79 (m, 2H)

[0395] A mixture of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (11 g, 41.9 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.7 g, 41.9 mmol, 1 eq), Pd(dppf)Cl2 (3.0 g, 4.2 mmol, 0.1 eq), K2CO3 (11.6 g, 83.9 mmol, 2 eq) in 1,4-dioxane (80 mL) and H2O (20 mL) was stirred at 110°C under N2 protection for 12 hours. After concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 40%) to give 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (INT-9, 10 g, 37.9 mmol, 90.5% yield) as a brown solid.

[0396] MS (ESI): 263.9 (M+H) + .

[0397] 1 H NMR (400MHz, DMSO-d6)δ=7.68(s,1H),7.43(s,1H),6.90(s,1H),6.73(s,1H),6.01(s,1H),3.84(s,3H),3.24-3.14(m,2H),2.68(br t,J=6.0Hz,2H),1.79(quin,J=5.9Hz,2H).

[0398] Example 2-2 (Synthesis of 2001)

[0399] To a solution of 5-chloro-2-methylbenzoic acid (50 g, 293.1 mmol, 1 eq) in concentrated sulfuric acid (350 mL) was added dropwise a solution of NIS (76 g, 331 mmol, 1.13 eq) in sulfuric acid (30 mL) at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction was poured into ice water (500 mL) and stirred for 30 minutes, then filtered to afford 5-chloro-3-iodo-2-methylbenzoic acid (68.5 g, 231 mmol, 78.8% yield) as a brown solid.

[0400] MS (ESI): 294.8 (MH) + .

[0401] To a solution of 5-chloro-3-iodo-2-methylbenzoic acid (68.5 g, 231 mmol, 1 eq) in MeOH (350 mL) was added concentrated H2SO4 (12 mL). The mixture was stirred at 60 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (300 mL), and the organic phases merged were washed with NaHCO3 aqueous solution (200 mL) and salt solution (200 mL), and dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 5-chloro-3-iodo-2-methylbenzoate (58.5 g, 188.4 mmol, 81.5% yield) as a yellow oil.

[0402] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.98 (d, J = 2.0Hz, 1H), 7.76 (d, J = 1.8Hz, 1H), 3.92 (s, 4H), 2.64 (s, 3H).

[0403] To the CCl4 (350ml) solution of 5-chloro-3-iodo-2-methylbenzoic acid methyl ester (55g, 177.12mmol, 1eq), add NBS (33g, 185.41mmol, 1.05eq) and BPO (4.5g, 18.58mmol, 1e-1eq). The mixture was stirred at 80 ℃ for 17 hours. The reaction mixture was filtered and concentrated under reduced pressure. Resistates obtained by column chromatography (petroleum ether / ethyl acetate=100 / 0 to 10 / 1) as a colorless oily compound 2-(bromomethyl)-5-chloro-3-iodobenzoic acid methyl ester (40g, 103.1mmol, 57% productive rate).

[0404] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.97 (d, J = 2.2Hz, 1H), 7.84 (d, J = 2.2Hz, 1H), 5.01 (s, 2H), 3.89 (s, 3H).

[0405] Compound 2-(bromomethyl)-5-chloro-3-iodobenzoic acid methyl ester (40 g, 102.5 mmol, 1 eq) was added to NH3 / MeOH (150 ml) solution. The mixture was stirred at 60 ° C for 2.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was washed 3 times with EA (150 mL) to obtain compound 2-(bromomethyl)-5-chloro-3-iodobenzoic acid methyl ester (20.6 g, 70.4 mmol, 68.5% yield) in the form of a white solid. MS (ESI): 295.8 (M+H) + .

[0406] 1H NMR (400MHz, DMSO-d6) δ = 8.96 (br s, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 4.18 (s, 2H)

[0407] To a solution of methyl 2-(bromomethyl)-5-chloro-3-iodobenzoate (17 g, 57.92 mmol, 1 eq) in DCM (150 mL) was added dropwise DIBALH (1 M, 202.73 mL, 3.5 eq) at 0°C under nitrogen. The mixture was stirred at 45°C for 54 hours. 100 mL of 15% NaOH was added at 0°C to quench the reaction, followed by filtration and washing with EtOAc. The filtrate was washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (silica gel flash column, 0-10% MeOH / DCM eluent) to give 6-chloro-4-iodoisoindole (5.5 g, 19.6 mmol, 33.9%) as a brown solid.

[0408] 1 H NMR (400MHz, DMSO-d6) δ = 7.64 (s, 1H), 7.37 (s, 1H), 4.20 (s, 2H), 3.93 (s, 2H).

[0409] To a solution of 6-chloro-4-iodoisoindole (4.5 g, 16.1 mmol, 1 eq) and TEA (4.1 g, 40.3 mmol, 5.6 mL, 2.5 eq) in DCM (80 mL) was added dropwise acetic anhydride (2.46 g, 24.1 mmol, 2.26 mL, 1.5 eq) at 0°C under N2 protection. The mixture was stirred at 25°C for 16 hours. The residue was diluted with H2O (100 mL) and extracted with DCM (40 mL*2). The combined organic layers were washed with saturated brine (40 mL*2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient elution) to give 1-(6-chloro-4-iodoisoindol-2-yl)ethan-1-one (3.25 g, 8.2 mmol, 51% yield, 70% purity) as a brown solid. MS (ESI): 322.3 (M+H) + .

[0410] The compound 1-(6-chloro-4-iodoisoindol-2-yl)ethan-1-one (1.15 g, 3.58 mmol, 1 eq), 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (941.6 mg, 3.58 mmol, 1 eq), NaOBu-t (859.2 mg, 8.94 mmol, 2.5 eq), and Cphos-Pd G3 (288.4 mg, 357.6 μmol, 0.1 eq) were dissolved in 1,4-dioxane (10 ml). The mixture was heated in a microwave at 110°C for 50 minutes. The reaction mixture was diluted with H2O (20 ml) and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to give a brown solid compound 1-(6-chloro-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-2-yl)ethan-1-one (INT-8, 700 mg, 1.53 mmol, 42.8% yield).

[0411] 1-(6-chloro-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-2-yl)ethan-1-one (600 mg, 1.31 mmol), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (450.71 mg, 1.31 mmol), XPhos Pd G3 (111.15 mg, 131.32 μmol) and K3PO4 (836.23 mg, 3.94 mmol) were dissolved in THF (5 mL) and H2O (1 mL). The mixture was heated in a microwave at 60°C for 30 minutes. The mixture was extracted with EtOAc (20 mL) and washed with brine (10 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM / MeOH from 100% to 80%) to afford benzyl 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (714 mg, 1.12 mmol, 85.3% yield) as a brown oil. LCMS (ESI+): m / z 638.4 (M+H), Rt: 1.91 min.

[0412] To a solution of benzyl 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (714 mg, 1.12 mmol) in THF (10 mL) was added Pd(OH)2 (393.08 mg, 559.81 μmol, 20% purity). The mixture was stirred at 15 ° C. under an atmosphere of H2 (15 psi) for 16 hours. The mixture was filtered and concentrated to give the crude product, which was purified by prep-HPLC (FA) to give INT-7 (30 mg, 59.34 μmol, 30.0% yield) as a white solid. LCMS (ESI+): 506.4 (M+H)+, Rt: 1.88 min.

[0413] 1 H NMR (400MHz, DMSO-d6) δ8.30(br s,1H),7.71(br s,1H),7.47(s,1H),7.35 -6.98(m,3H),6.90-6.53(m,1H),6.43-6.28(m,1H),4.85(br s,1H),4.72-4.38(m,1H),4.26(br s,1H),3.83(s,3H),3.70-3.16(m,6H),3.06-2.61(m,5H),2.12 -1.59(m,8H).

[0414] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (874 mg, 3.17 mmol) in DMSO (20.0 mL) was added tert-butyl 2-(aminomethyl)morpholine-4-carboxylate hydrochloride (800 mg, 3.17 mmol) and DIPEA (1227 mg, 9.50 mmol). The mixture was then stirred at 130 ° C for 6 hours. LCMS showed that the starting material was consumed and the desired product was detected. The reaction was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4, and purified by silica gel chromatography to afford tert-butyl 2-((2-(2,6-dioxapiperidin-3-yl)-1,3-dioxoindolin-4-yl)amino)methyl)morpholine-4-carboxylate (1.3 g, 60% yield) as a yellow solid. LC-MS: m / z [M-100+H] + 373.2.

[0415] To a solution of tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)morpholine-4-carboxylate (1.2 g, 2.5 mmol) in DCM (10.0 mL) was added HCl / 1,4-dioxane (4 M, 5.0 mL). The mixture was then stirred at 20 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The resulting mixture was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-4-((morpholin-2-ylmethyl)amino)isoindolin-1,3-dione (0.95 g, 100% yield) as a yellow solid. LC-MS: m / z[M+H] + 373.1.

[0416] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-((morpholin-2-ylmethyl)amino)isoindoline-1,3-dione (1.22 g, 3.3 mmol) in ACN (20.0 mL) was added 2-bromo-1,1-diethoxyethane (0.72 g, 3.6 mmol) and DIPEA (1.28 g, 9.9 mmol). The mixture was then stirred at 100 ° C for 48 hours. LCMS showed that the starting material was consumed and the desired product was detected. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc in PE from 0% to 50%, then by flash column chromatography eluting with MeOH in DCM from 0% to 5% to give 4-((4-((2,2-diethoxyethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.6 g, 100% yield) as a yellow solid. LC-MS: m / z [M+H] + 489.3.

[0417] To a solution of 4-((4-((2,2-diethoxyethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (500 mg, 1.02 mmol) in DCM (1.0 mL) was added HCl / 1,4-dioxane (4M, 10 mL). The mixture was then stirred at 25 ° C for 10 hours. LCMS showed that the starting material was consumed and the desired product was detected. The resulting mixture was concentrated under reduced pressure to give 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)morpholino)acetaldehyde (400 mg, 94% yield) as a yellow solid. LC-MS: m / z[M+H2O+H] + 433.1.

[0418] To a solution of 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)morpholino)acetaldehyde (300 mg, 0.72 mmol) in DMSO (2.0 mL) and THF (2.0 mL) were added 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindolin-2-yl}-ethanone (366.0 mg, 0.72 mmol) and trimethyl orthoacetate (87.0 mg, 0.72 mmol). The mixture was then stirred at 25° C. for 1 hour. Sodium acetate borohydride (767.1 mg, 3.62 mmol) was added to the mixture. The mixture was stirred at 25° C. for 12 hours. LCMS showed that the starting material was consumed and the desired product was detected. The crude product was purified by prep-HPLC using 0.1% FA / ACN in water eluting from 26% to 36% in 8 minutes to give 4-((4-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)ethyl)morpholin-2-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (81.3 mg, 12% yield) (Compound 001) as a white solid.

[0419] 1 H NMR (400MHz, DMSO-d6) δ11.09(s,1H),7.74(s,1H),7.60–7.56(m,1H),7.49(s,1H),7.16–7.10(m,4H),7.07(d,J= 15.2Hz,1H),7.03–6.73(m,1H),6.62–6.59(m,1H),6.41(d,J=28.8Hz,1H),5.07–5.03(m,1H),4.85(s,1H),4.64(s ,1H),4.28(s,1H),3.86(s,3H),3.81(d,J=10.8Hz,1H),3.66–3.60(m,2H),3.61–3.44(m,5H),3.00–2.98(m,2H),2 .95–2.81(m,4H),2.79–2.65(m,2H),2.65–2.51(m,4H),2.51–2.29(m,4H),2.18–1.87(m,10H),1.83–1.53(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-108.12.LC-MS:m / z[M+H] +904.4.

[0420] Example 2-3 (Synthesis of 2003)

[0421] To a THF (100 mL) solution of methyl 4-(2-methoxy-2-oxyethyl)benzoate (5.0 g, 24.0 mmol), LiAlH (2.7 g, 72.0 mmol) was added dropwise at 0° C. over 20 minutes. After addition, the mixture was stirred at 20° C. for 16 hours. The mixture was quenched with H O (1.6 mL), 10% NaOH (1.6 mL) and H O (4.8 mL), and the organic layer was dried over Na SO , filtered, and concentrated to give a crude product. Purified by silica gel column chromatography from 100% to 40% petroleum ether / ethyl acetate to give 2-(4-(hydroxymethyl)phenyl)ethane-1-ol (1.7 g, 11.2 mmol, 46.5% yield) as a white solid.

[0422] 1 H NMR (400MHz, DMSO-d6) δ7.23-7.18(m,2H),7.18-7.12(m,2H),5.09(t,J=5.6Hz,1H),4. 62(t,J=5.0Hz,1H), 4.44(d,J=5.6Hz,2H), 3.57(q,J=6.3Hz,2H), 2.69(t,J=7.2Hz,2H).

[0423] To a solution of 2-(4-(hydroxymethyl)phenyl)ethane-1-ol (4.4 g, 28.9 mmol) in CHCl (100 mL) was added MnO (25.1 g, 289.1 mmol). The mixture was stirred at 70° C. for 16 hours. The mixture was filtered through filter paper, and the filtrate was concentrated to give the crude product. Purification by silica gel column chromatography from 100% to 60% petroleum ether / ethyl acetate gave 4-(2-hydroxyethyl)benzaldehyde (2.6 g, 17.6 mmol, 60.8% yield) as a yellow oil.

[0424] 1 H NMR (400MHz, DMSO-d6) δ9.96 (s, 1H), 7.82 (d, J = 7.8Hz, 2H), 7.45 (d, J = 7.8Hz, 2H), 4.71 (t, J = 5.0Hz, 1H), 3.65 (q, J = 6.4Hz, 2H), 2.82 (t, J = 6.7Hz, 2H)

[0425] To a solution of 4-(2-hydroxyethyl)benzaldehyde (4.3 g, 28.6 mmol) in DCM (50 mL) was added EtN (8.7 g, 85.7 mmol, 11.9 mL) and TosCl (8.2 g, 42.9 mmol). The mixture was stirred at 20° C. for 16 hours. The mixture was quenched with water. NaHCO (20 mL), the organic layer was dried over NaSO, filtered and concentrated to give a crude product. It was purified by silica gel column chromatography from 100% to 65% petroleum ether / ethyl acetate to give 4-formylphenethyl 4-methylbenzenesulfonate (7.6 g, 25.0 mmol, 87.4% yield) as a yellow solid.

[0426] 1 H NMR (400MHz, DMSO-d6) δ9.97 (s, 1H), 7.77 (d, J = 7.7Hz, 2H), 7.64 (d, J = 7.9Hz, 2H) ,7.37(t,J=6.8Hz,4H),4.30(t,J=6.1Hz,2H),2.99(t,J=6.2Hz,2H),2.39(s,3H)

[0427] To a solution of 4-formylphenethyl 4-methylbenzenesulfonate (1.5 g, 4.9 mmol) and 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (1.1 g, 4.2 mmol) in ACN (150 mL) was added K2CO3 (1.7 g, 12.3 mmol). The mixture was stirred at 80 ° C for 16 hours. The mixture was filtered through filter paper and the filtrate was concentrated to give the crude product. Purification by silica gel column chromatography from 100% to 20% petroleum ether / ethyl acetate gave 4-(2-((2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)benzaldehyde (220 mg, 560.7 μmol, 11.4% yield) as a white solid.

[0428] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.98(s,1H),7.86(d,J=7.9Hz,2H),7.57(d,J=7.9Hz,2H),7.51-7.44(m,1H),7.33-7.26(m,2H),5.14-5.06 (m,1H),4.42-4.35(m,2H),4.32-4.24(m,1H),4.19-4.11(m,1H),3.17(t ,J=6.4Hz,2H),2.96-2.85(m,1H),2.63-2.54(m,2H),2.47-2.40(m,1H).

[0429] To a solution of 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)benzaldehyde (40 mg, 101.9 μmol) in MeOH (2 mL) was added THF (2 mL) and DMSO (2 mL), 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindolin-2-yl)ethan-1-one (51.5 mg, 101.9 μmol), AcOH (6.1 mg, 101.9 μmol), and NaBH3CN (32.0 mg, 509.7 μmol). The mixture was stirred at 30°C for 16 hours. HO (20 mL) was added to the mixture, which was then filtered to obtain a filter cake. The filter cake was purified by prep-HPLC (FA) to give 3-(4-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)phenethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (33.1 mg, 37.5 μmol, 36.8% yield) as a light yellow solid. MS ES + :882.5.

[0430] 1 H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.75(s,1H),7.53-7.40(m,2H),7.32-7.23(m,1H),7.18 -7.07(m,3H),6.90-6.58(m,1H),6.46-6.32(m,1H),5.16-5.06(m,1H),4.84(s,1H),4.63(s,1 H),4.37-4.25(m,4H),4.23-4.10(m,2H),3.85(s,3H),3.60-3.52(m,3H),3.06-2.99(m,2H),2 .95-2.83(m,5H),2.60-2.53(m,2H),2.46-2.39(m,1H),2.16-1.87(m,9H),1.79-1.60(m,4H).

[0431] Example 2-4 (Synthesis of 2004)

[0432] To a stirred solution of piperidine-2,6-dione (10.0 g, 88.4 mmol) in chloroform (100 mL) was added Br2 (13.9 g, 87.2 mmol) under nitrogen at 20°C. The reaction mixture was stirred at 110°C for 4 hours. The mixture was concentrated and purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by filtration using ethyl acetate / petroleum ether to afford 3-bromopiperidine-2,6-dione (8.1 g, 42.1 mmol, 47.7% yield) as a white solid.

[0433] 1 H NMR (400MHz, DMSO-d6) δ10.96-11.19(m,1H)4.89(t,J=4.52Hz,1H)2.53-2.68(m,2H)2.43-2.50(m,1H)2.15(m,1H).

[0434] At 0 ° C, a solution of 3-bromopiperidine-2,6-dione (12.5 g, 65.1 mmol), (4-methoxyphenyl) methanol (9.89 g, 71.6 mmol) and PPh3 (18.7 g, 71.6 mmol) in anhydrous THF (240 mL) was stirred for 1 hour, and then DEAD (17.0 g, 97.6 mmol, 17.75 mL) was added dropwise at 0 ° C and N2 for 30 minutes. The mixture was stirred for another 16 hours at 20 ° C and N2. The mixture was quenched with H2O (100 mL) at 0 ° C. and extracted with ethyl acetate (150 mL*3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 2 / 1). The residue was then purified by column chromatography (SiO2, petroleum ether / dichloromethane = 1 / 0 to 1 / 1) to give 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (12.7 g, 40.6 mmol, 62.4% yield) as a light yellow solid.

[0435] 1 H NMR (400MHz, DMSO-d6) δ7.32 (d, J=8.68Hz, 2H) 6.78-6.87 (m, 2H) 4.82-5.06 (m, 2H) 4.67-4.76(m,1H)3.04(m,1H)2.70-2.81(m,1H)2.30-2.43(m,1H)2.19-2.28(m,1H)

[0436] At 0 ° C, trifluoroacetic anhydride (1.88 g, 8.96 mmol) was added to a solution of 8-bromooctanoic acid (1.00 g, 4.48 mmol) in DCM (20.0 mL). The solution was stirred at 15 ° C for 2 hours. Then tert-butyl alcohol (996 mg, 13.4 mmol) was added and the solution was stirred at 15 ° C for 16 hours. Then saturated NaHCO3 aqueous solution (10 mL) was added, the organic layer was separated and dried over anhydrous Na2SO4. After filtration and concentration. By flash silica gel chromatography ( 20g Silica gel flash column, The crude product was purified by eluting with ethyl acetate / petroleum ether gradient (40 mL / min) to give tert-butyl 8-bromooctanoate (0.9 g, 3.2 mmol, 71.9% yield) as a light yellow oil.

[0437] 1 H NMR(400MHz,CHLOROFORM-d)δ3.33(t,J=6.85Hz,2H)2.14(t,J=7.46Hz,2H)1.78(m,2H)1.51(m,2H)1.32-1.42(m,11H)1.20-1.30(m,4H)

[0438] A reaction solution of 2-fluoro-4-nitrobenzoic acid (15 g, 81.0 mmol) and CH 3 NH 2 (41.9 g, 405 mmol, 45 mL, 30% purity) was stirred at 80° C. in a sealed tube for 40 hours. The mixture was cooled to room temperature and diluted with water (500 mL). Acidified to pH=6 with HCl (2 M) solution. The filtered filter cake was washed with water (50 mL). The filter cake was dried under reduced pressure to give 2-(methylamino)-4-nitrobenzoic acid (15 g, crude product) as a yellow solid.

[0439] 1 H NMR (400MHz, DMSO-d6) δ 8.07 (d, J = 8.68 Hz, 1H) 7.45 (d, J = 2.20 Hz, 1H) 7.38 (dd, J = 8.68, 2.32 Hz, 1H) 2.99 (s, 3H).

[0440] To a solution of 2-(methylamino)-4-nitrobenzoic acid (10.0 g, 50.9 mmol) and DIPEA (19.7 g, 152.9 mmol) in t-BuOH (60 mL) was added DPPA (16.8 g, 61.1 mmol, 13.26 mL) at 20°C under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by flash silica gel chromatography ( 120g Silica gel flash column, The crude product was purified by eluting with ethyl acetate / petroleum ether gradient at 40 mL / min to give 3-methyl-5-nitro-1H-benzimidazol-2-one (7 g, 36.2 mmol, 71.0% yield) as a light yellow solid.

[0441] 1 H NMR (400MHz, DMSO-d6) δ11.65(s,1H)7.94-8.05(m,2H)7.13-7.17(m,1H)3.37(s,3H).

[0442] At 0 ° C, NaH (2.5 g, 62.1 mmol, 60% purity) was added dropwise to a solution of 3-methyl-5-nitro-1H-benzimidazol-2-one (6.0 g, 31.0 mmol) in DMF (80 mL) was added dropwise. After the addition, the mixture was stirred at this temperature for 1 hour, and then a solution of 3-bromo-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (14.5 g, 46.5 mmol) in DMF (30 mL) was added dropwise at 0 ° C, and the resulting mixture was stirred at 20 ° C for 16 hours. After completion, the mixture was acidified to pH = 3-5 with FA, diluted with water (200 mL), and extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the product was purified by flash silica gel chromatography ( 80g Silica gel flash column The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min eluent) to give 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-5-nitro-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (3.5 g, 6.6 mmol, 21.5% yield, 81% purity) as a light yellow solid. MS ES + :425.3.

[0443] 1 H NMR(400MHz,CHLOROFORM-d)δ7.81-7.90(m,2H)7.28(d,J=8.68Hz,2H)6.72-6.82(m,2H)6.44(d,J=8.56Hz,1H)5.17(dd,J=1 3.33, 5.50Hz, 1H) 4.90 (d, J = 1.47Hz, 2H) 3.74 (s, 3H) 3.44 (s, 3H) 2.93-3.05 (m, 1H) 2.71-2.81 (m, 1H) 2.52 (m, 1H) 2.16 (m, 1H).

[0444] 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-5-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3.5 g, 8.3 mmol), Fe (4.6 g, 82.4 mmol) and NH4Cl (4.4 g, 82.4 mmol) were dissolved in THF (100 mL) and H2O (40 mL), and the mixture was stirred at 60 ° C. under N2 atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The product was purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by HPLC (eluting with ethyl acetate / petroleum ether gradient at 40 mL / min) to give 3-(5-amino-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (2.7 g, 6.8 mmol, 83.0% yield) as a light yellow solid.

[0445] 1 H NMR(400MHz, DMSO-d6)δ7.20(d,J=8.68Hz,2H)6.81-6.88(m,2H)6.63(d,J=8.31Hz,1H)6.38(d,J=1.96Hz,1H)6.22(dd,J=8.31,1.96Hz,1H)5.37( dd,J=13.08,5.26Hz,1H)4.70-4.92(m,4H)3.70-3.76(m,3H)3.20-3.30( m,3H)2.96-3.12(m,1H)2.75-2.83(m,1H)2.66(m,1H)1.98-2.07(m,1H).

[0446] A mixture of 3-(5-amino-3-methyl-2-oxobenzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (700 mg, 1.8 mmol), 8-bromooctanoic acid tert-butyl ester (594.6 mg, 2.1 mmol) K2CO3 (735.8 mg, 5.3 mmol), NaI (266.0 mg, 1.8 mmol) and DMF (10 mL) was stirred at 110 ° C for 16 hours. The reaction mixture was filtered and concentrated in vacuo. The product was purified by flash silica gel chromatography ( 20g Silica gel flash column, The crude product was purified by HPLC-MS / MS (eluting with ethyl acetate / petroleum ether gradient at 40 mL / min) to give tert-butyl 8-[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-5-yl]amino]octanoate (700 mg, 1.2 mmol, 66.5% yield) as a light yellow solid.

[0447] 1 H NMR(400MHz,CHLOROFORM-d)δ7.30(d,J=8.68Hz,2H)6.75(d,J=8.68Hz,2H)6.10-6.35 (m,3H)5.08(dd,J=13.08,5.38Hz,1H)4.83-4.93(m,2H)3.72(s,3H)3.51(m,1H)3.26- 3.34(m,3H)2.92-3.17(m,2H)2.89-2.91(m,1H)2.68-2.79(m,1H)2.44-2.56(m,1H)2. 03-2.18(m,3H)1.53-1.59(m,3H)1.42-1.51(m,2H)1.31-1.41(m,9H)1.21-1.30(m,4H)

[0448] Tert-butyl 8-[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-5-yl]amino]octanoate (160 mg, 269 μmol) and MsOH (1.3 g, 13.5 mmol) were dissolved in toluene (1 mL), and the mixture was stirred at 110°C under N2 atmosphere for 4 hours. After cooling to room temperature, the resulting mixture was added dropwise to ice water (2 mL) at 0°C. The reaction mixture was then adjusted to pH = 7 by saturated NaHCO3 solution. The aqueous layer was extracted with ethyl acetate (4×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 8-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]octanoic acid (80 mg, crude) as a light yellow solid. MS ES + :417.4

[0449] 8-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxobenzimidazol-5-yl]amino]octanoic acid (50.0 mg, 120 μmol), 1-[4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)isoindol-2yl]ethanone (60.7 mg, 120 μmol) and DIPEA (46.5 mg, 360 μmol) were dissolved in DMF (5.00 mL) and HATU (68.4 mg, 180 μmol) was added. The resulting solution was stirred at 15 ° C for 16 hours. H2O (5 mL) was added dropwise to quench the reaction and the solid was filtered. The crude product was then further purified by prep-HPLC (FA). Pure fractions were collected and volatiles were removed under vacuum. The residue was dissolved in acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to give 3-[5-[[8-[4-[2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]isoindol-5-yl]-1-piperidinyl]-8-oxooctyl]amino]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (17 mg, 18.1 μmol, 15.1% yield, 96.6% purity) as a light yellow solid. MS ES + :904.5

[0450] 1 H NMR(400MHz,METHANOL-d4)δ11.05(s,1H),7.74(s,1H),7.49(s,1H),7.18-7.10(m,3H),6.88-6.60(m,2 H),6.45-6.35(m,2H),6.27(d,J=8.2Hz,1H),5.23(dd,J=5.1,12.9Hz,2H),4.84(s,1H),4.65-4.52(m,2H ),4.27(m,1H),3.96(m,1H),3.86(s,3H),3.54(s,2H),3.24(s,3H),3.09-2.97(m,2H),2.87(s,3H),2.6 6-2.55(m,3H),2.31(m,2H),2.08(s,5H),2.03-1.97(m,5H),1.79(m,2H),1.53(m,4H),1.39-1.27(m,6H)

[0451] Example 2-5 (Synthesis of 2005)

[0452] To a solution of 4-bromoisobenzofuran-1,3-dione (5.0 g, 22.0 mmol) and 3-aminopiperidine-2,6-dione (3.1 g, 24.2 mmol) in HOAc (50 mL) was added KOAc (6.5 g, 66.1 mmol), and the reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was cooled to 25°C and diluted with ice water (100 mL), then stirred at 0°C for 0.5 hours. The reaction mixture was filtered, and the filter cake was dried under vacuum to provide 4-bromo-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (5.7 g, 16.9 mmol, 76.7% yield) as a light yellow solid.

[0453] 1 H NMR(400MHz, DMSO-d6)δ11.18(s,1H)8.07(d,J=7.95Hz,1H)7.94(d,J=7.21Hz,1H)7.74-7.8 2(m,1H)5.18(dd,J=12.84,5.38Hz,1H)2.82-2.97(m,1H)2.52-2.66(m,2H)2.01-2.14(m,1H)

[0454] To a solution of 4-bromo-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (2.0 g, 5.9 mmol) in DMF (15 mL) was added tert-butyl 4-ethynylpiperidine-1-carboxylate (1.4 g, 6.5 mmol), Pd(dppf)Cl2 (217 mg, 296 μmol), CuI (112 mg, 593 μmol) and TEA (6.0 g, 59.3 mmol). The resulting mixture was stirred at 80 ° C under nitrogen for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The product was purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min eluent) to give tert-butyl 4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]ethynyl]piperidine-1-carboxylate (1.8 g, 3.3 mmol, 56.0% yield, 86% purity) as a light yellow solid. MS ES + :488.4(M+23)

[0455] 1H NMR(400MHz, DMSO-d6)δ11.15(s,1H)8.03-8.10(m,1H)7.83-7.86(m,1H)7.54-7.62(m,1H)5.15-5.20(m,1H)3.62(d,J=6. 24Hz,2H)3.02(m,1H)2.84-2.93(m,1H)2.57-2.70(m,2H)2.01-2.14(m,2H)1.82(m,2H)1.50-1.67(m,2H)1.36-1.47(s,9H)

[0456] To a solution of tert-butyl 4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethynyl]piperidine-1-carboxylate (900 mg, 1.9 mmol) in ethyl acetate (20 mL) was added PtO2 (219 mg, 96.6 μmol, 10% purity) and the reaction mixture was stirred at 20 ° C under a balloon of H2 (15 Psi) for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give tert-butyl 4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethyl]piperidine-1-carboxylate (600 mg, 1.3 mmol, 66.1% yield) as a light yellow solid.

[0457] 1 H NMR(400MHz,CHLOROFORM-d)δ8.01(s,1H)7.66(d,J=6.72Hz,1H)7.57(m,1H)7.45(d,J=7.70Hz,1H)4.90(dd,J=12.29,5.32Hz ,1H)2.96-3.09(m,2H)2.49-2.91(m,6H)2.05-2.14(m,1H)1.69(m,3H)1.48-1.58(m,3H)1.32-1.47(m,11H)1.04-1.16(m,2H)

[0458] Tert-butyl 4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethyl]piperidine-1-carboxylate (600 mg, 1.3 mmol) and HCl / 1,4-dioxane (4M, 9.6 mL) were dissolved in 1,4-dioxane (10 mL), and the reaction mixture was stirred at 25° C. under N2 atmosphere for 3 hours. The mixture was concentrated under reduced pressure to give 2-(2,6-dioxo-3-piperidinyl)-4-[2-(4-piperidinyl)ethyl]isoindoline-1,3-dione (700 mg, crude, 2HCl) as a light yellow solid.

[0459] 1 H NMR(400MHz, DMSO-d6)δ11.13(s,1H)8.68(s,1H)8.40(s,1H)7.63-7.87(m,3H)5.13(dd,J=12.72,5.38Hz,1H)3.20-3.30(m,2H )2.99-3.11(m,2H)2.75-2.96(m,3H)2.52-2.66(m,2H)2.02-2.10(m,1H)1.82-1.94(m,2H)1.48-1.63(m,3H)1.29-1.42(m,2H).

[0460] 2-(2,6-dioxo-3-piperidinyl)-4-[2-(4-piperidinyl)ethyl]isoindole-1,3-dione (300 mg, 739 μmol, hydrochloride) 2-bromo-1,1-dimethoxyethane (374 mg, 2.22 mmol) and DIPEA (382 mg, 3.0 mmol) were dissolved in ACN (10 mL), and the reaction mixture was stirred at 80° C. under N2 atmosphere for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / n-butyl acetate = 1 / 0 to 0 / 1, then methanol: dichloromethane = 0 / 1 to 9 / 1) to give 4-[2-[1-(2,2-dimethoxyethyl)-4-piperidinyl]ethyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (160 mg, 349.7 μmol, 47.3% yield) as a light yellow solid. MS ES + :458.4.

[0461] 1 H NMR(400MHz, DMSO-d6)δ11.13(s,1H)7.64-7.83(m,3H)5.13(dd,J=12.90,5.32Hz,1H)4.45(s,1H)3.24(s,6H)2.99-3.09(m,2H)2. 83-2.89(m,2H)2.56-2.66(m,1H)2.38(m,2H)1.86-2.12(m,3H)1.67(m,2H)1.47-1.57(m,2H)1.10-1.32(m,4H)0.83-0.90(m,1H).

[0462] To a solution of 4-[2-[1-(2,2-dimethoxyethyl)-4-piperidinyl]ethyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (100 mg, 218 μmol) in ACN (3 mL) was added 3M HCl (1 mL, 218 μmol), and the reaction mixture was stirred at 55°C under an N2 atmosphere for 16 hours. The reaction mixture was cooled to 0°C and adjusted to pH 7 with saturated NaHCO3 solution. It was then diluted with 5 mL of ethyl acetate and extracted with 20 mL of ethyl acetate (10 mL*2). The combined organic layers were washed with brine 5 mL (5 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue to obtain 2-[4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethyl]-1-piperidinyl]acetaldehyde (80 mg, crude) as a light yellow solid. MS ES + :412.4.

[0463] 2-[4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethyl]-1-piperidinyl]acetaldehyde (80 mg, 194 μmol) and 1-[4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)isoindol-2-yl]ethanone (88.4 mg, 174 μmol) were dissolved in THF (1 mL), MeOH (1 mL) and DMSO (1 mL), followed by the addition of NaBH3CN (36.6 mg, 583 μmol) and stirring at 30 ° C under N2 atmosphere for 16 hours. The reaction was quenched by the addition of water (5 mL) at 20 ° C. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC and prep-HPLC (TFA conditions) to obtain the desired compound. 1M HCl (2 mL) was then added and lyophilized to give 4-(2-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-yl)isoindoline-5-yl)piperidin-1-yl)ethyl)piperidin-4-yl)ethyl)-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (4.86 mg, 4.5 μmol, 2.3% yield, 83.9%) as a yellow solid. MS ES + :901.6.

[0464] 1H NMR(400MHz,DMSO-d6)11.14(s,1H),10.76(s,1H),10.46(s,1H),7.87-7.65(m,4H),7.5 0(s,1H),7.30-7.10(m,3H),6.93-6.59(m,1H),6.50-6.32(m,1H),5.14(dd,J=5.4,12.7 Hz,1H),4.89(m,1H),4.68(m,1H),4.29(m,1H),3.86(s,3H),3.76(m,3H),3.58-3.42(m, 5H),3.17-2.82(m,10H),2.61(m,5H),2.16-1.93(m,12H),1.57(m,4H),1.28-1.21(m,1H)

[0465] Example 2-6 (Synthesis of 2006)

[0466] To a solution of 3-(4-hydroxy-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (2000 mg, 7.7 mmol) and Na2CO3 (815 mg, 7.7 mmol) in DMF (20 mL) were added 4-(bromomethyl)benzaldehyde (1071 mg, 5.4 mmol) and KI (191 mg, 1.2 mmol). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure. The residue was added H2O / EtOAc (20 mL) and filtered to give 4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oxy}methyl)benzaldehyde (960 mg, 30% yield) as a brown solid. LC-MS: m / z[M+H] + 379.1.

[0467] To a solution of 4-({[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-4-yl]oxy}methyl)benzaldehyde (0.67 g, 0.0017 mol), 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindol-2-yl}ene ketone (0.8 g, 0.0016 mol) and AcOH (0.1 g, 0.0016 mol) in DMSO / MeOH (24 mL) was added sodium triacetate oxyborohydride (1.4 g, 0.0064 mol). The mixture was stirred at 45° C. for 4 hours. The mixture was eluted by prep-HPLC to give 3-[4-({4-[(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)methyl]phenyl}methoxy)-1-oxo-3H-isoindol-2-yl]piperidine NE-2,6-dione (0.5 g, 38% yield) as a yellow solid.

[0468] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.74(s,1H),7.51–7.42(m,4H),7.38–7.30(m,4H),7.09-7.17(m,3H),6.87 -6.59(m,1H),6.43-6.36(m,1H),5.23(s,2H),5.11-5.08(m,1H),4.84(s,1 H),4.64(s,2H),4.42(d,J=16.2Hz,1H),4.25(d,J=16.8Hz,2H),3.86(s,3H ),3.60–3.47(m,4H),2.96–2.83(m,5H),2.56(d,J=18.6Hz,2H),2.43(d,J= 8.4Hz,1H),2.09–1.94(m,8H),1.75-1.63(m,4H).LC-MS:m / z[M+Na]+868.6.

[0469] Example 2-7 (Synthesis of 2007)

[0470] To 5-oxo-tetrahydrofuran-2-carboxylic acid (3.5 g, 26.9 mmol) was slowly added SOCl2 (6.40 g, 53.8 mmol) at 0° C. The mixture was stirred at 80° C. for 3 hours. The mixture was concentrated in vacuo to give 5-oxo-tetrahydrofuran-2-carbonyl chloride (4 g, crude) as a light yellow oil.

[0471] At 0 ° C and under nitrogen protection, (2,4-dimethoxyphenyl)methylamine (4.5g, 26.9mmol) and TEA (5.5g, 53.8mmol) were dissolved in dry DCM (40mL). After that, a solution of 5-oxo-tetrahydrofuran-2-carbonyl chloride (4g, 26.9mmol) in DCM (10mL) was added, and the mixture was stirred at 15 ° C for 1 hour. Water (60mL) was added, and the mixture was extracted with DCM (3×50mL). The combined organic phase was washed with brine (50mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. By flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min as eluent) to give N-[(2,4-dimethoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (2 g, 7.2 mmol, 26.59% yield) as a light yellow solid.

[0472] 1 H NMR (400MHz, DMSO-d6) δ8.45 (t, J = 5.44Hz, 1H) 7.02-7.12 (m, 1H) 6.55 (m, 1H) 6.49 (m, 1H) 4.9 1(m,1H)4.14-4.26(m,2H)3.77(m,6H)2.51-2.59(m,2H)2.37-2.48(m,1H)2.04-2.19(m,1H).

[0473] N-[(2,4-dimethoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (4.6 g, 16.4 mmol) was dissolved in anhydrous THF (50 mL) and cooled to -70 ° C. Then, a solution of t-BuOK (2.0 g, 18.1 mmol) in anhydrous THF (30 mL) was slowly added dropwise at -70 ° C under a nitrogen atmosphere. The resulting reaction mixture was stirred at -50 ° C for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution (100 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give 1-[(2,4-dimethoxyphenyl)methyl]-3-hydroxypiperidine-2,6-dione (5 g, crude product) as a light yellow solid.

[0474] 1H NMR(400MHz,CHLOROFORM-d)δ6.96(d,J=8.19Hz,1H)6.37-6.45(m,2H)4.85-5.05(m,2H)4.25(dd,J=12.59,5.62H z,1H)3.79(d,J=9.54Hz,6H)2.85-2.99(m,1H)2.61-2.75(m,1H)2.31-2.45(m,1H)1.93(qd,J=13.08,4.77Hz,1H).

[0475] To a solution of 1-[(2,4-dimethoxyphenyl)methyl]-3-hydroxypiperidine-2,6-dione (7.4 g, 26.5 mmol) and pyridine (4.2 g, 52.9 mmol) in DCM (140 mL) was added dropwise Tf2O (11.2 g, 39.7 mmol) at -10 °C. The mixture was stirred at -10 °C under nitrogen for 1.5 hours. After completion, the mixture was concentrated in vacuo. The product was purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by eluting with ethyl acetate / petroleum ether gradient at 40 mL / min to give [1-[(2,4-dimethoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (6.2 g, 15.1 mmol, 56.9% yield) as a light yellow solid.

[0476] 1 H NMR(400MHz,CHLOROFORM-d)δ7.06(d,J=9.05Hz,1H)6.37-6.44(m,2H)5.30-5.33(m,1H)4.9 8-5.06(m,1H)4.78-4.90(m,1H)3.78(s,6H)2.93-3.04(m,1H)2.74(m,1H)2.29-2.46(m,2H).

[0477] 2-Fluoro-3-nitrobenzoic acid (15.0 g, 81.0 mmol) was dissolved in CH NH 2 (41.9 g, 405.2 mmol, 30% purity, ethanol) and stirred at 80° C. in a sealed tube for 40 hours. The mixture was cooled to room temperature and diluted with water (500 mL). Acidified to pH=6 with HCl (2 M) solution. The resulting mixture was filtered. The filter cake was washed with water (50 mL). The filter cake was dried under reduced pressure to give 2-(methylamino)-3-nitrobenzoic acid (19 g, crude product) as a light yellow solid.

[0478] 1H NMR (400MHz, DMSO-d6) δ 13.46 (s, 1H) 8.62 (s, 1H) 7.93-8.23 (m, 2H) 6.73 (t, J = 7.89Hz, 1H) 2.70 (s, 3H).

[0479] To a solution of 2-(methylamino)-3-nitrobenzoic acid (15 g, 76.4 mmol) and DIPEA (29.6 g, 229.4 mmol) in t-BuOH (100 mL) was added DPPA (25.2 g, 91.7 mmol) at 20°C under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min as eluent) to give 3-methyl-4-nitro-1H-benzimidazol-2-one (11.5 g, 59.5 mmol, 77.9% yield) as a light yellow solid.

[0480] 1 H NMR (400MHz, DMSO-d6) δ 11.64 (s, 1H) 7.61 (dd, J = 8.44, 0.73Hz, 1H) 7.33 (dd, J = 7.70, 0.73Hz, 1H) 7.10-7.21 (m, 1H) 3.36 (s, 3H).

[0481] At -10 ° C, t-BuOK (1.9 g, 16.5 mmol) was added to a solution of 3-methyl-4-nitro-1H-benzimidazol-2-one (1.6 g, 8.28 mmol) in THF (50 mL) at -0 ° C. After one hour, a solution of [1-[(2,4-dimethoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (5.1 g, 12.4 mmol) in THF (50 mL) was added to the above mixture, and the reaction mixture was stirred at 0-20 ° C for 15 hours. The mixture was acidified to pH = 3-5 with acetic acid, diluted with water (100 mL), and extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (100 mL) and then concentrated in vacuo. The product was purified by flash silica gel chromatography ( 40g Silica gel flash column, The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min eluent) to give 1-[(2,4-dimethoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.5 g, 3.3 mmol, 39.2% yield, 59% purity) as a light yellow oil. MS ES + :455.3.

[0482] 1-[(2,4-dimethoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.5 g, 2.5 mmol), NH4Cl (1.35 g, 25.3 mmol) and Fe (1.4 g, 25.3 mmol) were dissolved in THF (50 mL) and H2O (20 mL), and the mixture was stirred at 60°C under N2 atmosphere for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, then dichloromethane / methanol = 1 / 0 to 85 / 15) to give 3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(2,4-dimethoxyphenyl)methyl]piperidine-2,6-dione (1.4 g, crude) as a light yellow solid. MS ES + :425.4.

[0483] A mixture of 3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(2,4-dimethoxyphenyl)methyl]piperidine-2,6-dione (0.8 g, 1.9 mmol), tert-butyl 7-bromoheptanoate (624 mg, 2.4 mmol) K2CO3 (781 mg, 5.7 mmol), NaI (282 mg, 1.9 mmol) and DMF (10 mL) was stirred in an oil bath at 100°C for 16 hours. The reaction mixture was filtered and concentrated under vacuum. The product was purified by flash silica gel chromatography ( 12g Silica gel flash column, The crude product was purified by ethyl acetate / petroleum ether gradient (40 mL / min eluent) to give tert-butyl 7-[[1-[1-[(2,4-dimethoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoate (260 mg, 380.1 μmol, 20.2% yield, 89% purity) as a dark brown oil. MS ES + :609.7.

[0484] A mixture of tert-butyl 7-[[1-[1-[(2,4-dimethoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoate (200 mg, 328 μmol) was dissolved in TFA (3 mL) and degassed and purged 3 times with N2, and the mixture was then stirred in a sealed tube at 100 ° C for 96 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, dichloromethane / methanol=1 / 0 to 85 / 15) to give 7-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoic acid (150 mg, 283.3 μmol, 86.2% yield, 76% purity) as a dark brown solid. MS ES + :403.5.

[0485] 7-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoic acid (50 mg, 124 μmol) was dissolved in DMF (2 mL), DIPEA (48.1 mg, 372 μmol), HATU (70.8 mg, 186 μmol), and 1-[4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)isoindolin-2-yl]ethanone (50.2 mg, 99.3 μmol). The resulting solution was stirred at 20° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 3-[4-[7-[4-[2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]isoindol-5-yl]-1-piperidinyl]-7-oxoheptyl]amino]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (26.19 mg, 29.4 μmol, 23.7% yield, 100%) as a white solid.

[0486] MS ES + :890.4

[0487] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H)7.75(s,1H)7.49(s,1H)7.08-7.23(m,3H )6.58-6.94(m,2H)6.33-6.54(m,3H)5.28(d,J=7.51Hz,1H)4.81-5.03(m,2H) 4.42-4.75(m,3H)4.28(s,1H)3.97(s,1H)3.86(s,3H)3.61(s,3H)3.55(s,2H) 2.75-3.15(m,8H)2.68(s,2H)2.34(s,2H)1.73-2.11(m,8H)1.29-1.66(m,10H)

[0488] Example 2-8 (Synthesis of 2009)

[0489] Refer to the synthesis of 004.

[0490] Example 2-9 (Synthesis of INT-6)

[0491] A solution of 8-bromo-6-chloroisoquinoline (8.6 g, 35.46 mmol) in AcOH (80 mL) was cooled to 0° C., and then NaBH 4 (2.68 g, 70.93 mmol) was added portionwise, and the mixture was stirred at 25° C. for 0.5 hours. The mixture was poured into H 2 O to quench the reaction, and then the pH was adjusted to 8 with NH 4 Cl, extracted with EtOAc (200 ml), and concentrated to give 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline (8.48 g, 34.40 mmol, 97.0% yield, crude product) as a yellow solid.

[0492] 1 H NMR (400MHz, CD3Cl) δ7.42(s,1H),7.09(s,1H),4.00(s,2H),3.15-3.18(m,2H),2.85-2.88(m,2H).

[0493] To a solution of 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline (8.48 g, 34.40 mmol) in DCM (100 mL) was added TEA (6.96 g, 68.79 mmol) and Boc2O (11.26 g, 51.60 mmol). The mixture was stirred at 25°C for 12 hours. The mixture was washed with saturated brine (50 mL x 2) to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to obtain tert-butyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (6.7 g, 19.33 mmol, 56.2% yield) as a yellow oil.

[0494] 1 H NMR (400MHz, CD3Cl) δ7.42(s,1H),7.10(s,1H),4.49(s,2H),3.61-3.63(m,2H),2.80-2.82(m,2H),1.50(s,9H).

[0495] 8-Bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (29.3 g, 84.52 mmol, 29.3 mg, 84.52 mmol), 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1.2,3.3,4-tetrahydroquinoline (13.35 g, 50.71 mmol), tBuONa (24.37 g, 253.57 mmol), CPHOS PD G3 (6.82 g, 8.45 mmol) were dissolved in 1,4-dioxane (300 mL). The mixture was degassed and replaced with N2 three times, and then stirred at 100° C. under N2 for 2 hours. The mixture was extracted with EtOAc (200 ml) to give a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to give tert-butyl 6-chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroxyisoquinoline-2(1H)-carboxylate (22.6 g, 42.72 mmol, 50.5%) as a yellow oil. LCMS (ESI+): m / z 529.3 (M+H) + ,Rt:2.38min.

[0496] To a solution of tert-butyl 6-chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (300 mg, 0.567 mmol) and benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (292 mg, 0.851 mol) in THF (10 mL) and H2O (1.0 mL) was added K3PO4 (360 mg, 1.70 mmol) and XPhos-Pd G3 (47.9 mg, 0.0567 mmol) at 25° C. The reaction mixture was stirred at 60° C. under N2 for 2 h. The mixture was quenched with water (100 mL) and then extracted with ethyl acetate (100 mL×2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol in DCM from 0% to 5% to give 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (308 mg, 77% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 710.3.

[0497] To a solution of tert-butyl 6-(1-((benzyloxy)carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (308 mg, 0.434 mmol) in DCM (3.0 mL) was added TFA (3.0 mL) at 25 °C. The reaction mixture was stirred at 25°C for 1 hour and then concentrated under reduced pressure to give benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (270 mg, crude product) as a brown oil. It was used directly in the next step without further purification. LC-MS: (ESI) m / z [M+H] + 610.4.

[0498] To a solution of benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (265 mg, 0.435 mmol) in DCM (8.0 mL) was added TEA (132 mg, 0.869 mmol) at 25 °C. The reaction mixture was stirred at 25°C for 10 minutes and then concentrated under reduced pressure to give benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate as a white solid (260 mg, 85% yield). LC-MS: (ESI) m / z [M+H] + 627.3.

[0499] To a solution of benzyl 4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(methylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (260 mg, 0.390 mmol) in MeOH (10 mL) was added Pd / C (41.5 mg, 0.390 mol). The mixture was stirred under H2 balloon pressure at 25°C for 16 hours, filtered to remove solids, and concentrated to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (160 mg, 73% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 535.3.

[0500] Example 2-10 (Synthesis of 2010)

[0501] To 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)morpholino)acetaldehyde (200 mg, 443 μmol, HCl) dissolved in MeOH (2 mL), THF (2 mL) and DMSO (2 mL) was added 8-(7-(difluoromethyl)-6-(1-methyl-1Hpyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(2 1H)-carboxamide (237 mg, 443 μmol), AcOH (26.6 mg, 443 μmol) and NaBH 3 CN (139 mg, 2.2 mmol). The reaction mixture was stirred at 30° C. for 16 hours. To the mixture was added H2O (20 mL) and then filtered to obtain a filter cake. Purification by prep-HPLC (FA) gave 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)morpholino)ethyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (20.7 mg, 22.2 μmol, 5.0% yield) as a yellow solid. MS ES + :933.5.

[0502] 1 H NMR (400MHz, DMSO-d6)11.12(s,1H),8.24(s,1H),7.72(s,1H),7.57(t,J=7.8Hz,1H),7.47(s,1H),7.14(d,J=8.7Hz,1H),7 .09-6.98(m,4H),6.72-6.54(m,2H),6.53-6.45(m,1H),6.18(s,1H),5.05(dd,J=5.4,12.9Hz,1H),4.41(d,J=16.8Hz,1H),4 .10(d,J=16.8Hz,1H),3.85(s,3H),3.83-3.77(m,2H),3.65-3.59(m,4H),3.01-2.93(m,3H),2.89-2.79(m,6H),2.73-2.66 (m,2H),2.55-2.53(m,J=4.3Hz,4H),2.44(s,4H),2.11-1.97(m,6H),1.88(t,J=10.5Hz,1H),1.77-1.52(m,6H),1.23(s,1H)

[0503] Example 2-11 (Synthesis of 2012)

[0504] To a solution of 4-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)benzaldehyde (40 mg, 101.9 μmol) in MeOH (2 mL), THF (2 mL), and DMSO (2 mL) was added 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (54.5 mg, 101.9 μmol), AcOH (6.1 mg, 101.9 μmol, 5.8 uL), and NaBH3CN (32.0 mg, 509.7 μmol). The mixture was stirred at 30°C for 12 hours. To the mixture was added H2O (20 mL) and then filtered to obtain a filter cake. The filter cake was purified by prep-HPLC (FA) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)ethyl)benzyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (24.4 mg, 26.7 μmol, 26.2% yield) as a pink solid. MS ES + :911.4.

[0505] 1 H NMR (400MHz, DMSO-d6)11.00(s,1H),8.30(s,1H),7.71(s,1H),7.49-7.43(m,2H),7.31-7.23(m,6H),7. 11-6.96(m,3H),6.83-6.54(m,1H),6.53-6.43(m,1H),6.17(s,1H),5.10(dd,J=5.0,13.3Hz,1H),4.46-4 .38(m,1H),4.34-4.27(m,3H),4.22-4.04(m,4H),3.85(s,4H),3.45(s,3H),3.03(t,J=6.4Hz,2H),2.95- 2.78(m,7H),2.59(s,1H),2.54(d,J=4.0Hz,3H),2.47-2.37(m,2H),2.09-1.94(m,5H),1.74-1.55(m,4H)

[0506] Example 2-12 (Synthesis of 2013)

[0507] To a solution of 8-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]octanoic acid (220 mg, 528 μmol) and 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide (254 mg, 475 μmol) in DMF (4 mL) was added DIPEA (204 mg, 1.6 mmol) and HATU (301 mg, 792 μmol). The resulting solution was stirred at 15° C. for 16 hours. H O (5 mL) was added dropwise and the solid was filtered. The crude product was then further purified by prep-HPLC (column: Welch Xtimate C18 150×30 mm×5 μm, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient condition from 0% B to 40%). Pure fractions were collected and volatiles were removed under vacuum. The residue was dissolved in acetonitrile (2 mL) and water (10 mL) and lyophilized to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(8-((1-(2,6-dioxopyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)octanoyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (50 mg, 50.5 μmol, 9.6% yield, 94.2% purity) as a light yellow solid. MS ES + :933.5.

[0508] 1H NMR(400MHz,DMSO-d6)11.06(s,1H)7.72(s,1H)7.47(s,1H)6.96-7.12(m,3H)6.55-6.85(m,2H)6.4 9(s,1H)6.38(s,1H)6.27(d,J=8.56Hz,1H)6.18(s,1H)5.19-5.35(m,2H)4.34-4.60(m,2H)4.11(dd, J=16.81,5.93Hz,1H)3.80-4.00(m,4H)3.44(m,4H)3.25(s,2H)2.96-3.10(m,2H)2.80-2.93(m,5H)2 .62-2.75(m,3H)2.53-2.59(m,5H)2.31(m,2H)1.90-2.13(m,4H)1.76(m,2H)1.52(m,6H)1.31(m,6H)

[0509] Example 2-13 (Synthesis of 2014)

[0510] A mixture of 2-[4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]ethyl]-1-piperidinyl]acetaldehyde (40 mg, 97.2 μmol) and 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide (52.0 mg, 97.2 μmol) was dissolved in DCE (2 mL) and DMF (1 mL), degassed, and purged with N2 three times. Sodium acetate borohydride (123 mg, 583 μmol) was added, and the mixture was stirred at 30°C for 16 hours. The reaction was quenched by the addition of water (5 mL) at 20°C. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC and prep-HPLC (TFA conditions) to give the desired compound. 1M HCl (2 mL) was then added and lyophilized to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[2-[4-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-4-yl]ethyl]-1-piperidinyl]ethyl]-4-piperidinyl]-N-methyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (2 mg, 2.1 μmol, 2.1% yield, HCl salt) as a light yellow solid. MS ES + :930.5.

[0511] 1 H NMR (400MHz, DMSO-d6)11.13(s,1H),10.63(s,1H),10.42(s,1H),7.75(d,J=11.2Hz,5H),7.47(s,1H),7.16-6.95(m,3H),6.85- 6.54(m,1H),6.17(s,1H),5.13(d,J=11.5Hz,1H),4.43(d,J=17.9Hz,1H),4.11(d,J=16.4Hz,2H),3.84(s,3H),3.56(s,9H),3.49 -3.30(m,2H),3.05(s,3H),2.87(d,J=13.7Hz,9H),2.62(s,3H),2.53(s,3H),2.03(m,8H),1.70(m,1H),1.55(m,4H)

[0512] Example 2-14 (Synthesis of 2015)

[0513] To a solution of 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde (50 mg, 132.1 μmol) in THF (1 mL), MeOH (1 mL) and DMSO (1 mL) was added 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (91.8 mg, 171.8 μmol), AcOH (7.9 mg, 132.1 μmol, 7.6 uL) and NaBH3CN (41.5 mg, 660.7 μmol). The mixture was stirred at 20°C for 16 hours. To the mixture was added H2O (30 mL) and then filtered to obtain a filter cake. The filter cake was purified by prep-HPLC (FA) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (11.6 mg, 12.9 μmol, 9.8% yield) as a white solid. MS ES + :897.5.

[0514] 1H NMR(400MHz,DMSO-d6)10.98(s,1H),8.26-8.07(m,1H),7.72(s,1H),7.51-7.41(m,4H),7.39-7.29(m,4H), 7.13-6.94(m,3H),6.86-6.43(m,2H),6.21-6.12(m,1H),5.22(s,2H),5.16-5.07(m,1H),4.50-4.37(m,2H) ,4.29-4.20(m,1H),4.14-4.04(m,1H),3.85(s,3H),3.59(s,1H),3.49-3.35(m,5H),2.98-2.74(m,7H),2.6 8-2.60(m,1H),2.57(s,1H),2.54(d,J=3.9Hz,4H),2.43-2.38(m,1H),2.14-1.91(m,5H),1.76-1.56(m,3H)

[0515] Example 2-15 (Synthesis of 2016)

[0516] 7-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoic acid (50 mg, 124 μmol) was dissolved in DMF (2 mL), and DIPEA (48.1 mg, 372 μmol), HATU (70.8 mg, 186 μmol), and 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide (53.1 mg, 99.3 μmol) were added. The resulting solution was stirred at 15° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[7-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]amino]heptanoyl]-4-piperidinyl]-N-methyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (22.44 mg, 24.4 μmol, 19.6% yield, 100% purity) as a white solid. MS ES + :941.3(M+23).

[0517] 1H NMR(400MHz,DMSO-d6)δ11.07(s,1H)7.72(s,1H)7.47(s,1H)6.99-7.13(m,3H)6.53-6.93(m, 2H)6.37-6.51(m,3H)6.18(s,1H)5.28(dd,J=12.46,5.30Hz,1H)5.01(s,1H)4.36-4.58(m,2H) 3.91-4.17(m,2H)3.84-3.89(m,3H)3.61(s,3H)3.47-3.53(m,3H)2.97-3.11(m,3H)2.78-2.9 6(m,6H)2.61-2.77(m,6H)2.28-2.36(m,3H)1.89-2.15(m,4H)1.77(s,2H)1.31-1.67(m,10H).

[0518] Example 2-16 (Synthesis of 2018)

[0519] To a solution of 9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nonanoic acid (100 mg, 0.23 mmol) and 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (124.2 mg, 0.23 mmol) in DMF (2.0 mL) was added DIPEA (90.1 mg, 0.70 mmol) and HATU (106.0 mg, 0.28 mmol). The mixture was then stirred at 25° C. for 1 hour. The reaction was quenched by adding water (20 mL), extracted with EtOAc (20 mL×3), evaporated to dryness and purified by prep-HPLC, eluting with 0.1% FA / ACN in water from 30% to 60% in 8 minutes to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-((2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)nonanoyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (38 mg, 17% yield) as a white solid.

[0520] 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),7.71(s,1H),7.46(s,1H),7.08(s,1H),7.04–7.00(m,2H),6.83(s,0.24H),6.79(d,J=8.4Hz,1H),6.6 9(s,0.50H),6.55(s,0.26H),6.47–6.44(m,1H),6.37(d,J=2.0Hz,1H ),6.31–6.24(m,1H),6.17(s,1H),5.26–5.20(m,2H),4.52–4.39(m,3H ),4.13–4.08(m,1H),3.96–3.91(m,1H),3.85(s,3H),3.62–3.35(m,4 H),3.24(s,3H),3.09–3.03(m,1H),2.98–2.96(m,2H),2.93–2.80(m,4 H),2.75–2.61(m,5H),2.54(d,J=4.4Hz,3H),2.38–2.24(m,2H),2.08– 1.94(m,4H),1.79–1.72(m,2H),1.56–1.48(m,4H),1.40–1.21(m,8H). 19 F NMR(400MHz,DMSO-d6)δ108.04.LC-MS:m / z 947.4[M+H] + .

[0521] Example 2-17 (Synthesis of 2019)

[0522] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1 g, 3.6 mmol) in DMSO (15 mL) was added DIPEA (2.3 g, 18.1 mmol, 3.2 mL) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (775.9 mg, 3.6 mmol). The mixture was stirred at 90 ° C for 12 hours. The reaction mixture was quenched with H2O (10 mL). The residue was diluted with 20 mL of ethyl acetate and extracted with 20 mL of ethyl acetate (20 mL x 2). The combined organic layer was washed with 10 mL of brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by silica gel column chromatography gave tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidine-1-carboxylate (850 mg, 1.8 mmol, 49.9% yield) as a yellow solid. MS ES + :471.3.

[0523] To a solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidine-1-carboxylate (2.4 g, 5.1 mmol) in 1,4-dioxane (10 mL) was added HCl / 1,4-dioxane (4 M, 15 mL). The mixture was stirred at 20 °C for 2 hours. The mixture was concentrated to give 2-(2,6-dioxopiperidin-3-yl)-4-((piperidin-4-ylmethyl)amino)isoindoline-1,3-dione (2.6 g, crude, HCl) as a yellow solid, which was used directly in the next step. MS ES + :371.2.

[0524] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-((piperidin-4-ylmethyl)amino)isoindoline-1,3-dione (2.57 g, 6.9 mmol) in ACN (30 mL) was added DIPEA (9.0 g, 69.4 mmol, 12.1 mL) and 2-bromo-1,1-diethoxyethane (5.5 g, 27.8 mmol, 4.2 mL). The mixture was stirred at 80°C for 12 hours. The mixture was concentrated to give the crude product. After purification by silica gel column chromatography and then by prep-HPLC (FA), 4-((1-(2,2-diethoxyethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.5 g, 3.0 mmol, 43.5% yield) was obtained as a yellow solid. MS ES + :487.4.

[0525] To a solution of 4-((1-(2,2-diethoxyethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (470 mg, 966.0 μmol) in ACN (3 mL) was added HCl (3 M, 8 mL). The mixture was stirred at 55 ° C for 16 hours. The mixture was neutralized with aqueous NaHCO 3 solution and then extracted with DCM (20 mL). The organic layer was dried over Na 2 SO 4, filtered and concentrated to give 2-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)amino)methyl)piperidin-1-yl)acetaldehyde (230 mg, crude, HCl) as a yellow solid, which was used directly in the next step.

[0526] 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),9.57(s,1H),7.60-7.53(m,1H),7.14(d,J =8.7Hz,1H),7.02(d,J=7.0Hz,1H),6.65-6.54(m,1H),5.05(dd,J=5.2,12.8Hz, 1H),3.23(t,J=6.3Hz,2H),3.11(s,2H),2.94-2.86(m,1H),2.82(d,J=11.0Hz,2 H),2.62-2.52(m,2H),2.09-1.97(m,3H),1.71-1.50(m,3H),1.35-1.22(m,2H).

[0527] To a solution of 2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-1-yl)acetaldehyde (80 mg, 194.0 μmol) in MeOH (2 mL), THF (2 mL), DMSO (2 mL) and THF (2 mL) was added 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindolin-2-yl)ethan-1-one (107.9 mg, 213.4 μmol), AcOH (11.7 mg, 194.0 μmol, 11.1 uL) and NaBH3CN (61.0 mg, 969.8 μmol). The mixture was stirred at 30 ° C for 16 hours. H2O (20 mL) was added to the mixture and then filtered to obtain a filter cake. The filter cake was purified by prep-HPLC (TFA) to give 4-((1-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)ethyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (1.9 mg, 2.1 μmol, 1% yield) as a yellow solid. MS ES + :902.5.

[0528] 1H NMR (400MHz, DMSO-d6)11.11(s,1H),10.75(s,1H),10.39(s,1H),7.75(s,1H),7.59(t,J=7.6Hz,1H),7.49( s,1H),7.24-7.09(m,4H),7.07-7.01(m,1H),6.91-6.59(m,2H),6.46-6.31(m,1H),5.11-5.00(m,1H),4.88 (s,1H),4.67(s,1H),4.29(s,1H),3.86(s,3H),3.79-3.66(m,4H),3.56(s,2H),2.88(s,6H),2.67(s,2H),2 .60(s,3H),2.42(s,1H),2.33(s,1H),2.06-1.97(m,9H),1.61-1.42(m,3H),1.23(s,6H),0.88-0.80(m,1H)

[0529] Example 2-18 (Synthesis of 2020)

[0530] 1-[4-[7-(Difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)isoindol-2-yl]ethanone (150 mg, 296 μmol), tert-butyl 4-formylpiperidine-1-carboxylate (63.2 mg, 296 μmol) and sodium acetate borohydride (66.0 mg, 311.5 μmol) were dissolved in DCM (4 mL) and stirred at 15° C. for 48 hours. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM:MeOH = 1 / 0 to 9 / 1) to give tert-butyl 4-[[4-[2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]isoindol-5-yl]-1-piperidinyl]methyl]piperidine-1-carboxylate (100 mg, 139 μmol, 47.0% yield, 98% purity) as a light yellow solid. MS ES + :703.7.

[0531] To a solution of tert-butyl 4-[[4-[2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]isoindol-5-yl]-1-piperidinyl]methyl]piperidine-1-carboxylate (100 mg, 142 μmol) in MeOH (1 mL) was added HCl / 1,4-dioxane (5 mL). The mixture was stirred at 15 °C for 2 hours. The mixture was concentrated under reduced pressure to give 1-[4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-(4-piperidinylmethyl)-4-piperidinyl]isoindol-2-yl]ethanone (200 mg, crude, 2HCl) as a light yellow solid. MS ES + :603.6.

[0532] To a solution of 1-[4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-(4-piperidinylmethyl)-4-piperidinyl]isoindol-2-yl]ethanone (80.0 mg, 125.1 μmol, HCl salt) and 3-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-4-yl]propyl 4-methylbenzenesulfonate (58.8 mg, 125.1 μmol) in ACN was added DIPEA (80.8 mg, 625 μmol, 4 mL). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 4-[3-[4-[2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]isoindol-5-yl]-1-piperidinyl]methyl]-1-piperidinyl]propyl]-2-(2,6-dioxo-3-piperidinyl)isoindole-1,3-dione (28.32 mg, 28.4 μmol, 22.6% yield, 90.2%) as a white solid. MS ES + :901.4.

[0533] 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H)8.15(s,1H)7.68-7.85(m,4H)7.46-7.51(m,2H )7.08-7.18(m,4H)6.59-6.91(m,1H)6.35-6.48(m,1H)5.14(dd,J=12.70,5.42Hz,1H )4.86(s,1H)4.65(s,1H)4.30(s,1H)3.87(s,3H)3.55(d,J=4.77Hz,1H)3.03-3.17(m ,6H)2.84-3.02(m,6H)2.55-2.65(m,5H)2.22-2.31(m,4H)1.97-2.16(m,8H)1.89(br s,2H)1.59-1.83(m,6H)1.14-1.26(m,2H)

[0534] Example 2-19 (Synthesis of 2021)

[0535] To a solution of 2-(4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-1-yl)acetaldehyde (91 mg, 202.7 μmol, HCl) in MeOH (2 mL), DMSO (2 mL) and THF (2 mL) was added 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(piperidin-4-yl)-3,4-dihydroisopropanolquinoline-2(1H)-carboxamide (108.4 mg, 202.7 μmol), AcOH (12.2 mg, 202.7 μmol, 11.6 uL) and NaBH3CN (63.7 mg, 1.0 mmol). The mixture was stirred at 30 ° C for 2 hours. H2O (20 mL) was added to the mixture and then filtered to obtain a filter cake. The filter cake was purified by prep-HPLC (FA) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)methyl)piperidin-1-yl)ethyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (18.6 mg, 19.9 μmol, 9.8% yield) as a yellow solid. MS ES + :931.5.

[0536] 1H NMR (400MHz, DMSO-d6)11.11(s,1H),8.27(s,1H),7.71(s,1H),7.57(t,J=7.8Hz,1H),7.46(s,1H),7.15-7.07(m,2H),7.05-6 .94(m,3H),6.85-6.54(m,2H),6.52-6.43(m,1H),6.17(s,1H),5.09-5.00(m,1H),4.41(d,J=16.6Hz,1H),4.10(d,J=16.8Hz, 1H),3.85(s,3H),3.49-3.45(m,3H),3.44-3.40(m,2H),3.20(t,J=5.6Hz,2H),3.00-2.85(m,7H),2.85-2.76(m,3H),2.62-2. 58(m,1H),2.54(d,J=4.0Hz,3H),2.44(s,4H),2.10-1.98(m,5H),1.93(t,J=11.1Hz,2H),1.74-1.53(m,7H),1.28-1.16(m,2H)

[0537] Example 2-20 (Synthesis of 2022)

[0538] 2-(2,6-dioxopiperidin-3-yl)-4-iodoisoindoline-1,3-dione (1 g, 2.6 mmol), tert-butyldimethyl(propyl-2-yn-1-yloxy)silane (532.1 mg, 3.1 mmol, 633.4 uL), Pd(PPh3)2Cl2 (182.7 mg, 260.3 μmol), CuI (49.6 mg, 260.3 μmol) and DIPEA (3.4 g, 26.0 mmol, 4.5 mL) were dissolved in ACN (15 mL), degassed and purged with N2 three times, and then the mixture was stirred at 100 ° C. under a nitrogen atmosphere for 16 hours. The mixture was concentrated to give a crude product. Purification by silica gel column chromatography gave 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (680 mg, 1.6 mmol, 61.2% yield) as a yellow solid.

[0539] 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.95-7.90(m,1H),7.89-7.83(m,2H),5.15(dd,J=5.3,12.8Hz, 1H),4.64(s,2H),2.95-2.83(m,1H),2.64-2.53(m,2H),2.10-2.01(m,1H),0.90(s,9H),0.15(s,6H).

[0540] To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (788 mg, 1.9 mmol) in EtOAc (50 mL) was added PtO (419.5 mg, 1.9 mmol) under N₂ atmosphere. The mixture was stirred at 20°C under H₂ (15 Psi) atmosphere for 16 hours. The mixture was filtered and concentrated to afford 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(2,6-dioxopyridin-3-yl)isoindoline-1,3-dione (700 mg, crude) as a yellow solid, which was used directly in the next step.

[0541] 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.80-7.73(m,2H),7.71-7.65(m,1H),5.13(dd,J=5.3,12.9Hz,1H),3.62(t,J=6.2Hz, 2H),3.11-3.04(m,2H),2.95-2.84(m,1H),2.64-2.52(m,2H),2.09-2.00(m,1H),1.85-1.77(m,2H),0.85(s,9H),0.02(s,6H)

[0542] To a solution of 4-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (700 mg, 1.6 mmol) in THF (5 mL) was added TBAF (1 M, 3.3 mL). The mixture was stirred at 20 ° C for 16 hours. The mixture was extracted with EA (20 mL) and washed with NaCl (10 mL x 2), dried, filtered and concentrated to give the crude product. Purification by silica gel column chromatography gave 2-(2,6-dioxopiperidin-3-yl)-4-(3-hydroxypropyl)isoindoline-1,3-dione (250 mg, 790.4 μmol, 48.6% yield) as a light yellow solid.

[0543] 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),7.79-7.72(m,2H),7.72-7.67(m,1H),5.13(dd,J=5.1,12.7Hz,1H),4.54(t,J=5.0Hz ,1H),3.47-3.40(m,2H),3.05(t,J=7.6Hz,2H),2.95-2.83(m,1H),2.64-2.53(m,2H),2.09-2.01(m,1H),1.80-1.71(m,2H)

[0544] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-(3-hydroxypropyl)isoindoline-1,3-dione (130 mg, 411.0 μmol) in DCM (4 mL) was added TEA (124.8 mg, 1.2 mmol, 171.6 uL) and TosCl (117.5 mg, 616.5 μmol). The mixture was stirred at 20 ° C for 16 hours. The mixture was concentrated to give a crude product. Purification by silica gel column chromatography gave 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)propyl 4-methylbenzenesulfonate (170 mg, 361.3 μmol, 87.9% yield) as a colorless oil.

[0545] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),7.79-7.68(m,4H),7.56(d,J=7.1Hz,1H),7.46(d,J=8.1Hz,2H),5.13(dd,J=5.4,12.7Hz,1H), 4.03(t,J=6.1Hz,2H),3.01(t,J=7.5Hz,2H),2.94-2.84(m,1H),2.65-2.52(m,2H),2.41(s,3H),2.05-1.98(m,1H),1.97-1.89(m,2H)

[0546] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (120 mg, 189.9 μmol) in ACN (5 mL) was added DIPEA (122.7 mg, 949.7 μmol, 165.4 uL), NaI (28.5 mg, 189.9 μmol) and 3-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl 4-methylbenzenesulfonate (80.4 mg, 170.9 μmol). The mixture was stirred at 80° C. for 16 hours. The mixture was extracted with EA (20 mL) and washed with NaCl (10 mL x 2), dried, filtered and concentrated to give a crude product. The crude product was purified by prep-HPLC (FA) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-((1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)piperidin-4-yl)methyl)piperidin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide (69.8 mg, 75.1 μmol, 39.5% yield)) as a white solid. MS ES + :930.5.

[0547] 1 H NMR(400MHz,DMSO-d6)11.12(s,1H),8.22(s,1H),7.79-7.69(m,4H),7.46(s,1H),7.09-6.97(m,3H),6.84-6.54(m,1H),6.51-6 .44(m,1H),6.18(s,1H),5.16-5.09(m,1H),4.41(d,J=16.9Hz,1H),4.11(d,J=16.8Hz,1H),3.85(s,3H),3.53-3.50(m,1H),3.4 4-3.41(m,1H),3.03(t,J=7.5Hz,2H),2.94-2.78(m,10H),2.69-2.56(m,2H),2.54(d,J=4.3Hz,3H),2.46-2.39(m,2H),2.37-2. 31(m,2H),2.11(d,J=6.8Hz,2H),2.08-2.01(m,3H),1.96-1.86(m,4H),1.81-1.75(m,2H),1.73-1.56(m,7H),1.11-1.01(m,2H)

[0548] Example 2-21 (Synthesis of 2023)

[0549] In a 25 mL round-bottom flask, 3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-5-yl]amino]ethoxy]ethoxy]ethoxy]propanoic acid (15.0 mg, 28.8 μmol) was dissolved in DMF (4 mL), and DIPEA (11.1 mg, 86.4 μmol), HATU (16.4 mg, 43.2 μmol), and 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(4-piperidinyl)isoindoline-2-carboxamide (15.0 mg, 28.8 μmol) were added. The resulting solution was stirred at 15° C. for 16 hours. The reaction mixture was quenched by adding 5 mL of H2O, then diluted with 10 mL of ethyl acetate and extracted with 10 mL of ethyl acetate (10 mL*2). The combined organic layers were washed with 5 mL of brine (5 mL*1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethoxy]ethoxy]propanoyl]-4-piperidinyl]-N-methyl-isoindolin-2-carboxamide (6 mg, 5.9 μmol, 20.3% yield, 100% purity) as a light yellow solid. MS ES + :1024.5.

[0550] 1 H NMR(400MHz,DMSO-d6)11.08(s,1H)7.74(s,1H)7.46-7.62(m,2H)7.06-7.28(m,4H) 7.00(s,1H)6.89(m,2H)6.24-6.39(m,2H)5.03(dd,J=12.78,5.20Hz,1H)4.45-4.63( m,2H)4.28(s,1H)3.98(m,1H)3.86(s,3H)3.43-3.67(m,22H)3.06(m,1H)2.73-2.93 (m,4H)2.58(m,6H)2.51-2.54(m,2H)1.93-2.06(m,3H)1.79(m,2H)1.36-1.68(m,2H)

[0551] Example 2-22 (Synthesis of 2024)

[0552] Methyl 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)isoindoline-2-carboxylate (20 mg, 38.3 μmol, 1 equivalent) was dissolved in DMF (1 mL), and DIPEA (4.96 mg, 38.3 μmol), HATU (14.6 mg, 38.3 μmol), and 3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]amino]ethoxy]ethoxy]ethoxy]propanoic acid (20 mg, 38.3 mol) were added. The resulting solution was stirred at 20° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give methyl 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindol-5-yl]amino]ethoxy]ethoxy]ethoxy]propoxy]-4-piperidinyl]isoindole-2-carboxylate (8.68 mg, 8.47 μmol, 22.1% yield) as a light yellow solid. MS ES + :1025.3

[0553] 1 H NMR(400MHz,DMSO-d6)11.06(s,1H)8.42(s,1H)7.75(s,1H)7.45-7.60(m,2H)7.0 9-7.21(m,4H)7.00(s,1H)6.58-6.93(m,2H)6.38(d,J=4.29Hz,1H)5.03(m,1H)4.6 6(s,2H)4.53(m,1H)4.32(m,2H)3.99(m,1H)3.86(s,3H)3.44-3.71(m,21H)3.07(m ,2H)2.80-2.94(m,4H)2.52-2.63(m,5H)2.01(m,3H)1.79(m,2H)1.33-1.68(m,3H)

[0554] Example 2-23 (Synthesis of 2025)

[0555] 1-[8-[7-(Difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (20 mg, 30.4 μmol, 79% purity) was dissolved in DMF (1 mL), and DIPEA (3.93 mg, 30.41 μmol), HATU (11.6 mg, 30.4 μmol), and 8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]amino]octanoic acid (12.6 mg, 30.4 μmol) were added. The resulting solution was stirred at 20°C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 5-[[8-[4-[2-acetyl-8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-3,4-dihydro-1H-isoquinolin-6-yl]-1-piperidinyl]-8-oxooctyl]amino]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (8 mg, 8.72 μmol, 28.7% yield, 100% purity) as a yellow solid. MS ES + :939.3(M+23).

[0556] 1 H NMR(400MHz, DMSO-d6)11.06(s,1H)7.71(s,1H)7.55(d,J=8.34Hz,1H)7.47(s,1H)7.07-7.14(m,3H)7.04(br s,1H)6.93(s,1H)6.67-6.87(m,2H)6.12-6.23(m,1H)5.02(dd,J=12.87, 5.36Hz,1H)4.43-4.60(m,2H)4.21-4.34(m,1H)3.91-4.03(m,1H)3.85(s, 3H)3.51-3.73(m,3H)3.14(m,3H)2.71-2.95(m,7H)2.54-2.61(m,2H)2.3 1(m,2H)1.94-2.08(m,6H)1.77(m,2H)1.46-1.62(m,5H)1.18-1.41(m,8H)

[0557] Example 2-24 (Synthesis of 2026)

[0558] 8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-5-yl]amino]octanoic acid (5.4 mg, 13.0 μmol) was dissolved in DMF (2 mL), and DIPEA (5.1 mg, 39.2 μmol), 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester (4-piperidinyl)-7.0 mg, 13.0 μmol) and HATU (7.5 mg, 19.6 μmol) were added. The resulting solution was stirred at 15 ° C for 16 hours. The reaction was quenched by adding water (5 mL) at 20 ° C. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The reaction mixture was purified by prep-HPLC (FA) to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[8-[[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindol-5-yl]amino]octanoyl]-4-piperidinyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid methyl ester (9 mg, 9.6 μmol, 73.8% yield, 100% purity) as a light yellow solid. MS ES + :933.4.

[0559] 1 H NMR(400MHz, DMSO-d6)11.08(s,1H)8.41(s,1H)7.73(s,1H)7.56(d,J=8.31Hz,1H)7.48(s,1H)7.0 0-7.17(m,4H)6.55-6.96(m,3H)6.17(s,1H)5.03(dd,J=12.90,5.44Hz,1H)4.39-4.64(m,1H)4.38 -4.64(m,1H)4.25(s,1H)3.95(m,1H)3.86(m,3H)3.46-3.64(m,2H)3.00-3.17(m,4H)2.66-2.97(m ,8H)2.54-2.61(m,2H)2.31(m,2H)1.93-2.09(m,4H)1.76(m,2H)1.42-1.61(m,5H)1.19-1.41(m,9

[0560] H)

[0561] Example 2-25 (Synthesis of 2027)

[0562] To a solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)-1-(2-methoxy-5-methylphenyl)piperidine-2,6-dione (1.03 g, 2.2 mmol) and tert-butyl 7-aminoheptanoate (0.53 g, 2.6 mmol) in 1,4-dioxane (70 mL) were added X-Phos Pd G3 (0.19 g, 0.2 mmol) and Cs2CO3 (2.15 g, 6.6 mmol). The mixture was then stirred at 110° C. for 16 hours under a N2 atmosphere. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (EtOAc / DCM from 0% to 20%) to give tert-butyl 7-({1-[1-(2-methoxy-5-methylphenyl)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-5-yl}amino)heptanoate (0.41 g, 32% yield) as a yellow oil. LC-MS: m / z 579.3 [M+H] + .

[0563] Tert-butyl 7-({1-[1-(2-methoxy-5-methylphenyl)-2,6-dioxopiperidin-3-yl]-3-methyl-2-oxo-1,3-benzodiazol-5-yl}amino)heptanoate (410 mg, 0.71 mmol) was dissolved in TFA (2 mL) and TfOH (0.2 mL) and stirred at 60° C. for 6 hours. The reaction solution was concentrated under reduced pressure and purified by reverse phase chromatography (H 2 O (0.1% FA)-ACN, 20%) to give 7-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]amino}heptanoic acid (120 mg, 42% yield) as a white solid. LC-MS: m / z 403.2 [M+H] + .

[0564] 7-{[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]amino}heptanoic acid (120 mg, 0.30 mmol) and 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindol-2-yl}ethanone (151 mg, 0.30 mmol) were dissolved in DMF (5 mL), and DIEA (116 mg, 0.89 mmol) and HATU (136 mg, 0.36 mmol) were added. The mixture was then stirred at 25° C. for 1 hour. Water (50 mL) was added to quench the reaction, and the product was extracted with EtOAc (50 mL×3). The product was evaporated to dryness and purified by Prep-HPLC (chromatographic column: -Xbridge-C18 150×19 mm, 5 um; mobile phase: ACN-H2O (0.1% FA)) to give a white solid (62.8 mg, 24% yield).

[0565] 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.39(s,0.22H),7.74(s,1H),7.49(s,1H),7.18–7.09(m,3H),6.88(s,0.31H),6. 79(d,J=8.4Hz,1H),6.74(s,0.52H),6.60(s,0.30H),6.44–6.36(m,2H),6.27(d,J=8.4Hz,1H),5.31–5.20(m,2H),4.84 (s,1H),4.68–4.50(m,3H),4.28(s,3H),4.01–3.92(m,1H),3.86(s,3H),3.58–3.50(m,2H),3.24(s,3H),3.12–2.95(m, 3H),2.94–2.76(m,4H),2.70–2.55(m,3H),2.36–2.29(m,2H),2.05–1.93(m,6H),1.86–1.74(m,2H),1.62–1.28(m,10H). 19 F NMR(400MHz,DMSO-d6)δ108.09LC-MS:m / z 890.4[M+H] + .

[0566] Example 2-26 (Synthesis of 2028)

[0567] 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (750 mg, 1.9 mmol) and MsOH (6.4 g, 66.5 mmol) were dissolved in toluene (5 mL), and the mixture was stirred at 100 ° C for 5 hours under N2 atmosphere. After cooling to room temperature, the resulting mixture was added dropwise to ice water (10 mL) at 0 ° C. Saturated NaHCO3 solution was then added to adjust the reaction mixture to pH = 7. The aqueous layer was extracted with ethyl acetate (5×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 85 / 15) to give 3-(5-amino-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (260 mg, 947 μmol, 49.9% yield) as a light yellow solid.

[0568] 1 H NMR(400MHz, DMSO-d6)δ11.06(s,1H)6.79(d,J=8.31Hz,1H)6.43(s,1H)6.33(br d,J=8.31Hz,1H)5.37(br s,2H)5.24(dd,J=12.90,5.07Hz,1H)3.24(s,3H)2.82-2.96(m,1H)2.65-2.72(m,1H)2.58(s,1H)2.56-2.56(m,1H)1.91-2.02(m,1H).

[0569] To a mixture of 7-bromoheptanoic acid (0.5 g, 2.4 mmol) in DCM (20 mL) was added dichlorodioxalyl (607 mg, 4.8 mmol) and DMF (17.4 mg, 239 μmol), and the reaction mixture was stirred at 15° C. under N2 atmosphere for 16 hours. The reaction mixture was concentrated under reduced pressure to give 7-bromoheptanoyl chloride (0.5 g, 2.2 mmol, 91.8% yield) as a light yellow oil.

[0570] 1 H NMR (400MHz, DMSO-d6) δ3.55(t,J=6.66Hz,2H)2.23(t,J=7.27Hz,2H)1.82(m,2H)1.53(m,2H)1.38-1.46(m,2H)1.28-1.36(m,2H).

[0571] 8-[7-(Difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(4-piperidinyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide (50 mg, 93.5 μmol) was dissolved in DCM (5 mL), followed by the addition of TEA (36.2 mg, 358 μmol) and 7-bromoheptanoyl chloride (21.2 mg, 93.5 μmol). The resulting solution was stirred at 15° C. for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, DCM:MeOH = 1 / 0 to 75 / 25) to give 6-[1-(7-bromoheptanoyl)-4-piperidinyl]-8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (76 mg, 92.1 μmol, 98.5% yield, 88% purity) as a light yellow oil. MS ES + :749.0(M+23).

[0572] 6-[1-(7-bromoheptanoyl)-4-piperidinyl]-8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (76.0 mg, 104 μmol), 3-(5-amino-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (28.7 mg, 104 μmol) and K2CO3 (43.4 mg, 313 4 μmol), NaI (15.7 mg, 104 μmol) in DMF (4 mL), and then the mixture was stirred at 90 ° C. under N2 atmosphere for 16 hours. The reaction mixture was quenched by adding 5 mL of H2O at 15 ° C., then diluted with 10 mL of ethyl acetate and extracted with 20 mL of solvent (10 mL * 2). The combined organic layers were washed with 5 mL of brine (5 mL * 1), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-[7-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]heptanoyl]-4-piperidinyl]-N-methyl-3,4-dihydro-1H-isoquinoline-2-carboxamide (7 mg, 6.34 μmol, 6.1% yield, 83.2% purity) as a light yellow solid. MS ES + :919.5.

[0573] 1H NMR(400MHz,DMSO-d6)11.05(s,1H)8.46(s,1H)7.72(s,1H)7.47(s,1H)6.96-7.13(m,3 H)6.64-6.75(m,1H)6.23-6.59(m,3H)6.17(s,1H)5.29(d,J=7.09Hz,1H)4.84(s,1H)4.3 4-4.59(m,2H)4.10(d,J=16.87Hz,1H)3.80-3.99(m,4H)3.42-3.69(m,3H)3.21-3.29(m, 8H)2.70-3.10(m,10H)2.44(m,3H)2.01(m,4H)1.75(m,2H)1.37-1.59(m,5H)1.26(m,4H)

[0574] Example 2-27 (Synthesis of 2029)

[0575] To a solution of 2,4-difluoro-1-nitrobenzene (10 g, 0.0629 mol) in THF (150 mL) at 0°C was added a 40% aqueous solution of methylamine (3.91 g, 0.126 mol). The mixture was stirred at 25°C for 2 hours. Petroleum ether (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture, which was washed with water, 2 mol / L hydrochloric acid, aqueous sodium bicarbonate solution, and saturated brine, dried over sodium sulfate, and rotary evaporated to afford 5-fluoro-N-methyl-2-nitroaniline (10.3 g, 91%) as a yellow solid. LC-MS: m / z 171.1 [M+H] + .

[0576] Under nitrogen and 0 ° C, NaH (71.2 mg, 2.97 mmol) was added to a solution of tert-butyl 7-hydroxyheptanoate (500 mg, 2.4717 mmol) in DMF (10.0 mL). The reaction was stirred at 0 ° C for 30 minutes, and then 5-fluoro-N-methyl-2-nitroaniline (504 mg, 2.97 mmol) was added. The reactants were stirred at 25 ° C for 1.5 hours. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluted from 0% to 10% with MeOH / DCM and MeOH in 15 minutes to obtain tert-butyl 7-(3-(methylamino)-4-nitrophenoxy)heptanoate (610 mg, 63% yield) as a yellow solid. LC-MS: m / z 375.2[M+Na] + .

[0577] A mixture of tert-butyl 7-(3-(methylamino)-4-nitrophenoxy)heptanoate (500 mg, 1.42 mmol) and Pd / C (30.2 mg, 0.284 mmol) in MeOH (20 mL) was stirred at 25° C. under a H atmosphere for 4 hours. The mixture was filtered and concentrated to give tert-butyl 7-(4-amino-3-(methylamino)phenoxy)heptanoate (430 mg, 84%) as a yellow oil, which was used directly in the next step. LC-MS: m / z 323.3 [M+H] + .

[0578] To a solution of tert-butyl 7-(4-amino-3-(methylamino)phenoxy)heptanoate (420 mg, 1.30 mmol) in THF (20.0 mL) was added DIPEA (336 mg, 2.61 mmol) and triphosgene (193 mg, 0.651 mmol) at 0°C. The reactants were stirred at 25°C for 2 hours. The reactants were poured into a NaHCO3 aqueous solution (30 mL), and the aqueous layer was extracted with DCM (10 mL×3). The combined organic layers were dried over Na2SO4 and concentrated, and the residue was purified by silica gel chromatography, eluting with methanol in DCM from 0% to 7% in 10 minutes to give tert-butyl 7-((3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy)heptanoate (450 mg, 89%) as a yellow solid. LC-MS: m / z[M+Na] + 371.2.

[0579] To a solution of tert-butyl 7-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)heptanoate (350 mg, 1.00 mmol) in DMF (5.0 mL) was added NaH (241 mg, 10.0 mmol) at 0 ° C under nitrogen. The reaction was stirred at 0 ° C for 30 minutes, and then 3-bromopiperidine-2,6-dione (386 mg, 2.00 mmol) was added. The reactants were stirred at 25 ° C for 3 hours. The mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / petroleum ether (0% to 50% EtOAc over 15 minutes) to afford tert-butyl 7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)heptanoate (400 mg, 47% yield) as a colorless oil. LC-MS: m / z 482.2 [M+Na] + .

[0580] Tert-butyl 7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)heptanoate (400 mg, 0.870 mmol) was dissolved in DCM (6.0 mL) and TFA (2.0 mL) and stirred at 25°C for 0.5 h. The reaction was concentrated under reduced pressure and purified by reverse phase chromatography (HO (0.1% FA)-ACN, 20%) to afford 7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)heptanoic acid (253 mg, 64% yield) as a yellow solid. LC-MS: m / z 404.2 [M+H] + .

[0581] To a solution of 7-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)heptanoic acid (100 mg, 0.248 mmol) in DMF (5.0 mL) at 25° C. was added 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindolin-2-yl)ethan-1-one (163 mg ( The reaction was stirred at 25°C for 1 hour. The reaction was diluted with water (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC using acetonitrile in water (0.1% TFA) as the eluent, eluting from 32% to 42% in 9.0 minutes (Instrument: GILSON Prep LC with UV detector; column: Xbridge 5u C18 150×30mm; flow rate: 50ml / min) to give 3-(5-((7-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H))-yl)isoindol-5-yl)piperidin-1-yl)-7-oxoheptyl)oxy)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1.4mg, 0.61%) as a white solid.

[0582] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.74(s,1H),7.49(s,1H),7.17–7.10(m,3H),6.97(d,J=8.4Hz,1H),6.85(s,1H),6.74(t,J =55.2,1H),6.62–6.58(m,1H),6.40(d,J=28.4Hz,1H),5.35–5.28(m,1H),4.84(s,1H),4.64(s,1H),4.57–4.50(m,1H),4.27(s,1 H),3.97–3.93(m,2H),3.85(s,3H),3.57–3.50(m,2H),3.30(s,3H),3.15–3.0(m,2H),2.91–2.83(m,3H),2.72–2.57(m,5H),2.35 –2.31(m,2H),2.04–1.96(m,6H),1.83–1.67(m,4H),1.55–1.50(m,2H),1.45–1.40(m,2H),1.38–1.33(m,2H),1.25–1.21(m,2H). 19 F NMR(400MHz,DMSO-d6)δ-108.13.LC-MS:m / z 891.4[M+H] + .

[0583] Example 2-28 (Synthesis of 2030)

[0584] At 25°C and N2, oct-7-ynoic acid (165 mg, 1.20 mmol), 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (100 mg, 0.29 mmol), CuI (5 mg, 0.03 mmol), TEA (89 mg, 0.88 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) were dissolved in DMSO (2 mL). The mixture was heated to 90°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 25°C, diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 80% over 15 minutes to afford 8-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]oct-7-ynoic acid (80 mg, 57% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 398.1.

[0585] To a solution of 8-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]oct-7-ynoic acid (50 mg, 0.12 mmol), HATU (57 mg, 0.15 mmol) and TEA (38 mg, 0.37 mmol) in DMF (2 mL) was added 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl))-1,3-dihydroisoindol-2-yl}ene ketone (50 mg, 0.11 mmol) at 0 ° C. After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN from 10% to 80% in 10 minutes) to give 3-{5-[8-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)-8-oxo-1-yn-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl}piperidine-2,6-dione as a white solid (4 mg, 4% yield).

[0586] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.74(s,1H),7.50(s,1H),7.25–7.05(m,6H),6. 88–6.60(m,1H),6.48–6.37(m,1H),5.40–5.35(m,1H),4.80(s,1H),4.70–4.50(m,3H), 4.28(s,1H),4.02–3.98(m,1H),3.86(s,3H),3.60–3.50(m,2H),3.30(s,3H),3.15–3.0 1(m,1H),2.98–2.75(m,4H),2.74–2.33(m,8H),2.10–1.98(m,5H),1.81–1.44(m,10H). 19 F NMR(400MHz,DMSO-d6)δppm-108.08.LC-MS:(ESI)m / z[M+H] + 858.4.

[0587] Example 2-29 (Synthesis of 2031)

[0588] To a stirred mixture of 4-(2-chloroethyl)-benzoic acid (3.0 g, 16.2 mmol) in THF (40 mL) was added CDI (5.25 g, 32.4 mmol). The mixture was stirred at 60 ° C until gas evolution stopped. After cooling to room temperature, sodium borohydride (1.23 g, 32.4 mol) was slowly added to the mixture and stirred at 25 ° C for 3 hours. The solution was acidified with 1N HCl and extracted twice with EtOAc (15 mL × 2). The organic phase was separated and dried over MgSO4. After evaporation of the solvent, the residue was purified by silica gel column chromatography using PE / EtOAc (7:3) as eluent to obtain (4-(2-chloroethyl)phenyl)methanol (1.5 g, 49% yield) as a yellow oil.

[0589] 1 H NMR (400MHz, DMSO-d6) δ7.26–7.21(m,4H),5.12(t,J=5.6Hz,1H),4.46(d,J=5.6Hz,2H),3.82(t,J=7.2Hz,2H),3.00(t,J=7.2Hz,2H).

[0590] A mixture of (4-(2-chloroethyl)phenyl)methanol (1.0 g, 5.90 mmol) and NaI (1.77 g, 11.8 mmol) in acetone (20 mL) was heated at 60° C. with stirring for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc=6:1) to give (4-(2-iodoethyl)phenyl)methanol (0.8 g, 36% yield) as a white solid.

[0591] 1 H NMR (400MHz, CDCl3) δ7.33 (d, J = 8.4Hz, 2H), 7.19 (d, J = 8.0Hz, 2H), 4.68 (s, 2H), 3.35 (t, J = 7.2Hz, 2H), 3.18 (t, J = 7.2Hz, 2H).

[0592] To a solution of (4-(2-iodoethyl)phenyl)methanol (150 mg, 0.572 mmol), 3-(4-hydroxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (149 mg, 0.572 mmol) and PPh3 (195 mg, 0.744 mmol) in THF (8 mL) was added DIAD (139 mg, 0.687 mmol) at 25°C. After the addition, the mixture was stirred at this temperature for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC to give 3-(4-((4-(2-iodoethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (23 mg, 8% yield) as a yellow oil. LC-MS: m / z 505.0 [M+H] + .

[0593] 1-(4-(7-(Difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (23.0 mg, 0.0456 mmol), 3-(4-(4-(2-iodoethyl)benzyl)oxy)-1-oxoindole-2-yl)piperidine-2,6-dione (23 mg, 0.0456 mmol) and DIEA (29.5 mg, 0.228 mmol) were dissolved in DMF (0.5 mL) and reacted in a microwave at 100°C for 1 hour. After cooling to 25 °C, the mixture was purified by prep-HPLC to give 3-(4-((4-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)ethyl)benzyl)oxy)-1-oxoindolin-2-yl)piperidine-2,6-dione (1.5 mg, 4% yield) as a white solid.

[0594] 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.75(s,1H),7.49–7.40(m,4H),7.33–7.27(m,4H),7.18–7. 10(m,3H),6.88-6.61(m,1H),6.45-6.38(m,1H),5.21(s,2H),5.11(dd,J=12.8,4.8Hz,1H),4.86(s ,1H),4.65(s,1H),4.43-4.38(m,1H),4.26–4.22(m,1H),3.86(s,3H),3.56–3.53(m,2H),3.16(m,2 H),2.94–2.81(m,5H),2.67–2.50(m,6H),2.43–2.33(m,3H),2.04–1.98(m,6H),1.83–1.72(m,4H). 19 F NMR(400MHz,DMSO-d6)δ108.11.LC-MS:m / z 882.4[M+H] + .

[0595] Example 2-30 (Synthesis of 2032)

[0596] At 25°C and N2, hept-6-ynoic acid (111 mg, 0.88 mmol), 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (100 mg, 0.29 mmol), Pd(PPh)3Cl2 (20 mg, 0.03 mmol), CuI (5 mg, 0.03 mmol) and TEA (89 mg, 0.88 mmol) were dissolved in DMSO (3 mL). The mixture was heated to 90°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to 25°C, diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 100% in 15 minutes to give 7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-ynoic acid (80 mg, 70% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 384.1.

[0597] To a solution of 7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-ynoic acid (50 mg, 0.13 mmol), TEA (39 mg, 0.39 mmol) and HATU (59 mg, 0.15 mmol) in DMF (1 mL) was added 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindol-2-yl}ethanone (52 mg, 0.11 mmol) at 0 ° C. After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN from 10% to 70% in 10 minutes) to give 3-{5-[7-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)-7-oxohept-1-yn-1-yl]-3-methyl-2-oxo-1,3-benzodiazol-1-yl}piperidine-2,6-dione (4 mg, 4% yield) as a white solid.

[0598] 1 H NMR (400MHz, DMSO-d6) δ11.11(s,1H),7.74(s,1H),7.50(s,1H),7.13–7.03(m,6H),6. 88–6.60(m,1H),6.48–6.37(m,1H),5.40–5.35(m,1H),4.83(s,1H),4.63–4.50(m,3H), 4.28(s,1H),4.02–3.98(m,1H),3.86(s,3H),3.60–3.50(m,2H),3.30(s,3H),3.10–3. 01(m,1H),2.98–2.75(m,4H),2.74–2.33(m,8H),2.10–1.98(m,5H),1.81–1.47(m,8H). 19 F NMR(400MHz,DMSO-d6)δppm-108.09.LC-MS:(ESI)m / z[M+H] + 871.4.

[0599] Example 2-31 (Synthesis of 2035)

[0600] At 25°C and N2, methyl 6-bromopyridine-3-carboxylate (2.5g, 0.012mol), Pd(dppf)Cl2 (0.85g, 0.0012mol), potassium ethylene trifluoroborate (2.6g, 0.019mol) and TEA (3.5g, 0.035mol) were dissolved in isopropanol (50mL). The mixture was heated to 100°C and stirred at this temperature for 2 hours. The reaction mixture was cooled to 25°C, diluted with water (100mL) and extracted with EtOAc (200mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 80% in 15 minutes to obtain methyl 6-vinylpyridine-3-carboxylate (1.8g, 85% yield) as a yellow solid. LC-MS:(ESI)m / z[M+H] + 164.1.

[0601] At 25 ° C, to a solution of 6-vinylpyridine-3-carboxylic acid methyl ester (3.7 g, 0.023 mol) in H2O (50 mL) and t-BuOH (25 mL) was added N-bromosuccinimide (4 g, 0.023 mol). After addition, the mixture was stirred at 40 ° C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 75% with EtOAc / petroleum ether and EtOAc in 15 minutes to give 6-(2-bromo-1-hydroxyethyl)pyridine-3-carboxylic acid methyl ester (2 g, 32% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 262.0.

[0602] At 25 ° C, NaH (0.61 g, 250 mmol) was added to a solution of methyl 6-(1-bromo-2-hydroxyethyl)pyridine-3-carboxylate (2.2 g, 85 mmol) in THF (150 mL). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 75% with EtOAc / petroleum ether and EtOAc in 15 minutes to give methyl 6-(oxiran-2-yl)pyridine-3-carboxylate (1.3 g, 81% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 180.1.

[0603] At 25 ° C, ammonium formate (1.69 g, 0.027 mol) and Pd / C (0.71 g, 0.0067 mol) were added to a solution of methyl 6-(oxiran-2-yl)pyridine-3-carboxylate (1.2 g, 0.0067 mol) in ethanol (30 mL). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 85% with EtOAc / petroleum ether and EtOAc in 15 minutes to give methyl 6-(2-hydroxyethyl)pyridine-3-carboxylate (1 g, 77% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 182.1.

[0604] At 25 ° C, to a solution of methyl 6-(2-hydroxyethyl)pyridine-3-carboxylate (1.2 g, 0.0066 mol) in DCM (20 mL) was added imidazole (0.9 g, 0.013 mol) and TBSCl (1.49 g, 0.001 mol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 55% with EtOAc / petroleum ether and EtOAc in 15 minutes to give methyl 6-(2-{[tert-butyl(methyl)silyl]methoxy}ethyl)pyridine-3-carboxylate (1.7 g, yield 83%) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 296.2.

[0605] At 0 ° C, to a solution of methyl 6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridine-3-carboxylate (300 mg, 1.01 mmol) in THF (10 mL) was added LiAlH4 (38 mg, 1.01 mmol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 85% with EtOAc / petroleum ether and EtOAc in 15 minutes to give (6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-3-yl)methanol (180 mg, 62% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 268.2.

[0606] At 25 ° C, to a solution of (6-{2-[(tert-butyldimethylsilyl)oxy]ethyl}pyridin-3-yl)methanol (620 mg, 2.31 mmol) in DMF (10 mL) was added NaH (111 mg, 4.63 mmol) and TsCl (441 mg, 2.31 mmol). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 90% with EtOAc / petroleum ether and EtOAc in 15 minutes to give 2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-(chloromethyl)pyridine (400 mg, 54% yield) as a yellow solid. LC-MS:(ESI)m / z[M+H] + 286.2.

[0607] At 25 ° C, TBAF (205 mg, 0.78 mmol) was added to a solution of 2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-5-(chloromethyl)pyridine (150 mg, 0.52 mmol) in THF (3 mL). After addition, the mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting from 0% to 90% with EtOAc / petroleum ether and EtOAc in 15 minutes to give 2-[5-(chloromethyl)pyridin-2-yl]ethanol (50 mg, 49% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 172.1.

[0608] To a THF (3 mL) solution of 2-[5-(chloromethyl)pyridin-2-yl]ethanol (50 mg, 0.29 mmol), 3-(4-hydroxy-1-oxo-3H-isoindol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (113 mg, 0.29 mmol) and PPh3 (152 mg, 0.58 mmol) was added DIAD (176 mg, 0.87 mmol) at 0 ° C. After addition, the mixture was stirred at 25 ° C for 5 hours. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with EtOAc / petroleum ether and EtOAc from 0% to 90% over 15 minutes to give 3-(4-{2-[5-(chloromethyl)pyridin-2-yl]ethoxy}-1-oxo-3H-isoindol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 11% yield) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 544.1.

[0609] To a solution of 3-(4-{2-[5-(chloromethyl)pyridin-2-yl]ethoxy}-1-oxo-3H-isoindol-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 0.036 mmol) in ACN (5 mL) were added 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindol-2-yl}ethanone (27 mg, 0.055 mmol), K2CO3 (15 mg, 0.11 mmol) and KI (6 mg, 0.036 mmol) at 25° C. After the addition, the mixture was stirred at 50° C. for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate / petroleum ether and ethyl acetate from 0% to 90% in 15 minutes to give 3-[4-(2-{5-[(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)methyl]pyridin-2-yl}ethoxy)-1-oxo-3H-isoindol-2-yl]-1-{[2](trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 48% yield) as a yellow solid. LC-MS: (ESI) m / z [1 / 2M+H] + 507.3.

[0610] To a solution of 3-[4-(2-{5-[(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)methyl]pyridin-2-yl}ethoxy)-1-oxo-3H-isoindol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione in DCM (3 mL) was added TFA (1 mL). After the addition, the mixture was stirred at 25 ° C for 1 hour, and then aqueous ammonia (2 mL) was added. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with DCM (20 mL×2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN from 10% to 70% in 10 min) to give 3-[4-(2-{5-[(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)methyl]pyridin-2-yl}ethoxy)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione (1.5 mg, 8% yield) as a white solid.

[0611] 1 H NMR(400MHz,DMSO-d6)δ11.00(s,1H),8.50(s,1H),7.75(s,1H),7.62–7.60(m,1H),7.52–7.49(m,2 H),7.40–7.30(m,3H),7.20–7.02(m,3H),6.80–6.53(m,1H),6.45–6.36(m,1H),5.12–5.08(m,1H), 4.90(s,1H),4.70–4.45(m,3H),4.30–4.05(m,2H),3.86(s,3H),3.55–3.45(m,4H),3.25–3.18(m,2 H),2.98–2.80(m,6H),2.55–2.50(m,1H),2.48–2.33(m,2H),2.08–1.95(m,7H),1.75–1.50(m,6H),. 19 F NMR(400MHz,DMSO-d6)δppm-108.10.LC-MS:(ESI)m / z[M+H] + 883.1.

[0612] Example 2-32 (Synthesis of 2046)

[0613] To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.512 mmol) and KCO (106 mg, 0.768 mmol) in DMF (5.0 mL) was added 3-bromo-1-alkyne (91.4 mg, 0.768 mmol). The mixture was stirred at 25° C. for 17 hours. The mixture was quenched with NH Cl (25 mL), the aqueous layer was extracted with EtOAc (15 mL×3), and the combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography (THF) to give 3-(1-oxo-4-(prop-2-yn-1-yloxy)isoindol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (180 mg, 74% yield) as a yellow solid.

[0614] 1 H NMR (400MHz, DMSO-d6) δ7.53(t,J=8.0Hz,1H),7.37(d,J=7.6Hz,1H),7.32(d,J=8.0Hz,1 H),5.24(dd,J=13.6,5.2Hz,1H),5.05(t,J=9.6Hz,2H),4.95(d,J=2.4Hz,2H),4.44-4.39 (m,1H),4.22–4.18(m,1H),3.63(t,J=2.4Hz,1H),3.56–3.48(m,2H),3.11-3.02(m,1H), 2.80–2.76(m,1H),2.47–2.37(m,1H),2.05–2.03(m,1H),0.90–0.78(m,2H),0.00(s,9H).

[0615] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (200 mg, 0.396 mmol), 2-azidoacetic acid (48.0 mg, 0.475 mmol) and DIEA (76.7 mg, 0.593 mmol) in DMF (5.0 mL) was added HATU (181 mg, 0.475 mmol). The mixture was stirred at this temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (THF) to give 1-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)-2-azidoheptan-1-one (110 mg, 43% yield) as a colorless oil.

[0616] 1 H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.49(s,1H),7.17–7.12(m,3H),6.88-6.60(m,1H),6.43-6. 36(m,1H),4.85(s,1H),4.65(s,1H),4.51-4.49(m,1H),4.28(m,1H),4.17-4.12(m,2H),3.86(s,3 H),3.75–3.73(m,1H),3.55-3.54(m,2H),3.10-3.03(m,1H),2.87–2.82(m,3H),2.71-2.67(m,1H ),2.03–1.98(m,5H),1.84–1.76(m,2H),1.68-1.62(m,1H),1.52-1.47(m,1H),1.25-1.22(m,1H).

[0617] To a solution of 1-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-azidetitanone (100 mg, 0.170 mmol) and 3-(1-oxo-4-(propan-2-yn-1-yloxy)isoindol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (80.1 mg, 0.187 mmol) in ACN (10.0 mL) was added a solution of sodium ascorbate (42.1 mg, 0.213 mmol) and CuSO4.5H2O (21.2 mg, 0.0849 mmol) in H2O (4 mL) at 25°C. The mixture was stirred at 25°C for 2 hours. The aqueous layer was extracted with EtOAc (5 mL x 2), and the combined organic layers were dried and concentrated. The residue was purified by prep-TLC (THF) to give 3-(4-((2-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione 90 mg, 47% yield) as a yellow oil. LC-MS: m / z 1017.0 [M+H] + .

[0618] To a solution of 3-(4-((1-(2-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (90 mg, 0.0885 mmol L) in DCM (2.0 mL) was added TFA (1.01 g, 8.85 mmol) at 25° C. The mixture was stirred at this temperature for 1.5 hours. The mixture was cooled to 0°C, NH3H2O ​​(775 mg, 22.1 mmol) was added to the mixture, and the mixture was stirred at this temperature for 0.5 hours. The aqueous layer was extracted with DCM (5 mL x 2), and the combined organic layers were dried and concentrated. The residue was purified by prep-HPLC to give 3-(4-((2-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methoxy)-1-oxoindole-2-yl)piperidine-2,6-dione (20.5 mg, 25% yield) as a white solid.

[0619] 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.16(d,J=2.8Hz,1H),7.75(s,1H),7.54–7.47(m,3H),7.34(d,J=7.2Hz,1H),7.19-7.1 3(m,3H),6.89-6.61(m,1H),6.45-6.38(m,1H),5.51(s,2H),5.33(s,2H),5.10(dd,J=13.2,5.2Hz,1H),4.86(s,1H),4.66(s,1 H),4.45(s,1H),4.38-4.29(m,2H),4.22-4.17(m,1H),4.03-4.01(m,1H),3.86(s,3H),3.55(s,2H),3.23-3.16(m,1H),2.94–2 .83(m,4H),2.75-2.67(m,1H),2.54-2.50(m,2H),2.45-2.41(m,1H),2.04-1.95(m,6H),1.86–1.74(m,3H),1.54–1.48(m,1H). 19F NMR(400MHz,DMSO-d6)δ108.14,108.08.LC-MS:m / z 887.3[M+H] + .

[0620] Example 2-33 (Synthesis of 2047)

[0621] To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (20 mg, 0.062 mmol) and 4-(dimethoxymethyl)piperidine (30 mg, 0.19 mmol) in anhydrous DMSO (1 mL) was added Pd-PEPPSI-IPent (5 mg, 0.0061 mmol) and CsCO (61 mg, 0.19 mmol). The reaction mixture was reacted in a microwave oven at 130°C under a nitrogen atmosphere for 1 hour and 20 minutes. NHCl (6 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL x 3), evaporated to dryness, and purified by silica gel chromatography (THF / PE from 0% to 60%) to afford 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 65% yield) as a yellow solid. LC-MS: m / z 402.2 [M+H] + .

[0622] At 25 ° C, a solution of 3-(4-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (90 mg, 0.22 mmol) in DMF (1 mL) and HCl / 1,4-dioxane (4N, 1 mL) was stirred for 12 hours. The reaction was concentrated under reduced pressure and adjusted to pH = 8 with aqueous NaHCO3 solution and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidine-4-carboxaldehyde (70 mg, 88% yield) as a yellow solid. LC-MS: m / z 356.1[M+H] + .

[0623] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)piperidine-4-carbaldehyde (70 mg, 0.20 mmol) in DMSO (2 mL) was added 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindolin-2-yl)ethan-1-one (100 mg, 0.20 mmol). After stirring at 25° C. for 0.5 hour, sodium acetate borohydride (63 mg, 0.30 mmol) was added. The mixture was then stirred at 25° C. for 1 hour. The solution was purified by Prep-HPLC (column: Xbridge 5u C18 150×19 mm; mobile phase: ACN-H2O (0.1% FA); from 25% to 35% in 9 minutes; flow rate: 25 mL / min) to give 3-(4-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (25.6 mg, 14% yield) as a yellow solid.

[0624] 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.75(s,1H),7.49(s,1H),7.46–7.40(m,1H),7.30(d,J=7.4Hz,1H),7.21–7.06(m,4H),6.88(s, 0.22H),6.74(s,0.48H),6.61(s,0.25H),6.47–6.37(m,1H),5.12(dd,J=13.2,5.2Hz,1H),4.87(s,1H),4.76–4.56(m,2H),4.47–4.39( m,1H),4.38–4.25(m,2H),3.86(s,3H),3.59–3.54(m,2H),3.45–3.33(m,4H),3.28–3.17(m,2H),2.98–2.85(m,3H),2.82–2.69(m,3H) ,2.64–2.56(m,2H),2.55–2.52(m,1H),2.47–2.41(m,1H),2.07–1.95(m,6H),1.86(d,J=9.2Hz,7H),1.32(d,J=10.8Hz,2H).LC-MS:m / z 845.5[M+H] + .

[0625] Example 2-34 (Synthesis of 2048)

[0626] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (50.0 mg, 0.098 mmol) and Et3N (12.0 mg, 0.296 mmol) in THF (5.0 mL) was added 2-bromoacetyl bromide (22.0 mg, 0.108 mmol). The reaction solution was stirred at 25°C for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / DCM (MeOH from 0 to 10%) over 10 minutes to afford 1-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)-2-bromo-1-one (50.0 mg, 73% yield) as a yellow solid. LC-MS: m / z [M+H] + 588.1.

[0627] To a solution of 7-bromo-1-methyl-3H-1,3-benzodiazol-2-one (500 mg, 2.20 mmol) in THF (10.0 mL) was added LHMDS (1105 mg, 6.60 mmol) at 0°C. The mixture was stirred at 0°C for 0.5 hours. 3-bromopiperidine-2,6-dione (634 mg, 3.30 mmol) was then added and stirred at 70°C for 14.5 hours. The mixture was cooled to 25°C, quenched with NH4Cl (50 mL) and extracted with DCM (50 mL x 2). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EA / PE (EA from 0 to 50%) over 15 minutes to afford 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione as a white solid (140 mg, 18% yield). LC-MS: m / z [M+H] + 339.8.

[0628] To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (140 mg, 0.414 mmol) in DMF (6.0 mL) were added tert-butyl 4-ethynylpiperidine-1-carboxylate (130 mg, 0.621 mmol), CsCO (270 mg, 0.828 mmol), CuI (16.0 mg, 0.082 mmol), and Pd(PPh)Cl (58.0 mg, 0.082 mmol). The reaction solution was heated to 80°C and stirred at this temperature under N for 5 hours. The reaction mixture was cooled to 25°C, diluted with water (25 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / DCM (0 to 5% MeOH) over 10 minutes to afford tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ethynyl)piperidine-1-carboxylate (140 mg, 65% yield) as a yellow solid. LC-MS: m / z [M+Na] + 489.1.

[0629] To a solution of tert-butyl 4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethynyl)piperidine-1-carboxylate (25.0 mg, 0.053 mmol) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated under reduced pressure to afford 3-(3-methyl-2-oxo-4-(piperidin-4-ylethynyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (20.0 mg, 96% yield) as a yellow oil. LC-MS: m / z [M+H] + 367.0.

[0630] To a solution of 1-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-bromopyridin-1-one (25.0 mg, 0.039 mmol) in DMF (4.0 mL) was added KCO (17.0 mg, 0.119 mmol) and 3-(3-methyl-2-oxo-4-(piperidin-4-ylethynyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (18.0 mg, 0.047 mmol). The solution was stirred at 25° C. for 12 hours. The mixture was concentrated and the residue was purified by Prep-HPLC (ACN from 25% to 55% in 8 min) to give 3-(4-((1-(2-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)-2-oxoethyl)piperidin-4-yl)ethynyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione as a white solid (1.8 mg, 5% yield).

[0631] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),7.69(s,1H),7.46(s,1H),7.15(d,J=12.0Hz,1H),7.09(d,J=8.0Hz,3H ),7.04(d,J=8.0Hz,1H),6.98(t,J=12.0Hz,1H),6.82–6.55(m,1H),6.44(d,J=24.0Hz,1H),5.34–5.30(m,1H ),4.85(s,1H),4.63(d,J=24.0Hz,2H),4.33(s,1H),3.86(s,3H),3.64(s,3H),3.57–3.53(m,2H),2.86(s,5H ),2.77–2.63(m,6H),2.55–2.45(s,1H),2.32(d,J=12.0Hz,2H),2.03–1.97(m,7H),1.89(s,5H),1.69(s,5H). 19 F NMR(400MHz,DMSO-d6)δ-108.07.LC-MS:m / z[M+H] + 912.4.

[0632] Example 2-35 (Synthesis of 2050)

[0633] At 0 ° C, sodium hydride (2.82 g, 70.4 mmol, 60% oil solution) was added to a solution of tert-butyl propan-2-yn-1-carbamate (10 g, 64 mmol) in DMF (50 mL). After stirring at 0 ° C for 30 minutes, 3-bromo-1-alkyne (8.37 g, 70.4 mmol) was added to the above solution. The reaction mixture was stirred at 25 ° C for 4 hours and then quenched with ice water. LCMS showed that the starting material had recovered and the desired product was detected. The mixture was extracted with ethyl acetate (50 mL × 2), and the combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (PE: EA = 10: 1) to give tert-butyl di(propan-2-yn-1-yl)carbamate (5 g, 38% yield) as a yellow oil. LC-MS: (ESI) m / z [M + Na] + 216.1.

[0634] 1 H NMR (400MHz, DMSO) δ4.04 (d, J = 2.4Hz, 4H), 3.23 (t, J = 2.4Hz, 2H), 1.41 (s, 9H).

[0635] At 25 ° C and N2 protection, tris(triphenylphosphine) rhodium (190 mg, 0.2 mmol) was added to a solution of tert-butyl bis(prop-2-yn-1-yl)carbamate (2 g, 10.3 mmol) and 1,4-dimethylbut-2-ynedioate (5.85 g, 41.2 mmol) in ethanol (20 mL). The reaction mixture was stirred at 80 ° C for 12 hours. LCMS showed that the desired product was detected. The reaction mixture was cooled to 25 ° C and concentrated in vacuo. The obtained brown residue was diluted in ethyl acetate (100 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 5: 1) to give 2-(tert-butyl) 5,6-dimethyl-isoindoline-2,5,6-tricarboxylate (750 mg, 19% yield) as a white solid. LC-MS: (ESI) m / z [M + H] + 336.1.

[0636] To a solution of 2-(tert-butyl) 5,6-dimethyl-isoindoline-2,5,6-tricarboxylate (700 mg, 2 mmol) in ethanol (10 mL) was added NaOH (3 mL, 3 M H2O solution) at 25°C. The reaction mixture was stirred at 80°C for 3 hours. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was quenched with water (10 mL) and acidified to pH = 4 with HCl (1 M H2O solution), then extracted with ethyl acetate (20 mL x 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2-(tert-butyloxycarbonyl)isoindoline-5,6-dicarboxylic acid (530 mg, crude product), which was used in the next step without further purification. LC-MS: (ESI) m / z [M+H] + 308.1.

[0637] 2-(tert-Butoxycarbonyl)isoindoline-5,6-dicarboxylic acid (300 mg, 0.97 mmol) was dissolved in Ac2O (4 mL) solution, and the reaction mixture was stirred at 100 ° C for 3 h. The reaction mixture was cooled to room temperature and ethyl acetate was added. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography (PE: EA = 1: 9) to give tert-butyl 1,3-dioxo-5,7-dihydro-1H-furo[3,4-f]isoindole-6(3H)-carboxylate (200 mg, yield 71%) as a yellow solid. LC-MS: (ESI) m / z [M + H] + 290.1.

[0638] 1 H NMR (400MHz, DMSO) δ8.04 (d, J = 2.4Hz, 2H), 4.74 (d, J = 8.8Hz, 4H), 1.47 (s, 9H).

[0639] To a solution of tert-butyl 1,3-dioxo-5,7-dihydro-1H-furo[3,4-f]isoindole-6(3H)-carboxylate (230 mg, 0.79 mmol) in toluene (5 mL) was added 3-aminopiperidine-2,6-dione (196 mg, 1.2 mmol) and Et3N (241 mg, 2.38 mmol). The reaction mixture was stirred at 80 ° C for 3 hours and then cooled to room temperature. The mixture was quenched with water (10 mL) and then extracted with ethyl acetate (20 mL × 2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EA=1:9) to give tert-butyl 6-(2,6-dioxopyridin-3-yl)-5,7-dioxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-carboxylate (195 mg, 64% yield) as a yellow solid.

[0640] 1 H NMR (400MHz, DMSO) δ11.12(s,1H),7.89(d,J=2.4Hz,2H),5.15(dd,J=12.8,5.2Hz,1H),4.72(d,J=9.6 Hz,4H),2.97–2.81(m,1H),2.68–2.52(m,2H),2.15–2.03(m,1H),1.47(s,9H).LC-MS:(ESI)m / z[M+H] + 400.1.

[0641] To a solution of tert-butyl [6-(2,6-dioxopiperidine-3-yl)-5,7-dioxo-1H,3H-pyrrolo[3,4-f]isoindol-2-yl]carboxylate (280 mg, 0.7 mmol) in 1,4-dioxane (1 mL) was added HCl (3.0 mL, 4 M in 1,4-dioxane). The reaction mixture was stirred at 25 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired compound was detected. The mixture was concentrated under reduced pressure to give 2-(2,6-dioxopyridin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (180 mg, 86% yield) as a yellow solid, which was used directly in the next step without further purification.

[0642] 1 H NMR (400MHz, DMSO) δ11.14(s,1H),9.96(s,2H),7.96(s,2H),5.16(dd,J=12.8,5.2Hz,1H),4.65 (s,4H),2.97–2.82(m,1H),2.70–2.52(m,2H),2.17–2.00(m,1H).LC-MS: (ESI)m / z[M+H]+300.1.

[0643] To a solution of 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindol-2-yl}ethylene (200 mg, 0.4 mmol) and EtN (120 mg, 1.2 mmol) in THF (5 mL) was added 2-bromoacetyl bromide (88 mg, 0.44 mmol). The reaction solution was stirred at 25 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH / DCM (0 to 10% MeOH) over 10 minutes to afford 1-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)-2-bromo-1-one (100 mg, 36% yield) as a yellow solid. LC-MS: (ESI) m / z [M+Na]+ 648.2.

[0644] To a solution of 1-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)-2-bromoethanone (100 mg, 0.16 mmol) in DMF (3 mL) were added DIEA (62 mg, 0.48 mmol) and 3-{1,3-dioxo-5H,6H,7H-pyrrolo[3,4-f]isoindol-2-yl}piperidine-2,6-dione (72 mg, 0.24 mmol) and stirred at 25 ° C. for 40 minutes. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated. The residue was purified by Prep HPLC (column: -Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O, 45-55% ACN in 0.1% FA / water, 25 mL / min) to give 6-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)-2-oxoethyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (24 mg, 17% yield) as a white solid.

[0645] 1H NMR (400MHz, DMSO) δ11.12(s,1H),8.24(s,0.17H),7.81(d,J=5.2Hz,2H),7.75–7.72(m,1H),7.49(s,1H),7.19–7 .09(m,1H),6.87(s,0.26H),6.74(s,0.52H),6.60(s,0.26H),6.45–6.33(m,1H),5.13(dd,J=13.2,5.2Hz,1H),4. 84(s,1H),4.72–4.45(m,3H),4.27(s,1H),4.18–4.01(m,5H),3.86(s,3H),3.75–3.62(m,2H),3.57–3.49(m,2H), 3.18–3.03(m,1H),2.96–2.77(m,4H),2.65–2.51(m,3H),2.13–1.95(m,6H),1.90–1.74(m,2H),1.71–1.40(m,2H). 19 F NMR(400MHz,DMSO)δ-228.81.LC-MS:(ESI)m / z[M+H] + 845.3.

[0646] Example 2-36 (Synthesis of 2053)

[0647] To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (200 mg, 0.511 mmol) in DMF (8.0 ml) were added 4-(bromomethyl)benzaldehyde (102 mg, 0.511 mmol), KI (17.0 mg, 0.102 mmol), and NaCO (54.1 mg, 0.511 mmol). The mixture was stirred at 25° C. for 12 hours. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in DCM from 0 to 5% over 10 minutes to give 4-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindol-4-yl)oxy)methyl)benzaldehyde (220 mg, 76% yield) as a yellow solid.

[0648] 1H NMR (400MHz, DMSO-d6) δ10.02(s,1H),7.94(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,2H),7.50(t,J=7.6 Hz,1H),7.34(dd,J=13.6,6.8Hz,2H),5.38(s,2H),5.26(dd,J=13.6,5.2Hz,1H),5.05(dd,J=19.2 ,9.6Hz,2H),4.48(d,J=17.2Hz,1H),4.26(d,J=17.2Hz,1H),3.57–3.45(m,2H),3.14–2.99(m,1H) ,2.84–2.72(m,1H),2.46–2.38(m,1H),2.08–2.01(m,1H),0.89–0.78(m,2H),-0.00–-0.05(m,9H).

[0649] To a solution of 4-((2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzaldehyde (180 mg, 0.353 mmol), 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindolin-2-yl)ethan-1-one (179 mg, 0.353 mmol) and AcOH (2.12 mg, 0.0353 mmol) in DCM (10.0 ml) was added sodium acetate borohydride (225 mg, 1.060 mmol). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in DCM from 0% to 8% to give 3-(4-((4-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (240 mg, 64%) yield) as a yellow solid after 10 minutes. LC-MS: m / z [M+H] + 998.4.

[0650] A solution of 3-(4-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (100 mg, 0.100 mmol) in HCl / 1,4-dioxane (4N, 10 mL) was stirred at 25° C. for 12 hours. The mixture was concentrated and eluted with aqueous acetonitrile (0.1% FA) from 16% to 46% in 9.0 minutes (instrument: Waters MS triggered Prep LC with QDA detector; column: Xbridge 5u C18 150×19 mm; flow rate: 20 ml / min) to give 3-(4-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)benzyl)oxy)-1-oxoisoindol-2-yl)-1-(hydroxymethyl)piperidine-2,6-dione (23.5 mg, 24.88% yield) as a light yellow solid.

[0651] 1 H NMR(400MHz, DMSO-d6)7.74(s,1H),7.52–7.42(m,4H),7.37–7.32(m,4H),7.17–7.09(m,3H),6.74(t,J=55 .2Hz,1H),6.40(d,J=28.8Hz,1H),6.20–5.95(s,1H),5.26–5.17(m,3H),5.10–4.97(m,2H),4.84(s,1H),4 .64(s,1H),4.45–4.40(m,1H),4.30–4.22(m,2H),3.86(s,3H),3.57–3.49(m,5H),3.09–2.99(m,1H),2.93 –2.85(m,4H),2.77–2.70(m,1H),2.48–2.32(m,2H),2.08–1.97(m,8H),1.78–1.63(m,4H).LC-MS:m / z[M+H] + 899.3.

[0652] Example 2-37 (Synthesis of 2054)

[0653] To a solution of tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)carbonate (2 g, 5.5 mmol) in DMF (20 mL) was added DBU (1.67 g, 11 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.38 g, 8.2 mmol). The reaction mixture was stirred at 25 ° C. under N2 for 1 hour. LCMS showed that the starting material was consumed and the desired compound was detected. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EA in PE from 0% to 80% to give tert-butyl (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-4-yl)carbonate (2 g, 71% yield) as a white solid. LC-MS: (ESI) m / z [M + Na] + 513.5.

[0654] To a solution of tert-butyl (2-(2,6-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)piperidin-3-yl)-1-oxoisoindolin-4-yl)carbonate (2 g, 4.1 mmol) in DCM (20 mL) was added piperidine (6 mL) at 25 ° C. The reaction mixture was stirred at 25 ° C for 1 hour. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was quenched with water (30 mL) and acidified to pH = 4 with HCl (1 M in H2O) and then extracted with DCM (30 mL × 2). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using EA / PE (EA from 0 to 100%) over 25 minutes to give 3-(4-hydroxy-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione as a white solid (1.3 g, 80% yield). LC-MS: (ESI) m / z [M+Na] + 413.3.

[0655] To a solution of 3-(4-hydroxy-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (1300 mg, 3.3 mmol) in DMF (13 mL) was added cesium carbonate (1830 mg, 5.6 mmol) and 1,2-dibromoethane (2480 mg, 13.2 mmol). The solution was stirred at 60 ° C under N2 for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was quenched with H2O (20 mL) and extracted with EA (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EA / PE (EA 0-100%) over 25 minutes to give 3-(4-(2-bromoethoxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (0.56 g, 33% yield) as a white oil. LC-MS: (ESI) m / z [M+Na] + 518.9.

[0656] To a solution of 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[1-(piperidin-4-ylmethyl)piperidin-4-yl]-1,3-dihydroisoindol-2-yl}ethylene (245 mg, 0.406 mmol) in DMF (7 mL) was added EtN (164 mg, 1.62 mmol) and 3-(4-(2-bromoethoxy)-1-oxoisoindolin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (304 mg, 0.609 mmol). The solution was stirred at 100 ° C in a microwave for 1 h. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was diluted with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by prep-TLC (DCM / MeOH = 10:1) to give 3-(4-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethoxy)-1-(2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (240 mg, 58% yield) as a white solid. LC-MS: (ESI) m / z [M+H] + 1019.3.

[0657] To a solution of 3-(4-(2-(4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethoxy)-1-(2-(trimethylsilyl)ethoxy)methyl)piperidine-2,6-dione (240 mg, 0.235 mmol) in THF (2.0 mL) was added TFA (4 mL) at 0 ° C. The mixture was stirred at 25 ° C for 2 hours. Aqueous ammonia (5 mL) was then added and stirred at 0 ° C for 0.5 hours. LCMS showed that the starting material was consumed and the desired product was detected. The mixture was quenched with H2O (20 mL) and extracted with EA (30 mL×2). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC using ACN eluted in 0.1% NH4HCO3 / water from 48% to 58% in 20 minutes to give 3-(4-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethoxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (65 mg, 30% yield) as a yellow solid.

[0658] 1 H NMR(400MHz,DMSO-d6)δ10.97(s,1H),7.74(s,1H),7.55–7.43(m,2H),7.34–7.23(m,2H),7.19–7.06(m,3H),6.8 8(s,0.25H),6.74(s,0.50H),6.60(s,0.26H),6.46–6.35(m,1H),5.18–5.04(m,1H),4.84(s,1H),4.69–4.55(m,1 .5H),4.43–4.30(m,1.5H),4.29–4.15(m,3H),3.86(s,3H),3.63–3.49(m,2H),3.01–2.82(m,7H),2.76–2.65(m,2 H),2.63–2.53(m,2H),2.48–2.37(m,2H),2.18–1.90(m,12H),1.81–1.59(m,6H),1.49(s,1H),1.17–1.02(m,2H). 19 F NMR(400MHz,DMSO)δ-108.10.LC-MS:(ESI)m / z[M+H] + 889.1.

[0659] Example 2-38 (Synthesis of 2055)

[0660] To a solution of 1-{6-[1-(2-chloroethyl)piperidin-4-yl]-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}ethanone (30 mg, 0.05 mmol) in DMF (2 mL) was added 3-[1-oxo-4-(piperidin-4-ylmethoxy)-3H-isoindol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 0.04 mmol), TEA (16 mg, 0.15 mmol) and KI (8 mg, 0.05 mmol) at 25°C. After addition, the mixture was stirred at 50°C for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL × 2). The combined organic phases were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 3-[4-({1-[2-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)ethyl]piperidin-4-yl}methoxy)-1-oxo-3H-isoindol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 33% yield) as a yellow solid. LC-MS: (ESI) m / z[M+H] + 1019.5.

[0661] To a solution of 3-[4-({1-[2-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)ethyl]piperidin-4-yl}methoxy)-1-oxo-3H-isoindol-2-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2,6-dione (20 mg, 0.02 mmol) in THF (2 mL) was added TFA (2 mL) at 25° C. After the addition, the mixture was stirred at 25° C. for 1 hour, and then NH 3 H 2 O (2 mL) was added. The mixture was stirred at 25° C. for 1 hour. The reaction was purified by prep-HPLC (10% to 70% ACN over 10 min) to afford 4-{1-[2-acetyl-6-(2-oxopiperidin-4-yl)-1,3-dihydroisoindol-4-yl]-7-(difluoromethyl)-3,4-dihydro-2H-quinolin-6-yl}-N,N,1-trimethylpyrazole-3-carboxamide (2.1 mg, 12% yield) as a white solid.

[0662] 1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),7.75(s,1H),7.60–7.48(m,2H),7.40–7.25(m,2 H),6.85–6.61(m,1H),6.50–6.38(m,1H),5.15–5.05(m,1H),4.88(s,1H),4.70–4.60(m ,2H),4.40–4.21(m,3H),4.05–4.01(m,2H),3.86(s,3H),3.60–3.50(m,2H),3.40–3.30 (m,12H),3.00–2.88(m,4H),2.60–2.40(m,3H),2.10–1.90(m,12H),1.70–1.60(m,2H). 19 F NMR(400MHz,DMSO-d6)δppm-108.10.LC-MS:(ESI)m / z[M+H] + 890.3.

[0663] Example 2-39 (Synthesis of 2058)

[0664] 3-(5-bromo-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (400 mg, 1.23 mmol), 4-(dimethoxymethyl)piperidine (591 mg, 3.71 mmol), Pd-PEPPSI-IPent (104 mg, 0.12 mmol) and cesium carbonate (1209.9 mg, 3.71 mmol) were dissolved in DMSO (6 mL) and stirred at 100 ° C for 2 hours under nitrogen. LCMS showed that the desired product was detected. Water (20 mL) was added to quench the reaction and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (30 mL×3) and dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography (PE:EA=1:10) to give 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (300 mg, 60% yield) as a white solid. LC-MS: (ESI) m / z [M+H]+ 402.2.

[0665] To a solution of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.37 mmol) in DCM (1 mL) was added HCl / 1,4-dioxane (3.0 mL, 4N) at 25 ° C. The reaction mixture was stirred at 25 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired compound was detected. The mixture was quenched with water (30 mL) and acidified to pH = 9 with NaHCO3 (2M in H2O) and then extracted with ethyl acetate (30 mL×2). The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde (100 mg, crude product) as a white solid, which was used in the next step without further purification. LC-MS: (ESI) m / z [M+H] + 356.2.

[0666] To a solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (80 mg, 0.22 mmol) in DMSO (3.0 mL) was added 1-{4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(piperidin-4-yl)-1,3-dihydroisoindolin-2-yl}ene ketone (113 mg, 0.22 mmol). The mixture was then stirred at 0 ° C for 10 minutes. Sodium acetate borohydride (71 mg, 0.33 mmol) was added to the mixture. The mixture was stirred at 25 ° C for 2 hours. LCMS showed that the starting material was consumed and the desired product was detected. The crude product was purified by prep-HPLC eluting with 0.1% FA / ACN in water from 25% to 35% over 10 min to afford 3-(5-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (17.7 mg, 8% yield) as a yellow solid.

[0667] 1 H NMR (400MHz, DMSO) δ10.94(s,1H),8.21(s,0.55H),7.75(s,1H),7.49(t,J=4.4Hz,2H),7.22–7.07(m,3H),7.06–7 .00(m,2H),6.88(s,0.25H),6.74(s,0.5H),6.61(s,0.25H),6.48–6.33(m,1H),5.04(dd,J=13.6,4.8Hz,1H),4.8 5(s,1H),4.74–4.54(m,2H),4.42–4.13(m,3H),3.86(s,3H),3.74–3.48(m,2H),3.65–3.48(m,8H),3.02–2.75(m, 2H),2.64–2.52(m,1H),2.44–2.29(m,1H),2.18(s,2H),2.08–1.91(m,9H),1.84–1.60(m,7H),1.30–1.10(m,2H). 19 F NMR(400MHz,DMSO)δ-73.41,-108.11.LC-MS:(ESI)m / z[M+H]+845.6.

[0668] Example 2-40 (Synthesis of 2059)

[0669] To a solution of ethyl 2-(4-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidin-1-yl)methanesulfonate (50 mg, 0.079 mmol) in DMSO (3 mL) was added DIEA (31 mg, 0.239 mmol), potassium iodide (26 mg, 0.159 mmol) and 3-{1,3-dioxo-5H,6H,7H-pyr Rolo[3,4-f]isoindol-2-yl}piperidine-2,6-dione (40 mg, 0.119 mmol). The solution was stirred at 50 °C for 6 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was concentrated and the residue was purified by Prep HPLC (column: -Xbridge-C18 150 x 19 mm, 5 um mobile phase: ACN-H2O, 35-65% ACN in 0.1% FA / water, 25 mL / min) to give 6-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)ethyl)-2-(2,6-dioxopiperidin-3-yl)-6,7-dihydropyrrolo[3,4-isoindole-1,3(2H,5H)-dione (3.2 mg, 5% yield) as a yellow solid.

[0670] 1 H NMR (400MHz, DMSO) δ11.12(s,1H),7.83–7.77(m,2H),7.74(s,1H),7.49(s,1H),7.23–7.08(m, 3H),6.88(s,0.24H),6.74(s,0.5H),6.60(s,0.27H),6.47–6.34(m,1H),5.13(dd,J=12.4,5.2 Hz,1H),4.85(s,1H),4.72–4.44(m,2H),4.28(s,1H),4.01(s,3H),3.86(s,4H),3.55(s,2H),3 .11–2.98(m,2H),2.95–2.79(m,6H),2.64–2.54(m,4H),2.19–1.95(m,8H),1.84–1.59(m,4H). 19 F NMR(400MHz,DMSO)δ-108.10.LC-MS:(ESI)m / z[M+H] + 831.5.

[0671] Example 2-41 (Synthesis of 2060)

[0672] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (300 mg, 0.59 mmol) in DCM (4.0 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (379.7 mg, 1.8 mmol) and AcOH (3.56 mg, 0.06 mmol) at 25° C., and the mixture was stirred at 25° C. for 0.5 hour. To the mixture was then added sodium acetate borohydride (251.5 mg, 1.2 mmol), and the mixture was stirred at 25° C. for 2.5 hours. The reaction was quenched with water (20 mL), extracted with DCM (3 x 20 mL), evaporated to dryness, and purified by silica gel chromatography eluting with EtOAc in PE from 0% to 50%, then by flash column chromatography eluting with methanol in dichloromethane from 0% to 5% to afford tert-butyl 4-((4-(2-acetyl-7-(7-(difluoromethyl))-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (340 mg, 82% yield) as a yellow solid. LC-MS: m / z 703.4 [M+H] + .

[0673] To a solution of tert-butyl 4-((4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (300 mg, 0.43 mmol) in 1,4-dioxane (1.0 mL) was added HCl / 1,4-dioxane (3.0 mL) at 25° C. The mixture was then stirred at 25° C. for 30 minutes. The mixture was concentrated under reduced pressure to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)ethan-1-one (280 mg, 98% yield) as a yellow solid. LC-MS: m / z 603.4 [M+H] + .

[0674] To a solution of 3-(4-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.77 mmol) in MeOH (1.0 mL) and THF (1.0 mL) were added 2-chloroacetaldehyde (181.7 mg, 2.3 mmol) and AcOH (46.3 mg, 0.77 mmol) at 25° C., and the mixture was stirred at 25° C. for 0.5 hour. To this mixture was then added borane-2-pyridine complex (165.0 mg, 1.5 mmol), and the mixture was stirred at 25° C. for 2.5 hours. The reaction was quenched with water (20 mL), extracted with DCM (3×20 mL), evaporated to dryness, and purified by silica gel chromatography, eluting with EtOAc in PE from 0% to 50%, and then by flash column chromatography, eluting with methanol in dichloromethane from 0% to 5%, to afford 3-(4-((2-chloroethyl))amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (200 mg, 81% yield) as a white solid. LC-MS: m / z 322.2 [M+H] + .

[0675] To a solution of 3-(4-((2-chloroethyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.47 mmol) in DMF (2.0 mL) were added 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindolin-2-yl)ethan-1-one (281.0 mg, 0.47 mmol), KI (77.3 mg, 0.47 mmol) and Et3N (141.5 mg, 1.40 mmol) at 25° C. The mixture was stirred at 100° C. for 9 hours. The reaction was purified by prep-HPLC eluting with ACN in H2O (0.1% NH4HCO3) from 48% to 58% in 9 minutes to afford 3-(4-((2-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethyl)amino)-1-oxoindolin-2-yl)piperidine NE-2,6-dione (12.6 mg, 3% yield) as a yellow solid.

[0676] 1H NMR (400MHz, DMSO-d6) δ11.00(s,1H),8.23(s,1H),7.74(s,1H),7.49(s,1H),7.29(t,J=8.0Hz,1H),7.17–7.09(m,3H),6.94(d,J=7 .6Hz,1H),6.78(d,J=8.0Hz,1H),6.75(t,J=55.2Hz,1H),6.40(d,J=28.8Hz,1H),5.45–5.42(m,1H),5.12–5.08(m,1H),4.85(s,1H) ,4.64(s,1H),4.60(s,1H),4.29(s,1H),4.25–4.10(m,3H),3.86(s,3H),3.59–3.47(m,2H),3.34–3.18(m,7H),2.97–2.79(m,4H),2 .70–2.56(m,2H),2.44–2.25(m,1H),2.15–2.11(m,2H),2.10–1.88(m,8H),1.78–1.61(m,5H),1.57–1.34(m,2H),1.16–1.07(m,2H). 19 F NMR(376MHz,DMSO-d6)δ-108.09.LC-MS:m / z 888.7[M+H] + .

[0677] Example 2-42 (Synthesis of 2061)

[0678] To a solution of 3-(4-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (500 mg, 1.928 mmol) in THF (10.0 mL) were added tert-butyl 4-formylpiperidine-1-carboxylate (411 mg, 1.928 mmol) and acetic acid (232 mg, 3.857 mmol), and the mixture was stirred at 25°C for 0.5 hours. Sodium acetate borohydride (613 mg, 2.892 mmol) was then added, and the mixture was stirred at 25°C for 11.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EA / PE (0 to 50% EA) over 15 minutes to give tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)piperidine-1-carboxylate (450 mg, 49% yield) as a white solid. LC-MS: m / z [M+H -100] + 357.2.

[0679] A solution of tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)methyl)piperidine-1-carboxylate (100 mg, 0.219 mmol) in HCl / 1,4-dioxane (5.0 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to afford 3-(1-oxo-4-((piperidin-4-ylmethyl)amino)isoindol-2-yl)piperidine-2,6-dione (100 mg, 90% yield) as a yellow oil. LC-MS: m / z [M+H] + 357.3.

[0680] To a solution of 3-(1-oxo-4-((piperidin-4-ylmethyl)amino)isoindol-2-yl)piperidine-2,6-dione (100 mg, 0.280 mmol) in DMF (5.0 mL) was added 1-{6-[1-(2-chloroethyl)piperidin-4-yl]-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}ethanone (159 mg, 0.280 mmol), Et3N (85.0 mg, 0.841 mmol), and KI (9.0 mg, 0.056 mmol). The reaction solution was heated to 80°C and stirred at this temperature for 12 hours. The reaction mixture was cooled to 25°C, diluted with water (25 mL), and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 ml) and dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN from 30% to 60% in 7 minutes) to give 3-(4-((1-(2-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)ethyl)piperidin-4-yl)methyl)amino)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.0 mg, 1% yield) as a white solid.

[0681] 1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),7.74(s,1H),7.49(s,1H),7.29–7.26(m,1H),7.21–7.08(m,3H),6.92 (d,J=8.0Hz,1H),6.88–6.60(m,2H),6.41(d,J=28.0Hz,1H),5.67(s,1H),5.32(s,1H),5.14–5.09(m,1H),4 .85(s,1H),4.65(s,1H),4.23(d,J=16.0Hz,2H),4.12(d,J=16.0Hz,1H),3.86(s,3H),3.54(s,2H),3.03(s, 6H),2.87(s,4H),2.68–2.57(m,4H),2.33–2.27(m,2H),2.16(s,2H),2.06–1.94(m,9H),1.78–1.68(m,8H). 19 F NMR(400MHz,DMSO-d6)δ-108.10.LC-MS:m / z[M+H] + 888.4.

[0682] Example 2-43 (Synthesis of 2062)

[0683] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(piperidin-4-yl)isoindol-2-yl)ethan-1-one (300 mg, 0.593 mmol) in DCM (2 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (253 mg, 1.19 mmol) and AcOH (0.01 mL), and the mixture was stirred at 25 ° C for 0.5 hours. Sodium acetate borohydride (252 mg, 1.19 mmol) was added to the reaction mixture. The reaction mixture was stirred at 25 ° C for 2 hours. LCMS showed the formation of the desired product. The reaction mixture was quenched with water, extracted with DCM, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with methanol in DCM from 0% to 6% to give tert-butyl 4-((4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (400 mg, 96%) as a yellow solid. LC-MS: (ESI) m / z [M+H] + 703.4.

[0684] Tert-butyl 4-((4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (400 mg, 0.569 mmol) was dissolved in HCl / 1,4-dioxane (2 mL) and stirred at 25° C. for 2 hours. LCMS showed the formation of the desired product. The solvent was removed under reduced pressure to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)ethan-1-one (340 mg, crude) as a white solid. It was used directly without further purification. LC-MS:(ESI)m / z[M+H] + 603.4.

[0685] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(piperidin-4-ylmethyl)piperidin-4-yl)isoindol-2-yl)ethan-1-one (150 mg, 0.25 mmol) in DMF (5 mL) was added 3-(5-((2-chloroethyl)amino)-1-oxoindole-2-yl)piperidine-2,6-dione (80 mg, 0.25 mmol), TEA (151 mg, 1.50 mmol) and KI (4 mg, 0.025 mmol). The reaction mixture was stirred at 100 °C for 8 hours. LCMS showed the formation of the desired product. The solvent was removed under reduced pressure and the residue was purified by prep-HPLC (column: -Xbridge-C18 150 mm×19 mm, 5 um mobile phase: ACN-H2O (0.1% NH4HCO3)) to give 3-(5-((2-((4-((2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)piperidin-1-yl)methyl)piperidin-1-yl)ethyl)amino)-1-oxoisoindol-2-yl)piperidine-2,6-dione (11.6 mg, 5%) as a yellow solid.

[0686] 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),7.74(s,1H),7.49(s,1H),7.38(d,J=8.0Hz,1H),7.18–7.07(m,3H),6.88(s,0.25H),6.72 (s,0.5H),6.70–6.62(m,2H),6.60(s,0.25H),6.45–6.35(m,1H),6.23–6.13(m,1H),5.01(dd,J=13.6,5.2Hz,1H),4.85(s,1H),4 .64(s,2H),4.27(d,J=16.8Hz,2H),4.16(d,J=16.8Hz,1H),3.86(s,3H),3.55(s,2H),3.19(d,J=6.0Hz,2H),2.97–2.81(m,8H), 2.69–2.59(m,2H),2.37–2.32(m,1H),2.13(s,2H),2.10–1.89(m,12H),1.80–1.73(m,2H),1.71–1.62(m,4H),1.17–1.07(m,2H). 19 FNMR(377MHz,DMSO-d6)δ108.10.LC-MS:(ESI)m / z[M+H] + 888.8.

[0687] Example 2-44 (Synthesis of 063)

[0688] At 0 ° C, to a solution of 3-(5-amino-1-oxo-3H-isoindol-2-yl)piperidine-2,6-dione (200 mg, 0.77 mmol) in DCM (15.0 mL) and AcOH (3 mL) was added tert-but...

Claims

1. A compound of formula I and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt: represents an aromatic aryl group or heteroaryl group, or represents a non-aromatic heterocyclic group; Ring A is selected from phenyl or 5-6 membered heteroaryl; X is selected from NR1, or CH; Y is selected from N or CH; when When it is a single bond, U is selected from Z1; Z1 is selected from N or CH; and one of Y and Z1 is N; when When it is a double bond, U is C; Each R1 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R1a: 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R, C 6-14 Aryl, 5-14 membered heteroaryl; wherein R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 3-12 Cycloalkyl; Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Each R2 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Ra is selected from the group consisting of -link-E or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more Ra1: 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl, C 1-12 alkyl; Each Ra1 is the same or different and is independently selected from H, oxo (=O), halogen, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, C 2-12 Alkenyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 2-12 Alkenyl C(=O)-, C 2-12 Alkynyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C(=O)-, 5-14 membered heteroaryl C(=O)-, 3-14 membered heterocyclyl C(=O)-, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 2-12 Alkenyl S(=O)-, C 1-12 Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 2-12 Alkenyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 2-12 Alkenyl-C(=O)-NH-, C 2-12 Alkynyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH-, C 2-12 Alkenyl-S(=O)2-NH-; Each Ra2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; R6 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R6a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl; Each R6a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; R7 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R7a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl; Each R7a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Alternatively, R6 and R7 together with the atoms to which they are attached form the following group which is unsubstituted or optionally substituted with 1, 2 or more Rsa, Rc, Rd or Re: 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group; the 5-14 membered heteroaryl, 3-14 membered heterocyclic group contains at least one N atom; Each Rsa is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more Rsb: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each Rsb is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; Rb, Rc, Rd, Re, and Rz are the same or different and are independently selected from the following groups which are oxo (=O), unsubstituted or optionally substituted with 1, 2 or more Rb1: 6-14 aryl, 5-14 membered heteroaryl; or, two adjacent groups in Rb, Rc, Rd, Re, and Rz and the atoms to which they are connected form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rb2: C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyl; Each Rb1, Rb2 is the same or different and is independently selected from H, halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Rb3: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; each Rb3 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; Alternatively, Rb and Rz together with the atoms to which they are attached form Z2 is selected from CR3 or N; R3 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6- 14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; Each R3a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3b: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each R3b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; R4 is selected from the group -link-E or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; Each R4a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4b: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each R4b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; and at least one of Ra and R4 is a -link-E group, the -link-E group in Ra is -link1-E1, and the -link-E group in R4 is -link2-E2; link1 and link2 are the same or different and are independently selected from -Cy1-L1-Cy2-L2-Q-; Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted with the following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, 5-14 membered heteroarylene; Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted with the following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene; L1 is absent or selected from N(R L ), unsubstituted or optionally substituted with one, two or more R L1 Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkyleneoxy; R L Select from H or C 1-12 alkyl; L2 is absent or selected from unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C 1-12 Alkylene, (C 1-12 Alkyleneoxy) t ; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; Q is absent or selected from O, N(R q ), ethynylene; R q Select from H or C 1-12 alkyl; R Cy1 , R Cy2 are the same or different and are independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy; R L1 , R L2 are the same or different and are independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy; Cy1 end connected, the Q terminal is connected to E1 or E2; E1 and E2 are the same or different and are independently selected from Ring G is selected from g Substituted 5-6 membered N-containing heterocyclic group; each R g are the same or different and are independently selected from H, oxo (=O), C 1-12 Alkyl or And ring G contains at least one R g1 Selected from H, hydroxyl C 1-12 Alkyl, (R g11 )(R g12 )-NC 1-12 Alkyl-C(O)OC 1-12 Alkyl; R g11 , R g12 The same or different, independently selected from H, C 1-12 alkyl; represents the junction site; Each R5 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R5a: 1-12 Alkyl, C 1-12 Alkoxy; Each R5a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; n is selected from 0, 1, 2; m is selected from 0, 1, 2, 3; p is selected from 0, 1, 2, 3, 4, 5; q is selected from 0, 1, 2.

2. The compound of formula III according to claim 1 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula (I): in, represents an aromatic aryl group or heteroaryl group, or represents a non-aromatic heterocyclic group; Ring A is selected from phenyl or 5-6 membered heteroaryl; X is selected from NR1, or CH; Y is selected from N or CH; Z1 is selected from N, C or CH; and one of Y and Z1 is N; Each R1 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R1a: 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R, C 6-14 Aryl, 5-14 membered heteroaryl; wherein R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 3-12 Cycloalkyl; Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Each R2 is the same or different and is independently selected from H, oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Ra is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more Ra1: 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl, C 1-12 alkyl; Each Ra1 is the same or different and is independently selected from H, oxo (=O), halogen, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: NH2, C 1-12 Alkyl, C 2-12 Alkenyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, C 2-12 Alkenyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 2-12 Alkenyl C(=O)-, C 2-12 Alkynyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C(=O)-, 5-14 membered heteroaryl C(=O)-, 3-14 membered heterocyclyl C(=O)-, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 2-12 Alkenyl S(=O)-, C 1-12 Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 2-12 Alkenyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 2-12 Alkenyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH-, C 2-12 Alkenyl-S(=O)2-NH-; Each Ra2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; Rb, Rc, Rd, Re, and Rz are the same or different and are independently selected from the following groups which are oxo (=O), unsubstituted or optionally substituted with 1, 2 or more Rb1: 6-14 aryl, 5-14 membered heteroaryl; or, two adjacent groups in Rb, Rc, Rd, Re, and Rz and the atoms to which they are connected form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rb2: C 6-14 Aryl, 5-14 membered heteroaryl, C 3-12 Cycloalkyl; Each Rb1, Rb2 is the same or different and is independently selected from H, halogen, CN, NH2, COOH, OH, the following groups which are unsubstituted or optionally substituted by 1, 2 or more Rb3: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; each Rb3 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; n＝0,1,2； m＝0，1，2，3； p＝0，1，2，3，4，5。 3. The compound according to claim 1 or 2, and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Preferably, Y is selected from N; Z is selected from C or CH; Preferably, Y is selected from CH; Z is selected from N; Preferably, ring A is selected from phenyl, pyrazolyl, imidazolyl; Preferably, ring A is selected from Preferably, is selected from phenyl or 5-6 membered heteroaryl; represents the junction site; Preferably, Selected from tetrahydropyrrolyl, piperidinyl, phenyl; Preferably, Selected from Preferably, Selected from in, and connected. Preferably, is selected from unsubstituted or optionally substituted by 1, 2 or more Rb1 or unsubstituted or optionally substituted with 1, 2 or more Rb2 Preferably, Selected from Preferably, each R1 is the same or different and is independently selected from -(C=O)C 1-6 Alkyl, -(C=O)-NH-C 1-6 Alkyl, C 1-6 Alkyl-substituted 5-6-membered heteroaryl; Preferably, each R1 is the same or different and is independently selected from -(C=O)CH3, -(C=O)-NH-CH3, Preferably, Ra is selected from the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra1: 3-8 membered heterocyclic group, C 3-8 Cycloalkyl; Preferably, Ra is selected from the following groups which are unsubstituted or optionally substituted with 1, 2 or more Ra1: cyclohexyl, piperidinyl or piperazinyl. Preferably, each Ra1 is the same or different and is independently selected from the following groups which are unsubstituted or optionally substituted by 1, 2 or more Ra2: 1-6 Alkyl, C 1-6 Alkyl C(=O)-, C 2-6 Alkenyl C(=O)-, C 2-6 Alkynyl C(=O)-, C 1-6 Alkyl-C(=O)-NH-, C 2-6 Alkenyl-C(=O)-NH-, C 2-6 Alkynyl-C(=O)-NH-, C 1-6 Alkyl-S(=O)2-, C 2-6 Alkenyl-S(=O)2-, C 1-6 Alkyl-S(=O)2-NH-, C 2-6 Alkenyl-S(=O)2-NH-, 3-6 membered heterocyclic group; Preferably, each Ra2 is the same or different and is independently selected from halogen, oxo (=O), (C 1-12 Alkyl)2-NH-; Preferably, each Ra1 is the same or different and is independently selected from methyl, Preferably, each Rb is the same or different and is independently selected from oxo (=O), unsubstituted or optionally substituted with 1, 2 or more Rb1. 6-10 Aryl; or, two Rb and the group to which they are connected form a C unsubstituted or optionally substituted by 1, 2 or more Rb2 6-10 Aryl; Preferably, each Rb is the same or different and is independently selected from oxo (=O), unsubstituted or phenyl optionally substituted by 1, 2 or more Rb1; or, two Rb and the groups to which they are connected form a phenyl group which is unsubstituted or optionally substituted by 1, 2 or more Rb2; Preferably, each Rb1 is the same or different and is independently selected from halogen, such as F; Preferably, each Rb2 is the same or different and is independently selected from CN, halogenated C 1-6 Alkyl, C 3-6 Alkyl, C 1-6 Alkyl-5-6 membered heteroaryl; Preferably, each Rb2 is the same or different and is independently selected from CN, difluoromethyl, cyclopropyl, 4. The compound according to any one of claims 1 to 3 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The formula III is further selected from the following structures: wherein ring A, R1, R2, Ra, Rb, m, and n are independently defined as in any one of claims 1 to 3; Rb 11 , Rb 12 The same or different, independently have the definition as described in Rb2; Preferably, the formula III is further selected from the following structures: Wherein, R1, Ra, and Rb1 independently have the definitions described in any one of claims 1 to 3; Rb 11 , Rb 12 are the same or different and independently have the meaning given above for Rb2.

5. The compound according to any one of claims 1 to 4 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: It has the structure shown in formula (II): in: n＝0,1,2； m＝0，1，2，3； p＝0，1，2，3，4，5； q＝0，1，2； X1, X2, X3, X4 are the same or different and are independently selected from C or N; Y is selected from C or N; Z2 is selected from CR3 or N; Each R1 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R1a: 1-12 Alkyl, C 1-12 Alkoxy, -(C=O)R; The R is selected from C 1-12 Alkyl, C 1-12 Alkoxy, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 3-12 Cycloalkyl; Each R1a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Each R2 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; Ra is selected from -link-E groups or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with 1, 2 or more R a1 The following groups are substituted: C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl, C 1-12 alkyl; Each R a1 are the same or different and are independently selected from H, oxo (=O), halogen, COOH, OH, unsubstituted or optionally substituted with 1, 2 or more R a2 The following groups are substituted: NH2, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, C 3-12 Cycloalkyl, C 6-14 Aryl C(=O)-, 5-14 membered heteroaryl C(=O)-, 3-14 membered heterocyclyl C(=O)-, C 3-12 Cycloalkyl C(=O)-, C 1-12 Alkyl S(=O)2-, C 1-12 Alkyl S(=O)-, C 1-12 Alkyl S(=O)(=NH)-, C 3-12 Cycloalkyl S(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C 1-12 Alkyl-S(=O)2-NH--; Each R a2 are the same or different and are independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino,; R3 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6- 14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; Each R3a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R3b: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each R3b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; R4 is selected from the group -link-E or H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4a: C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl, C 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C 3-12 Cycloalkyl; Each R4a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R4b: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each R4b is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino; and at least one of Ra and R4 is a -link-E group, the -link-E group in Ra is -link1-E1, and the -link-E group in R4 is -link2-E2; link1 and link2 are the same or different and are independently selected from -Cy1-L1-Cy2-L2-Q-; Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted with the following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, 5-14 membered heteroarylene; Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted with the following groups: 3-14 membered heterocyclylene, C 3-12 Cycloalkylene, C 6-14 Arylene, 5-14 membered heteroarylene; L1 is absent or selected from N(R L ), unsubstituted or optionally substituted with one, two or more R L1 Substituted with the following groups: C 1-12 Alkylene, C 1-12 Alkyleneoxy; R L Select from H or C 1-12 alkyl; L2 is absent or selected from unsubstituted or optionally substituted with one, two or more R L2 Substituted with the following groups: C 1-12 Alkylene, (C 1-12 Alkyleneoxy) t ; t is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8; Q is absent or selected from O, N(R q ), ethynylene; R q Select from H or C 1-12 alkyl; R Cy1 , R Cy2 are the same or different and are independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy; R L1 , R L2 are the same or different and are independently selected from halogen, oxo (=O), C 1-12 Alkyl, C 1-12 Alkoxy; Cy1 end connected, the Q terminal is connected to E1 or E2; E1 and E2 are the same or different and are independently selected from Ring G is selected from g Substituted 5-6 membered N-containing heterocyclic group; each R g are the same or different and are independently selected from H, oxo (=O), C 1-12 Alkyl or And ring G contains at least one R g1 Selected from H, hydroxyl C 1-12 Alkyl, (R g11 )(R g12 )-NC 1-12 Alkyl-C(O)OC 1-12 Alkyl; R g11 , R g12 The same or different, independently selected from H, C 1-12 alkyl; represents the junction site; Each R5 is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R5a: 1-12 Alkyl, C 1-12 Alkoxy; Each R5a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy; R6 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R6a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl; Each R6a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; R7 is selected from H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more R7a: 1- 12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl; Each R7a is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Or R6 and R7 together form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rsa: 6-14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group; the 5-14 membered heteroaryl, 3-14 membered heterocyclic group contains at least one N atom; Each Rsa is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted by 1, 2 or more Rsb: 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino, C 1-12 Alkyl C(=O)-, C 1-12 Alkoxy C(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl; Each Rsb is the same or different and is independently selected from oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino.

6. The compound according to any one of claims 1 to 5 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The part is selected from the following structures: Preferably, Each R1 is the same or different and is independently selected from oxo (=O), C 1-6 Alkyl, C 1-6 Alkoxy, -(C=O)R; wherein R is selected from C 1-6 Alkyl, C 1-6 Alkoxy, NH2-, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl; Preferably, R1 is -(C=O)CH3, -C(=O)OCH3, -C(=O)NH-CH3; Preferably, Ra is selected from a -link1-E1 group or a 5-8 membered heterocyclic group; the 5-8 membered heterocyclic group is, for example Preferably, R3 is selected from halogenated C 1-6 alkyl; Preferably, R3 is selected from -CHF2; Preferably, R4 is selected from -link2-E2 group or 5-6 membered heteroaryl (eg pyrazolyl) which is unsubstituted or optionally substituted by one, two or more R4a; each R4a is the same or different and is independently selected from C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R4 is Preferably, R6 and R7 together form the following group which is unsubstituted or optionally substituted by 1, 2 or more Rsa: 5-6 membered heterocyclyl, C 6- 10 aryl, such as piperidinyl or phenyl; Preferably, R6 and R7 together form the following structure which is unsubstituted or optionally substituted by 1, 2 or more Rsa: Preferably, The part is selected from the following structures: Preferably, Cy1 is selected from unsubstituted or optionally substituted with one, two or more R Cy1 Substituted with the following groups: 5-8 membered heterocyclylene, C 3-8 Cycloalkylene, 5-10 membered heteroarylene; Preferably, Cy1 is selected from piperidinylene, cyclohexylene, pyridinylene; for example Preferably, Cy2 is absent or selected from unsubstituted or optionally substituted with one, two or more R Cy2 Substituted with the following groups: 5-8 membered heterocyclylene, C 3-8 Cycloalkylene, C 6-10 Arylene, 5-10 membered heteroarylene; Preferably, Cy2 is absent or selected from piperidinylene, morpholinylene, piperazinylene, phenylene, pyridinylene, triazolylene; for example Preferably, L1 is absent or selected from unsubstituted or optionally substituted with one, two or more R L1 Substituted C 1-10 Alkylene; Preferably, L1 is absent or selected from NH, N(CH3), methylene, ethylene, Preferably, L2 is absent or selected from C 1-6 Alkylene, (C 1-6 Alkyleneoxy) t ; t is selected from 1, 2, 3, 4; Preferably, L2 is absent or selected from methylene, ethylene, propylene, ethyleneoxy, Preferably, Q is absent or selected from O, NH, ethynylene. Preferably, link1 and link2 are the same or different and are independently selected from Preferably, ring G is selected from g Substituted tetrahydropyrrolyl, imidazolidinyl; e.g. Preferably, ring G is selected from Preferably, each R g are the same or different and are independently selected from H, oxo (=O), C 1-6 Alkyl or Preferably, R g1 Selected from H, hydroxyl C 1-6 Alkyl, (C 1-6 Alkyl)(C 1-6 Alkyl)-NC 1-6 Alkylene-C(O)OC 1-6 Alkylene, H2N-C 1-6 Alkylene-C(O)OC 1-6 Alkylene; Preferably, R g1 Selected from H, hydroxymethyl, Preferably, E1 and E2 are the same or different and are independently selected from: Preferably, E1 and E2 are the same or different and are independently selected from:

7. The compound according to any one of claims 1 to 6 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: The formula (III) is further selected from the following structures: Wherein, R1, R2, Ra, R4, R5, R6, R7, X1, X2, X3, X4, Y, Z, m, n, q have the definitions as described in any one of claims 1 to 6; Preferably, the formula (III) is further selected from the following structures: Wherein, R1, R2, Ra, R4, R5, X1, X2, X3, X4, lm, n, p, q have the definitions as described in any one of claims 1-6; Preferably, the formula (III) is further selected from the following structures: Among them, R1, R2, Ra, R4, R5, R6, R7, X1, X2, X3, X4, Y, Z, link1, link2, E1, E2, m, n, p, q have the definitions described in any one of claims 1-6.

8. The compound according to any one of claims 1 to 7 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that: Exemplary specific compounds of the compound represented by formula (III) are as follows:

9. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound of formula III as described in any one of claims 1 to 8 and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof; Preferably, the pharmaceutical composition comprises a second therapeutic agent, Preferably, the second therapeutic agent can be selected from drugs conventionally used to treat cancer, heart disease, metabolic disease, inflammatory disease, fibrotic disease and viral infection; preferably, the category of the second therapeutic agent can include androgen receptor antagonists, such as enzalutamide, and inhibitors of CYP17A1 (17α-hydroxylase / C17,20 lyase), such as abiraterone; cytotoxic chemotherapeutic agents, such as docetaxel; the category of therapeutic agents for treating lung cancer includes cytotoxic chemotherapeutic agents, such as cisplatin, carboplatin, docetaxel; the category of therapeutic agents for treating bladder ... The first therapeutic agent class includes cytotoxic chemotherapeutics, such as gemcitabine, cisplatin or immunotherapy, such as bacillus Calmette-Guérin (BCG); the second therapeutic agent class can also be selected from immune checkpoint inhibitors, such as pembrolizumab, nivolumab, atezolizumab, ipilimumab; PARP (poly ADP ribose polymerase) inhibitors such as olaparib; and CDK4 / 6 (cyclin-dependent kinase 4 and 6) inhibitors; preferably, the second therapeutic agent can be selected from combination therapy with KRAS inhibitors, etc.

10. Use of a compound of formula III according to any one of claims 1 to 8 and its racemate, stereoisomer, tautomer, isotope-labeled substance, nitrogen oxide, solvate, polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 9 in the preparation of a medicament for preventing and / or treating diseases or conditions mediated by EP300 and / or CBP; Preferably, the EP300 and / or CBP-mediated disease or condition is selected from cancer, heart disease, metabolic disease, inflammatory disease, fibrotic disease and viral infection; the cancer includes but is not limited to prostate cancer, breast cancer, bladder cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, ovarian cancer, cervical cancer, bladder cancer, laryngeal cancer, multiple myeloma, liver cancer, lymphoma and leukemia, etc.; prostate cancer can be, for example, castration-resistant prostate cancer (CRPC); lung cancer can be, for example, non-small cell lung cancer or small cell lung cancer; the lymphoma can be selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, etc.

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