EP300 / CBP regulator and its manufacturing method and use

Abstract

The present disclosure relates to an EP300 / CBP modulator as shown in Formula I, and methods for preparing and using the same, wherein the structure of Formula I is as follows: [Case 1] JPEG2025529942000172.jpg39169

Description

Detailed Description of the Invention

[0001] The present invention provides Priority of the earlier application of patent application number 2022110436007, titled "EP300 / CBP inhibitors and their manufacturing methods and uses," filed with the State Intellectual Property Office of China on August 29, 2022; Priority of the earlier application of patent application number 2022111123014, titled "EP300 / CBP inhibitors and their manufacturing methods and uses," filed with the State Intellectual Property Office of China on September 13, 2022; Priority of U.S. Provisional Application No. US63 / 375,444, "EP300 / CBP Inhibitors and Methods for Making and Using the Same," filed September 13, 2022; Priority of the earlier application of patent application number 2023110490720, titled "EP300 / CBP inhibitors and their manufacturing methods and uses," filed with the State Intellectual Property Office of China on August 18, 2023; The entirety of the above-referenced prior application is incorporated herein by reference.

[0002] [Technical field] The present disclosure relates to the pharmaceutical field, and specifically to EP300 / CBP modulators and their preparation and use.

[0003] [Background technology] Histone acetyltransferases (HATs) and histone deacetylases (HDACs) affect histone acetylation. The recruitment and normal function of HATs and HDACs are crucial regulatory steps in gene expression and cell cycle regulation, and functional defects of these enzymes can lead to various diseases, including tumors. The E1A-binding protein EP300 (EP300) and its closely related homolog, the cAMP response element-binding protein (CBP)-binding protein, are ubiquitously expressed lysine acetyltransferases that transfer the acetyl group from acetyl-coenzyme A to ε-N-acetyllysine, thereby acetylating conserved lysine residues within histones.

[0004] EP300 / CBP acetylates non-histone proteins, such as nuclear receptors and other transcription factors, and forms transcription complexes with transcription factors, playing a transcriptional coactivating role and regulating gene expression. EP300 and CBP are protein molecules with multiple functional domains and mediate interactions between multiple proteins. As transcriptional coactivators, EP300 and CBP bind to various transcription factors to regulate target gene expression. The resulting changes in protein expression affect many fundamental functions, including cell proliferation, cell cycle, cell differentiation, and DNA damage response, and further influence cellular phenotype, playing an important role in the development and progression of multiple tumors. Current research has shown that EP300 / CBP is highly expressed and activated in various tumors and is closely associated with multiple tumor diseases. EP300 / CBP is therefore a promising target for tumor therapy, attracting increasing attention from researchers.

[0005] The EP300 / CBP bromodomain, a domain of approximately 110 amino acids, can recognize acetylated lysine residues. The bromodomain functions as a lysine acetylation "reader," transducing the signal from acetylated lysine residues and converting that signal into a normal or abnormal phenotype. The EP300 / CBP bromodomain has a wide range of functions, ranging from histone acetyltransferase activity and chromatin remodeling to mediating transcriptional coactivation. Currently, a growing body of evidence suggests that the bromodomain plays an important role in tumor progression, and modulators targeting specific EP300 / CBP bromodomains have significant developmental value and clinical significance in various tumors.

[0006] However, only a few EP300 / CBP-specific bromodomain modulators have been reported to date, and most are still in the research and development stage or early clinical trials. Furthermore, they suffer from low activity and poor safety, making them far from meeting clinical needs. Therefore, the development of EP300 / CBP modulators with novel structures, higher selectivity, and better activity is of great importance for the treatment of various EP300 / CBP-related tumors.

[0007] [Summary of the Invention] To solve the problems in the prior art, a first aspect of the present disclosure provides a compound of Formula I and its racemates, stereoisomers, tautomers, isotopic derivatives, nitroxides, solvates, crystalline polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof:

[0008] [ka]

[0009] Among them, n=0, 1, 2, m=0, 1, 2, 3, p=0, 1, 2, 3, 4, 5, q=0, 1, 2, X1, X2, X3, and X4 are independently selected from C or N; Each R1 may be the same or different and may independently be oxo (=O), halogen, CN, NH2, COOH, OH, C unsubstituted or optionally substituted with one, two or more R1a; 1-12 Alkyl group, C 1-12 an alkoxy group, and —(C═O)R; The above R is C 1-12 Alkyl group, C 1-12 Alkoxy group, NH2-, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 3-12 cycloalkyl groups, Each R1a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 selected from alkoxy groups, Each R2 may be the same or different and independently represent oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 selected from alkoxy groups, R2' is H, halogen, CN, NH2, COOH, OH, C unsubstituted or optionally substituted with one, two or more R2a; 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 Cycloalkyl groups, C 1-12 selected from alkyl groups, Each R2a is the same or different and independently represents H, oxo (=O), halogen, COOH, OH, NH2 unsubstituted or optionally substituted with one, two or more R2b, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkylthio group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 Cycloalkyl groups, C 6-14 Aryl C(=O)-, 5-14 membered heteroaryl C(=O)-, 3-14 membered heterocyclyl group C(=O)-, C 3-12 CycloalkylC(=O)-, C 1-12 AlkylS(=O)2-, C 1-12 AlkylS(=O)-, C 1-12 AlkylS(=O)(=NH)-, C 3-12 CycloalkylS(=O)2-, C 1-12 Alkyl-C(=O)-NH-, C1-12 alkyl-S(=O)2-NH--; Each R2b is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, R3 is H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with one, two or more R3a; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 cycloalkyl groups, Each R3a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C unsubstituted or optionally substituted with one, two or more R3b; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, Each R3b is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, R4 is H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with one, two or more R4a; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 cycloalkyl groups, Each R4a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C which is unsubstituted or optionally substituted with one, two or more R4b; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, Each R4b is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, Each R5 is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C unsubstituted or optionally substituted with one, two or more R5a; 1-12 Alkyl group, C 1-12 selected from alkoxy groups, Each R5a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12selected from alkoxy groups, R6 is H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with one, two or more R6a; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl groups, Each R6a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, R7 is H, halogen, CN, NH2, COOH, OH, unsubstituted or optionally substituted with one, two or more R7a; 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC(=O), N,N-diC 1-12 alkylaminocarbonyl groups, Each R7a is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12alkylaminocarbonyl groups, or R6 together with R7 form a 5-14 membered heteroaryl group, a 3-14 membered heterocyclyl group, which is unsubstituted or optionally substituted with one, two or more Rsa, and the 5-14 membered heteroaryl group, the 3-14 membered heterocyclyl group contains at least one N atom; Each Rsa may be the same or different and may independently be oxo (=O), halogen, CN, NH2, COOH, OH, C unsubstituted or optionally substituted with one, two or more Rsb. 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, Each Rsb may be the same or different and independently represent oxo (=O), halogen, CN, NH2, COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups.

[0010] In some embodiments, X1, X2, X3, and X4 are all selected from C; In some embodiments, X1 and X2 are N, and X3 and X4 are C; In some embodiments, In some embodiments, in Formula I:

[0011] [ka]

[0012] The moiety is selected from the following structures:

[0013] [ka]

[0014] On the above structure are present the R1, R2 substituents defined above.

[0015] In some embodiments, each R is the same or different and independently represents oxo (=O), C 1-6 Alkyl group, C 1-6 an alkoxy group, and —(C═O)R, wherein R is C 1-6 Alkyl group, C 1-6 Alkoxy group, NH2-, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl groups, In some embodiments, R1 is a substituent on a ring N atom, illustratively, for example,

[0016] [ka]

[0017] (* indicates the substitution position of R1 above).

[0018] In some embodiments, R1 is —(C═O)CH3; In some embodiments, each R is the same or different and is independently selected from =O, CH, -C(=O)CH, -C(=O)OCH, -C(=O)OCHCH, CHNHC(=O)-, CHCHNHC(=O)-, NHC(=O)-, cyclopropylC(=O)-; In some embodiments, R2' is H, Cl, unsubstituted or C optionally substituted with one, two or more R2a. 6-10 Aryl groups, 5-9 membered heteroaryl groups, 3-12 membered heterocyclyl groups, C 3-8 Cycloalkyl groups, C 1-3 alkyl groups, wherein the heterocyclyl group contains 1 to 4 (1, 2, 3, 4) heteroatoms selected from N, O, and S; In some embodiments, R2' is selected from the following structures: H, Cl, unsubstituted or optionally substituted with one, two or more R2a:

[0019] [ka]

[0020] .

[0021] In some embodiments, R2' is selected from the following structures:

[0022] [ka]

[0023] .

[0024] In some embodiments, R2a is H, halogen (e.g., F), a methyl group, an ethyl group, oxo (=O), a methoxy group, OH, COOH,

[0025] [ka]

[0026] CH3C(=O)-, -CH2CHF2, -CH2CF3, -Cbz, -Boc, amino group, methylamino group, dimethylamino group, methylthio group,

[0027] [ka]

[0028] -CHCN,

[0029] [ka]

[0030] Selected from.

[0031] In some embodiments, R2' is selected from the following structures: H, Cl,

[0032] [ka]

[0033] JPEG2025529942000012.jpg213169

[0034] JPEG2025529942000013.jpg43169

[0035] .

[0036] In some embodiments, R3 is H, unsubstituted or C optionally substituted with one, two or more R3a. 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 cycloalkyl groups, each R3a is the same or different and is independently selected from halogen, CN, NH2, COOH, and OH; In some embodiments, R3 is H, -CHF2,

[0037] [ka]

[0038] Selected from In some embodiments, R4 is selected from a 5-6 membered heteroaryl group (e.g., a pyrazolyl group) that is unsubstituted or optionally substituted with one, two or more R4a, and each R4a is the same or different and independently selected from C4a that is unsubstituted or optionally substituted with one, two or more R4b. 1-6 Alkyl group, C 1-6 Alkoxy group, N,N-diC 1-6 alkylaminocarbonyl groups, and each R4b is the same or different and independently represents oxo (=O), halogen, CN, NH2, COOH, OH, C 1-6Alkyl group, C 1-6 selected from alkoxy groups, In some embodiments, R4 is

[0039] [ka]

[0040] Selected from In some embodiments, each R5 is the same or different and independently represents H, halogen, C 1-6 Alkyl group, C 1-6 selected from alkoxy groups, In some embodiments, R6 is H, halogen, C 1-6 Alkyl group, C 1-6 selected from alkoxy groups, In some embodiments, R6 is H; In some embodiments, R7 is H, halogen, C 1-6 Alkyl group, C 1-6 selected from alkoxy groups, In some embodiments, R7 is F; In some embodiments, R6 together with R7 form a 5-6 membered heteroaryl group, a 5-6 membered heterocyclyl group that is unsubstituted or optionally substituted with one, two or more Rsa groups.

[0041] In some embodiments, R6 together with R7 form the following structure, unsubstituted or optionally substituted with one, two or more Rsa:

[0042] [ka]

[0043] .

[0044] In some embodiments, the above formula I is further selected from the structures shown in formula I-1 below:

[0045] [ka]

[0046] wherein X1, X2, X3, X4, R1, R2, R2', R3, R4, R5, R6, R7, R, N, m, p, and q are as defined for the compounds in formula (I); R1' has the definition given in R1; In some embodiments, R1' is oxo (=O), C 1-6 Alkyl group, C 1-6 an alkoxy group, and —(C═O)R, wherein R is C 1-6 Alkyl group, C 1-6 Alkoxy group, NH2-, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl groups, In some embodiments, R' is selected from H, CH, -C(=O)CH, -C(=O)OCH, -C(=O)OCHCH, -C(=O)OCH(CH), CHNHC(=O)-, CHCHNHC(=O)-, NHC(=O)-, cyclopropyl-C(=O)-; In some embodiments, R1' is -(C=O)CH3.

[0047] In some embodiments, the above formula I is further selected from the structures shown in formula II, formula III, and formula IV below:

[0048] [ka]

[0049] In the above formulas II, III and IV, X1, X2, X3, X4, R1, R2, R2', R3, R4, R5, R6, R7, R, N, m, p and q are as defined for the compounds in formula (I).

[0050] In some embodiments, the above formula I is further selected from the structures shown in formula IIa and formula IIIa below:

[0051] [ka]

[0052] In the above formula IIa and formula IIIa, X1, X2, X3, X4, R1, R2, R2', R3, R4, R5, R, n, m, p, and q are as defined for the compounds in formula (I).

[0053] In some embodiments, exemplary specific compounds of the compounds of formula (I) are as follows:

[0054] [Table 1]

[0055] JPEG2025529942000021.jpg214169

[0056] JPEG2025529942000022.jpg214169

[0057] JPEG2025529942000023.jpg214169

[0058] JPEG2025529942000024.jpg214169

[0059] JPEG2025529942000025.jpg214169

[0060] JPEG2025529942000026.jpg214169

[0061] JPEG2025529942000027.jpg214169

[0062] JPEG2025529942000028.jpg214169

[0063] JPEG2025529942000029.jpg214169

[0064] JPEG2025529942000030.jpg214169

[0065] JPEG2025529942000031.jpg214169

[0066] JPEG2025529942000032.jpg214169

[0067] JPEG2025529942000033.jpg214169

[0068] JPEG2025529942000034.jpg226169

[0069] JPEG2025529942000035.jpg187169

[0070] In a further aspect, the present disclosure further provides pharmaceutical compositions comprising a compound of Formula I (including Formulas II, III, IV, IIa, IIIa) and its racemates, stereoisomers, tautomers, isotopic derivatives, nitroxides, solvates, crystalline polymorphs, metabolites, esters, prodrugs, or pharmaceutically acceptable salts thereof.

[0071] In a further aspect, the present disclosure further provides the use of a compound of Formula I (including Formulas II, III, IV, IIa, and IIIa) and its racemate, stereoisomer, tautomer, isotopic derivative, nitroxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, and pharmaceutical compositions containing them, in the manufacture of a medicament for preventing and / or treating a disease or condition mediated by CBP and / or EP300.

[0072] In a further aspect, the present disclosure further provides a method for treating and / or preventing a disease or condition mediated by CBP and / or EP300, comprising administering to a subject a therapeutically effective amount of a compound represented by Formula I (including Formulas II, III, IV, IIa, and IIIa), and its racemate, stereoisomer, tautomer, isotopic derivative, nitroxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same.

[0073] The diseases or conditions mediated by CBP and / or EP300 described herein are selected from cancer, cardiac disease, metabolic disease, inflammatory disease, fibrodegenerative disease, and viral infection. The cancers include, but are 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. The prostate cancer may be, for example, castration-resistant prostate cancer (CRPC). The lung cancer may be, for example, non-small cell lung cancer or small cell lung cancer. The lymphoma may be selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and the like.

[0074] The compounds of the present disclosure can be used in combination with other drugs or other therapies.

[0075] In some embodiments, the compounds of the present disclosure are used in combination with radiation therapy.

[0076] In some embodiments, the present invention also provides for the use of the above compounds in combination with an immunomodulatory agent for the treatment of a CBP- and / or EP300-mediated disease or condition (eg, multiple myeloma).

[0077] In some embodiments, the immunomodulatory agent comprises tumor necrosis factor, interferon alpha, beta and gamma, IL-2 and other cytokines, F42K and other cytokine analogs, or MIP-1, MIP-1 beta, MCP-1, RANTES and other chemokines.

[0078] In some embodiments, the compounds of the present disclosure are used in combination with a second therapeutic agent, where the second therapeutic agent is selected from drugs commonly used to treat cancer, cardiac disease, metabolic disease, inflammatory disease, fibrotic disease, and viral infection. In some embodiments, categories of the second therapeutic agent include androgen receptor antagonists such as enzalutamide, CYP17A1 (17α-hydroxylase / C17,20 lyase) inhibitors such as abiraterone, and cytotoxic chemotherapeutic agents such as docetaxel. Categories of therapeutic agents used to treat lung cancer include cytotoxic chemotherapeutic agents such as cisplatin, carboplatin, and docetaxel. Categories of therapeutic agents used to treat bladder cancer include cytotoxic chemotherapeutic agents such as gemcitabine and cisplatin, or immunotherapeutic agents such as Bacillus Calmette-Guerin (BCG). Categories of the second therapeutic agent include, for example, immune checkpoint inhibitors such as pembrolizumab, nivolumab, atezolizumab, and 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 is used in combination with a KRAS inhibitor or the like, and can be selected for the treatment of various tumors such as lung cancer, colon cancer, pancreatic cancer, liver cancer, and blood tumors.

[0079] Accordingly, the present disclosure provides a combination composition comprising a compound of Formula I (including Formulas II, III, IV, IIa, and IIIa) and its racemate, stereoisomer, tautomer, isotopic derivative, nitroxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof, and the second therapeutic agent described above, The present disclosure further provides a combination method for treating and / or preventing a disease or condition mediated by CBP and / or EP300, comprising administering to a subject therapeutically effective amounts of a compound of Formula I (including Formulas II, III, IV, IIa, and IIIa), its racemate, stereoisomer, tautomer, isotopic derivative, nitroxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent.

[0080] Pharmaceutically acceptable salts of the compounds of the present disclosure may be inorganic salts or organic salts; if these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; and if these compounds contain both an acidic center (e.g., a carboxy group) and a basic center (e.g., an amino group), they can also form inner salts.

[0081] The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. For example, all isomers, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, and (L)-isomers, as well as racemic and other mixtures, and mixtures such as enantiomerically or diastereomerically enriched mixtures, are within the scope of the present disclosure. Substituents, such as alkyl groups, may contain other asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present disclosure.

[0082] The compounds and intermediates of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers with different energy states that are interconvertible via a low energy barrier. For example, proton tautomers (also called proton-transition tautomers) include interconversions via proton transitions, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds in the present disclosure are included within the scope of the present disclosure. The naming of a compound in a single way does not exclude any tautomers.

[0083] The present disclosure further includes certain isotopically labeled compounds of the present disclosure that have the same structure as described herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 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 Cl, etc. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0084] Unless otherwise specified, when a position is identified as deuterium (D), it is understood that the position contains a concentration of deuterium at least 1000 times greater than the natural abundance (0.015%) (i.e., at least 10% deuterium incorporation). In exemplary compounds, an abundance of deuterium greater than the natural abundance is at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or more than the natural abundance. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of compounds by referring to the relevant literature. When preparing deuterated forms of the compounds, commercially available deuterated starting materials may be used or they may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, lithium aluminum deuterated hydride, deuterated iodoethane, and deuterated iodomethane.

[0085] In this disclosure, the term "modulator" refers to a compound that alters (i.e., increases or decreases) the activity of a target biomolecule, such as, for example, an enzyme. Generally, modulators are small molecules.

[0086] The term "modulation" refers to the ability of a compound to increase or decrease the function and / or expression of a target (e.g., EP300 or CBP), where these functions include transcriptional regulatory activity and / or binding. Modulation can occur in vitro or in vivo. As used herein, "modulation" includes direct or indirect inhibition, antagonism, partial antagonism, degradation, activation, agonism, partial agonism of a function or property associated with EP300 or CBP, and / or direct or indirect upregulation or downregulation of EP300 or CBP expression. In another embodiment, modulation is direct. An inhibitor, antagonist, or degrader refers to a compound that partially or completely blocks, reduces, prevents, suppresses, delays activation, inactivates, blunts, or downregulates signal transduction (e.g., by binding). An activator or agonist agent refers to a compound that stimulates, increases, opens, activates, promotes, enhances activation, activates, sensitizes, or upregulates signal transduction (e.g., by binding). Thus, "EP300&CBP modulators" can further encompass "EP300&CBP inhibitors," "EP300&CBP degraders," and "EP300&CBP agonist agents."

[0087] In the present disclosure, the term "CBP- and / or EP300-mediated disease or condition" refers to a disease or condition in which the biological function of EP300, CBP, or both EP300 and CBP influences the progression and / or activity of the disease or condition, and / or refers to a disease or condition in which modulation of EP300, CBP, or both EP300 and CBP alters the progression, activity, and / or symptoms of the disease or condition. An EP300- or CBP-mediated disease or condition includes a disease or condition in which inhibition of EP300, CBP, or both EP300 and CBP provides a therapeutic benefit, for example, when treatment with an EP300 or CBP inhibitor (including a compound described herein) provides a therapeutic benefit to a subject with or at risk for the disease or condition. An EP300- or CBP-mediated disease or condition includes a cancer with a loss-of-function mutation in CBP or EP300, or a cancer in which activation of EP300 or CBP is observed. EP300- or CBP-mediated diseases or conditions also include cancers that express the androgen receptor.

[0088] In this disclosure, the term "therapeutically effective amount" refers to an amount of an active compound or drug that elicits a desired biological or medical response in a tissue, system, animal, individual, or human by a researcher, veterinarian, physician, or other clinician, etc., and includes one or more of the following: (1) disease prevention: e.g., preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not experiencing or exhibiting the pathology or symptoms of the disease; (2) disease inhibition: e.g., inhibiting a disease, disorder, or condition (i.e., preventing further progression of the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition; and (3) disease alleviation: e.g., alleviating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, disorder, or condition. In the case of a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. Determining an effective amount will vary from person to person, will depend on the age and general condition of the subject, and will also depend on the specific active agent, and an appropriate effective amount in any given case can be determined by one of ordinary skill in the art based on routine testing.

[0089] [Beneficial effects] The present disclosure provides novel compounds having a structure represented by formula (I), which have excellent EP300 / CBP modulating activity (eg, inhibitory activity) and potential pharmaceutical applications.

[0090] [Term definitions and explanations] Unless otherwise specified, terms used in the specification and claims have the following meanings.

[0091] 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 1-6(Alkyl groups). Non-limiting examples of alkyl groups 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. Alkyl groups may be substituted or unsubstituted.

[0092] The term "alkoxy group" refers to an -O-(alkyl group), where alkyl is as defined herein. Non-limiting examples of alkoxy groups include methoxyoxy, ethoxy, propoxy, and butoxy groups. Alkoxy groups may be substituted or unsubstituted.

[0093] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring preferably contains 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 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, and polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups.

[0094] The term "spiroalkyl group" refers to a polycyclic group in which each monocyclic ring in the system shares one carbon atom (referred to as a spiro atom) between them, and may contain one or more double bonds. It is preferably 6 to 12-membered, and more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Spirocycloalkyl groups are classified as monospirocycloalkyl groups, bisspirocycloalkyl groups, or polyspirocycloalkyl groups depending on the number of spiro atoms shared between the rings. Monospirocycloalkyl groups and bisspirocycloalkyl groups are preferred. More preferred are 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0095] [ka]

[0096] .

[0097] The term "fused cycloalkyl group" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and one or more of the rings may contain one or more double bonds. Preferably, it is 6 to 12-membered, more preferably 7 to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, fused cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0098] [ka]

[0099] .

[0100] The term "bridged cycloalkyl group" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and may contain one or more double bonds. Preferably, it has 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, bridged cycloalkyl groups may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, and are preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include the following:

[0101] [ka]

[0102] .

[0103] The cycloalkyl ring is a cycloalkyl group as defined 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 include:

[0104] [ka]

[0105] and the like, preferably

[0106] [ka]

[0107] The cycloalkyl groups may be substituted or unsubstituted.

[0108] The term "heterocyclyl group" means a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 14 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or sulfur, which sulfur may optionally be oxo-substituted (i.e., to form a sulfoxide or sulfone), but does not include -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) ring atoms, of which 1 to 4 (e.g., 1, 2, 3, 4) are heteroatoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, 8) ring atoms, of which 1 to 3 (e.g., 1, 2, 3) are heteroatoms, even more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms, and most preferably 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyran, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused-ring and bridged-ring heterocyclyl groups.

[0109] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group in which each monocyclic ring shares one atom (referred to as a spiro atom), in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which may be optionally substituted with oxo (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It preferably has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spiroheterocyclyl groups are classified as monospiroheterocyclyl groups, bisspiroheterocyclyl groups, or polyspiroheterocyclyl groups, with monospiroheterocyclyl groups and bisspiroheterocyclyl groups being preferred. More preferably, it is a 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0110] [ka]

[0111] .

[0112] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more rings optionally containing one or more double bonds, one or more ring atoms being a heteroatom selected from nitrogen, oxygen, and sulfur, which sulfur may optionally be oxo-substituted (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, the heterocyclyl group has 6 to 14 ring members, more preferably 7 to 10 ring members (e.g., 7, 8, 9, or 10 ring members). Depending on the number of constituent rings, the heterocyclyl groups may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered and 6-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of fused heterocyclyl groups include:

[0113] [ka]

[0114] .

[0115] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group in which any two rings share two atoms that are not directly connected, and may contain one or more double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or sulfur, which may optionally be oxo-substituted (i.e., to form sulfoxide or sulfone), and the remaining ring atoms are carbon. The heterocyclyl group preferably has 6 to 14 ring members, more preferably 7 to 10 ring members (e.g., 7, 8, 9, or 10 ring members). Depending on the number of ring members, the heterocyclyl group may be divided into bicyclic, tricyclic, tetracyclic, or polycyclic rings, and is preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0116] [ka]

[0117] .

[0118] The heterocyclyl ring is a heterocyclyl group as described herein (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a cyclyl group, and non-limiting examples include:

[0119] [ka]

[0120] etc. The heterocyclyl groups may be substituted or unsubstituted.

[0121] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic rings share adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, such as a phenyl group or naphthyl group. The aryl group rings described herein, including the aryl group rings, are fused to a heteroaryl group, heterocyclyl group, or cycloalkyl group ring, in which the ring connected to the parent structure is an aryl group ring, and non-limiting examples thereof include:

[0122] [ka]

[0123] The aryl group may be substituted or unsubstituted.

[0124] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furan, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, trizolyl, and tetrazolyl. The heteroaryl rings described herein, including heteroaryl groups, are fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring, and non-limiting examples thereof include:

[0125] [ka]

[0126] Heteroaryl groups may be substituted or unsubstituted.

[0127] Those skilled in the art will understand that the above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived by removing one hydrogen atom from a parent ring atom, or by removing two hydrogen atoms from two identical or different parent ring atoms, i.e., "divalent cycloalkyl," "divalent heterocyclyl," "arylene," and "heteroarylene" groups.

[0128] The term "halogen" refers to F, Cl, Br and I.

[0129] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and the phrase includes instances where the event or circumstance occurs and instances 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 the phrase 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.

[0130] The term "more than" includes three, four, five and more.

[0131] [Mode for Carrying Out the Invention] The technical solutions of the present disclosure will be described in more detail below in conjunction with specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present disclosure. Any technology realized based on the above content of the present disclosure is included within the scope of the claims of the present disclosure.

[0132] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available or may be prepared by known methods.

[0133] Example 1 Synthesis of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline:

[0134] [ka]

[0135] Synthesis of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline: 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 h. The reaction mixture was quenched by adding ice-cold HO (200 mL) and extracted with DCM (150 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 10%) to give compound 2 (16 g, 61.1 mmol, 62.1% yield) as a yellow solid. MS (ESI): C10H11F2N; found 262.6 (M+H) + . 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=6.3 Hz, 2H), 1.88 - 1.79 (m, 2H).

[0136] Synthesis of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline: 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-dioxybenzofuran-2-yl)pyrazole (8.7 g, 41.9 mmol, 1 eq), cyclopentyl(diphenyl)phosphine, palladium dichloride, iron (3.0 g, 4.2 mmol, 0.1 eq), and K2CO3 (11.6 g, 83.9 mmol, 2 eq) in dioxane (80 mL) and HO (20 mL) was stirred at 110 °C with N2 gas for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 0 to 40%) to give int-9 (10 g, 37.9 mmol, 90.5% yield) as a brown solid. MS (ESI): C14H15F2N3; found 263.9 (M+H) + . 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=6.0 Hz, 2H), 1.79 (quin, J=5.9 Hz, 2H).

[0137] Example 2 Synthesis of 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:

[0138] [ka]

[0139] Synthesis of 5-chloro-3-iodo-2-methylbenzoic acid: To a solution of compound 1 (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 h. The reaction mixture was poured into ice water (500 mL), stirred for 30 min, and filtered to give compound 2 (68.5 g, 231 mmol, 78.8% yield) as a brown solid. MS (ESI): C8H6ClIO2; found 294.8 (MH) + ..

[0140] Synthesis of methyl 5-chloro-3-iodo-2-methylbenzoate: To a solution of compound 2 (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 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (300 mL), and the combined organic phase was washed with aqueous NaHCO3 (200 mL) and brine (200 mL). It was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound 3 (58.5 g, 188.4 mmol, 81.5% yield) as a yellow oil. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.98 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 3.92 (s, 4H), 2.64 (s, 3H).

[0141] Synthesis of methyl 2-(bromomethyl)-5-chloro-3-iodobenzoate: To a solution of methyl 5-chloro-3-iodo-2-methylbenzoate (55 g, 177.12 mmol, 1 eq) in CCl4 (350 mL) were added NBS (33 g, 185.41 mmol, 1.05 eq) and BPO (4.5 g, 18.58 mmol, 1e-1 eq). The mixture was stirred at 80 °C for 17 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100 / 0 to 10 / 1) to give compound 4 (40 g, 103.1 mmol, 57% yield) as a colorless oil. 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.97 (d, J=2.2 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 5.01 (s, 2H), 3.89 (s, 3H).

[0142] Synthesis of methyl 2-(bromomethyl)-5-chloro-3-iodobenzoate: Compound 4 (40 g, 102.5 mmol, 1 eq) was added to a solution of NH3 / MeOH (150 mL). The mixture was stirred at 60 °C for 2.5 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was washed three times with EA (150 mL) to give compound 5 (20.6 g, 70.4 mmol, 68.5% yield) in the form of a white solid. MS (ESI): C8H6ClINO; found 295.8 (M+H) + . 1 H NMR (400MHz, DMSO-d6) δ = 8.96 (brs, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 4.18 (s, 2H).

[0143] Synthesis of 6-chloro-4-iodoisoindole: To a solution of compound 5 (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 gas. The mixture was stirred at 45 °C for 54 h. The reaction mixture was quenched by adding 100 mL of 15% NaOH at 0 °C, then filtered and washed with EtOAc. The filtrate was washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (flash silica gel column, eluent: 0-10% MeOH / DCM) to give compound 6 (5.5 g, 19.6 mmol, 33.9%) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ = 7.64 (s, 1H), 7.37 (s, 1H), 4.20 (s, 2H), 3.93 (s, 2H).

[0144] Synthesis of 1-(6-chloro-4-iodoisoindol-2-yl)ethan-1-one: To a solution of compound 6 (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 acetic anhydride (2.46 g, 24.1 mmol, 2.26 mL, 1.5 eq) dropwise under N gas at 0 °C. The mixture was stirred at 25 °C for 16 h. The residue was diluted with HO (100 mL) and extracted with DCM (40 mL × 2). The combined organic layers were washed with NaCl (40 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% ethyl acetate / petroleum ether gradient elution) to give compound 7 (3.25 g, 8.2 mmol, 51% yield, 70% purity) as a brown solid. MS (ESI): C 10 H9ClINO; found 322.3 (M+H) + ..

[0145] Synthesis of 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: Compound 7 (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 placed in a microwave tube containing dioxane (10 mL). The sealed tube was heated in a microwave at 110 °C for 50 min. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 8 (700 mg, 1.53 mmol, 42.8% yield) in the form of a brown solid. MS (ESI): C 24 H 23 ClF2N4O; found 457.0 (M+H) + ..

[0146] Compounds of the 5,6-linked ring (isoindole) class can be synthesized with reference to this method.

[0147] Example 3 Synthesis of M001014 (8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-formamide):

[0148] [ka]

[0149] Synthesis of 8-bromo-6-chloro-1,2,3,4-tetrahydroisoquinoline: 8-Bromo-6-chloroisoquinoline (8.6 g, 35.46 mmol) was dissolved in AcOH (80 mL), and the solution was cooled to 0 °C. NaBH (2.68 g, 70.93 mmol) was then added portionwise, and the mixture was stirred at 25 °C for 0.5 h. The mixture was quenched into HO, adjusted to pH = 8 with NH Cl, and extracted with EtOAc (200 mL) to give compound 2 (8.48 g, 34.40 mmol, 97.0% yield, crude) in the form of a yellow solid, which was confirmed by HNMR. 1 H NMR (400 MHz, CD3Cl) δ 7.42 (s, 1 H), 7.09 (s, 1 H), 4.00 (s, 2H), 3.15-3.18(m, 2H), 2.85-2.88 (m, 2H).

[0150] Synthesis of tert-butyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-formate: To a solution of 8-bromo-6-chloro-1,2,3,4-tetrahydroquinoline (8.48 g, 34.40 mmol) in DCM (100 mL) was added TEA (6.96 g, 68.79 mmol) and BocO (11.26 g, 51.60 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was washed with brine (50 mL × 2) to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to give compound 3 (6.7 g, 19.33 mmol, 56.2% yield) as a yellow oil, which was characterized by nuclear magnetic resonance. 1 H NMR (400 MHz, CD3Cl) δ 7.42 (s, 1 H), 7.10 (s, 1 H), 4.49 (s, 2H), 3.61-3.63(m, 2H), 2.80-2.82 (m, 2H), 1.50 (s, 9H).

[0151] Synthesis of 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)-formate: A mixture of tert-butyl 8-bromo-6-chloro-3,4-dihydroisoquinoline-2(1H)-formate (29.3 g, 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 purged with N three times, then the mixture was stirred at 100 °C with N gas for 2 h. The mixture was extracted with EtOAc (200 mL) to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 70%) to give compound 5 (22.6 g, 42.72 mmol, 50.5%) as a yellow oil. LCMS (ESI+): m / z 529.3 (M+H) + , Rt: 2.38 min.

[0152] Synthesis of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-formate: 6-Chloro-8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroxyisoquinoline-2(1H)-tert-butylformate (200 mg, 378.06 μmol), morpholine (164.68 mg, 1.89 mmol), XPhos (36.05 mg, 75.61 μmol), Pd(dba) (34.62 mg, 37.81 μmol), and t-BuONa (72.67 mg, 756.12 μmol) were dissolved in dioxane (5 mL), degassed, and purged with N three times. The mixture was then stirred at 100 °C under N gas for 2 h. The mixture was extracted with EtOAc (10 mL) and washed with brine (5 mL × 2). The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 35%) to give yellow gel-like compound 6 (70 mg, 118.34 μmol, 31.3%), which was checked by LCMS. LCMS (ESI+): m / z 580.4 (M+H) + , Rt:1.77 min.

[0153] Synthesis 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)morpholine: To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-formate (60 mg, 103.51 μmol) in DCM (5 mL) was added TFA (27.01 mmol, 2 mL). The mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated to give compound 7 (60 mg, 101.08 μmol, 97.7% yield, crude TFA salt) in the form of a yellow solid. LCMS (ESI+): m / z 480.2 (M+H) + , Rt:1.12 min.

[0154] Synthesis of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-morpholinyl-3,4-dihydroisoquinoline-2(1H)-formamide: To a solution of 4-(8-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-1,2,3,4-tetrahydroisoquinolin-6-yl)morpholine (60 mg, 101.08 μmol, TFA) in DCM (2 mL) was added TEA (30.68 mg, 303.24 μmol) and the methyl carbamate salt (11.34 mg, 121.30 μmol), and the mixture was stirred at 55° C. for 16 hours. The mixture was extracted with DCM (10 mL) and washed with brine (5 mL). The organic layer was dried over NaSO, filtered, and concentrated to give the crude product, which was purified by prep-HPLC (FA) to give M001014 (28.12 mg, 52.40 μmol, 51.8% yield) as a gray solid. LCMS (ESI+): m / z 559.4 (M+Na) + , Rt:1.75 min, 1 H NMR (400MHz, CD3Cl) δ 7.53 (s, 1H), 7.40 (s, 1H), 7.05 (s, 1H), 6.67 (d, J = 3.9Hz, 2H), 6.62 - 6.24 (m, 2H), 4.46 (d, J = 15.9 Hz, 1H), 4.36 - 4.27 (m, 1H), 4.16 -4.06 (m, 1H), 3.95 (s, 3H), 3.85 (t, J = 4.8 Hz, 4H), 3.78 - 3.68 (m, 1H), 3.63 - 3.43(m, 3H), 3.20 - 3.09 (m, 4H), 3.01 - 2.83 (m, 4H), 2.79 (d, J = 4.6 Hz, 3H), 2.24 -2.03 (m, 2H).

[0155] Compounds of the 6,6-bonded ring (dihydroisoquinoline group) type can be synthesized with reference to this method.

[0156] Example 4 Synthesis of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxopiperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (M001124):

[0157] [ka]

[0158] Synthesis of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one: To a solution of 4-bromo-1-methylpyridin-2-one (500 mg, 2.66 mmol) in 1,4-dioxane (10.0 mL) was added Bis(pinacolato)diboron (1350 mg, 5.31 mmol), AcOK (783 mg, 7.97 mmol), and Pd(dppf)Cl (113 mg, 0.132 mmol). The reaction mixture was heated to 100 °C and stirred at this temperature with N for 2 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (MeOH 0 to 10%) within 15 min to give 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxybenzofuran-2-yl)pyridin-2(1H)-one (500 mg, 62% yield) as a yellow oil.

[0159] Synthesis of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,3-dihydroisoquinoline-2(1H)-formate: 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-dihydroxyisoquinoline-2(1H)-formate (450 mg, 0.849 mmol) in THF (10.0 mL) and HO (1.0 mL) was added 1-methyl-4-(4,4,5,5,4-tetramethyl-1,3,2-dioxole-2(2H)-1(400). Potassium triphosphate (360 mg, 1.69 mmol) and X-phosphorus G3 (72.0 mg, 0.084 mmol). The reaction solution was heated to 60°C and stirred at this temperature with N2 for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (MeOH from 0 to 5%) within 10 minutes to give tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazolyl-pyrazolyl-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-3,4-dihydroxyquinoline-2(2H)-6-(2-methyl-2-oxy-1,2-dihydropyridine-4-formate) (460 mg, 85% yield) in the form of a yellow oil.

[0160] Synthesis 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)-1-methylpyridin-2(1H)-one: To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(2-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4H-dihydroisoquinoline-2(1H)-formate (450 mg, 0.746 mmol) in DCM (10.0 mL) was added TFA (3.0 mL). The solution was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was used directly in the next step without purification.

[0161] Synthesis of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-tetrahydroisoquinoline-2(1H)-formamide: 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)-1-methylpyridin-2(1H)-one (450 mg, 0.897 mmol) in DCM (10.0 mL) were added EtN (454 mg, 4.486 mmol) and N-methylcarbamoyl chloride (252 mg, 2.69 mmol). The reaction solution was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by prep HPLC (CHCN from 35% to 65% within 7 min) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (320 mg, 64% yield) in the form of a yellow solid.

[0162] Synthesis of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxopiperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide: To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (200 mg, 0.358 mmol) in MeOH (10.0 mL) was added PtO (81.0 mg, 0.358 mmol). The solution was stirred at 25 °C with H for 12 h. The mixture was filtered to remove solids and concentrated. The residue was purified by prep HPLC (CHCN from 25% to 50% within 8 min) to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(1-methyl-2-oxopiperidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (90.0 mg, 41% yield) in the form of a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.06 (m, 3H), 6.70 (m, 1H), 6.48 (d, J = 4.0 Hz, 1H), 6.17 (s, 1H), 4.43 (d, J = 16.0 Hz, 1H), 4.16 -4.08 (m, 1H), 3.86 (s, 3H), 3.59 - 3.41 (m, 4H), 3.28 - 3.22 (m, 1H), 3.05 (s, 1H), 2.81 (m, 7H), 2.54 (d, J = 4.0 Hz, 3H), 2.43 - 2.30 (m, 2H), 2.18 - 1.81 (m, 5H).

[0163] Example 5

[0164] [ka]

[0165] To a mixture of tert-butyl 2,4-dichloro-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formate (compound 1, 432 mg, 1.64 mmol, 1.0 eq) and 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (compound int-1, 1.0 g, 3.29 mmol, 2.0 eq) was added DIEA (637 mg, 4.93 mmol, 858 μL, 3.0 eq) at 20 °C. The mixture was stirred at 150 °C for 4 h. LC-MS showed that compound 1 was completely consumed. The resulting mixture was extracted with ethyl acetate (100 mL), washed with brine (10 mL × 3), dried over Na SO (25 g), and concentrated. The residue was purified by prep-HPLC (Phenomenex Luna C18 100 × 40 mm × 3 μm, mobile phase: [water-ACN], B%: 40% to 60%, 12 min) to obtain tert-butyl 2-chloro-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formate (compound 2, 100 mg, crude product) as a yellow oil. H NMR confirmed the purity.

[0166] To a mixture of compound 2 (100 mg, 188 μmol, 1.0 eq) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (compound 3, 79.1 mg, 376 μmol, 2.0 eq) in dioxane (4.0 mL) and HO (1.0 mL) was added Ruphos Pd G (31.5 mg, 37.6 μmol, 0.2 eq) and CsCO (184 mg, 564 μmol, 3.0 eq) in one portion at 90 °C. The mixture was heated to 90 °C and stirred for 16 h. LC-MS indicated that the desired compound was detected in 32% yield. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ISCO®, 25 g SepaFlash® flash silica gel column, 20–30% ethyl acetate / petroleum ether gradient elution @ 50 mL / min). TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.48) yielded tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formate (compound 4, 50.0 mg, 86.4 μmol, 45.9% yield) as a yellow oil.

[0167] To a mixture of compound 4 (50.0 mg, 86.4 μmol, 1.0 eq) in THF (5.0 mL) at 20° C., H and Pd / C (20.0 mg, 10% purity) (15 psi) were added in one portion. The mixture was heated to 20° C. and stirred for 16 h. LC-MS showed that the desired compound was detected in 46.5% yield. The reaction mixture was concentrated under reduced pressure to give tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formate (compound 5, 50.0 mg, crude) as a yellow oil.

[0168] To a solution of compound 5 (50.0 mg, 86.1 μmol, 1.0 eq) in DCM (3.0 mL) was added TFA (85.6 mg, 751 μmol, 55.6 μL, 8.72 eq) in one portion at 20°C under N2. The mixture was stirred at 20°C for 16 h. LC-MS showed that compound 5 was completely consumed. The reaction mixture was partitioned between water (20.0 mL) and ethyl acetate (20.0 mL). The organic layer was dried over Na2SO4 and concentrated to give the desired product. 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (compound 6, 50.0 mg, crude) was obtained as a yellow oil.

[0169] To a mixture of N-methyl-1H-imidazole-1-formamide (compound 7, 26.0 mg, 208 μmol, 2.0 eq) in DCM (5.0 mL) at 20 °C under N was added TEA (63.1 mg, 624 μmol, 86.8 μL, 6.0 eq) and compound 6 (50.0 mg, 104 μmol, 1.0 eq) in one portion. The mixture was stirred at 20 °C for 16 h. LC-MS showed that compound 6 was completely consumed. The reaction mixture was partitioned between water (20.0 mL) and ethyl acetate (20.0 mL). The organic layer was dried over NaSO and concentrated to give the required product. The residue was purified by preparative HPLC: Phenomenex Gemini-NXC 18 75 × 30 mm × 3 μm, mobile phase: [water (0.05% NH3H2O ​​+ 10 mM NH4HCO3)-ACN], B%: 22% to 62%, 11 min. 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-2-(tetrahydro-2H-pyran-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formamide (compound M001245, 34 mg, 62.4 μmol, 60.0% yield, 98.7% purity) was obtained as a yellow oil. M001245: 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 6.84 - 6.82 (m, 1H), 6.82 - 6.53 (m, 1H), 4.62 (s, 1H), 4.07 (s, 3H), 4.04 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.0 Hz, 2H), 3.68 (t, J = 6.4 Hz, 2H), 3.58 (dt, J = 2.4, 11.8 Hz, 2H), 3.06 - 2.90 (m, 5H), 2.68 (s, 3H), 2.18 - 2.10 (m, 2H), 2.07 - 1.96 (m, 2H), 1.94 - 1.87 (m, 2H).

[0170] Example 6

[0171]

change

[0172] 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-formate (700 mg, 1.36 mmol) in dioxane (5.0 mL) and HO (0.5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexyl-3-en-1-ol (609.2 mg, 2.72 mmol), KCO (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 h. LCMS indicated that the starting material had been consumed and the required product was detected. The residue was purified by flash column chromatography eluting with 0 to 50% EtOAc in PE, followed by 0 to 5% MeOH in DCM by flash column chromatography to give tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxylcyclohexyl-1-en-1-yl)isoindoline-2-formate as a yellow solid.

[0173] To a solution of tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohexyl-1-en-1-yl)isoindoline-2-formate (700 mg, 1.21 mmol) in DCM (3.0 mL) was added TFA (1.0 mL). The mixture was concentrated under reduced pressure to give a yellow solid, 4-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl-3-en-1-ol (600 mg, 98% yield).

[0174] To a solution of 4-(7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl-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 layer was washed with brine (50 mL × 3) and dried over anhydrous Na2SO4. The residue was purified by flash column chromatography eluting with 0 to 50% EtOAc in PE and 0 to 5% methanol in DCM to give a yellow solid, 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxycyclohexyl-1-en-1-yl)isoindolin-2-yl)ethan-1-one (600 mg, 92% yield).

[0175] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-hydroxylcyclohexyl-1-en-1-yl)isoindolin-2-yl)ethan-1-one (600 mg, 1.2 mmol) in THF (4.0 mL) was added Pd / C (60% in oil) (123.1 mg, 1.2 mol) at 25 °C under H atmosphere (15 PSI). After filtration, the filtrate was concentrated under reduced pressure to give a yellow solid, 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).

[0176] 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 h. The mixture was quenched with saturated aqueous NaHCO (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were dried over NaSO. After filtration, the filtrate was purified by flash column chromatography eluting with 0 to 50% EtOAc in PE and then by flash column chromatography eluting with 0 to 5% methanol in dichloromethane to give a white solid, 4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl-1-one (100 mg, 77% yield).

[0177] 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)cyclohexyl-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 h. To the mixture was then added NaCNBH (48.5 mg, 0.77 mmol). The mixture was stirred at 25° C. for 1 h. LCMS indicated that the starting material had been consumed and the required product was detected. The crude product was purified by preparative HPLC, eluting with CHCN from 38% to 45% in 8 min in 0.1% FA / water 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. M001301: 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.16 - 7.10 (m, 2H), 6.74 (t, J = 55.2 Hz, 1H), 6.40 (d, J = 28.0 Hz, 1H), 4.85 (s, 1H), 4.64 (s, 1H), 4.60 (s, 1H), 4.28 (s, 1H), 3.86 (s, 3H), 3.57 - 3.48 (m, 4H), 2.98 - 2.94 (m, 1H), 2.87 - 2.80 (m, 2H), 2.64 - 2.53 (m, 1H), 2.47 - 2.42 (m, 1H), 2.19 - 1.96 (m, 6H), 1.87 - 1.81 (s, 2H), 1.62 - 1.47 (m, 2H), 1.43 - 1.36 (m, 2H).

[0178] Further production was carried out using M001301 as a starting material to obtain M001320 and M001321.

[0179] [ka]

[0180] 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 BocO (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 N for 1 h. 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 MeOH solution)] = 50 / 40, 80 g / min, 35 °C) to give a white solid ((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)aminoformate (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)aminoformate (105.3 mg, 41%).

[0181] 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)aminoformate (37.2 mg, 0.0601 mmol) in dioxane (5 mL) was added HCl in dioxane (4 N, 5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The aqueous solution was dried by lyophilization to give 28.5 mg (84%) of a white solid, 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.

[0182] 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)aminoformate (105.3 mg, 0.170 mmol) in dioxane (5 mL) was added HCl in dioxane (4 N, 5 mL) at 25° C. The reaction mixture was stirred at 25° C. for 1 hour. The aqueous solution was dried by lyophilization 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. M001320: 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 3H), 7.75 (s, 1H), 7.49 (s, 1H), 7.19 - 7.10 (m, 3H), 6.74 (t, J = 55.2 Hz, 1H), 6.45 - 6.35 (m, 1H), 4.92 - 7.80 (m, 1H), 4.71 - 4.50 (m, 2H), 4.36 - 4.20 (m, 1H), 3.86 (s, 3H), 3.56 - 3.49 (m, 2H), 3.14 - 3.00 (m, 1H), 2.93 - 2.83 (m, 2H), 2.61 - 2.52 (m, 1H), 2.07 - 1.96 (m, 7H), 1.92 - 1.80 (m, 2H), 1.62 - 1.40 (m, 4H). M001321: 1H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 3H), 7.75 (s, 1H), 7.49 (s, 1H), 7.28 - 7.18 (m, 2H), 7.13 (s, 1H), 6.74 (t, J = 55.2 Hz, 1H), 6.46 - 6.34 (m, 1H), 4.92 - 4.81 (m, 1H), 4.74 - 4.52 (m, 2H), 4.45 - 4.22 (m, 1H), 3.86 (s, 3H), 3.62 - 3.51 (m, 2H), 3.45 - 3.42 (m, 1H), 2.92 - 2.84 (m, 2H), 2.65 - 2.55 (m, 1H), 2.05 - 1.98 (m, 5H), 1.89 - 1.72 (m, 6H), 1.69 - 1.58 (m, 2H).

[0183] Example 7

[0184]

change

[0185] 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 (60 mg, 0.12 mmol) in DCM (2.0 mL) and THF (1.0 mL) was added TEA (23.4 mg, 0.23 mmol) and acetyl chloride (13.6 mg, 0.17 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h. LCMS indicated that the starting material had been consumed and the required product was detected. The crude product was purified by preparative HPLC, eluting with CHCN from 33% to 43% in 7 min in HO (0.1% NH) 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)acetamide (2.8 mg, 4% yield) and N-((1r,4r)-4(2-acetyl-7-(7-[difluoromethyl]-6-(1-ethyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindolin-5-yl)cyclohexyl)acetamide (11.7 mg, 18% yield) as white solids. M001304 11H NMR (400 MHz, DMSO-d6) δ 7.76 - 7.73 (m, 2H), 7.49 (s, 1H), 7.17 (s, 1H), 7.15 - 7.07 (m, 2H), 6.74 (t, J = 55.1 Hz, 1H), 6.40 (d, J = 28.8 Hz, 1H), 4.85 (s, 1H), 4.64 (s, 1H), 4.61 (s, 1H), 4.28 (s, 1H), 3.86 (s, 3H), 3.58 - 3.52 (m, 3H), 2.90 - 2.86 (m, 2H), 2.60 - 2.53 (m, 1H), 2.10 - 1.96 (m, 5H), 1.91 - 1.81 (m, 4H), 1.79 - 1.77 (m, 3H), 1.59 - 1.49 (m, 2H), 1.32 - 1.24 (m, 2H). M001308 1 1H NMR (400 MHz, DMSO-d6) δ 7.83 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.19 (d, J = 11.2 Hz, 1H), 7.17 - 7.08 (m, 2H), 6.74 (t, J = 55.2 Hz, 1H), 6.40 (d, J = 27.2 Hz, 1H), 4.86 (s, 1H), 4.66 (s, 1H), 4.62 (s, 1H), 4.29 (s, 1H), 4.00 - 3.96 (m, 1H), 3.86 (s, 3H), 3.67 - 3.48 (m, 2H), 2.90 - 2.87 (m, 2H), 2.63 - 2.54 (m, 1H), 2.13 - 1.92 (m, 5H), 1.85 - 1.83 (m, 3H), 1.82 - 1.76 (m, 2H), 1.69 - 1.65 (m, 2H), 1.61 - 1.56 (m, 4H).

[0186] Example 8

[0187]

Chem.

[0188] To a solution of 4-methylsulfonylcyclohexan-1-one (0.6 g, 0.0034 mol) in DCM (10 mL) was added TfO (1.92 g, 0.0068 mol) and 2,6-di-tert-butyl-4-methylpyridine (1.54 g, 0.00748 mol). The reaction mixture was stirred at 40 °C for 16 h. TLC indicated the formation of the desired product. The reaction mixture was diluted with DCM, washed with HCl (1N), and extracted with DCM. The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with PE from 0% to 100% DCM to give 4-methylsulfonylcyclohexan-1-en-1-yl trifluoromethanesulfonate (490 mg, 47%) as a white solid.

[0189] To a solution of tert-butyl 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisoindole-2-formate (325 mg, 0.5359 mmol) in 1,4-dioxane (6 mL) and HO (1 mL) was added 4-methylsulfonylcyclohexan-1-en-1-yl trifluoromethanesulfonate (165 mg, 0.5359 mmol), XPhos Pd G3 (45 mg, 0.05359 mmol), and K2CO3 (2 mg, 1.6077 mmol). The reaction was heated to 100 °C and stirred at this temperature under N2 for 4 hours. LCMS indicated the desired product had been formed. The mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH in DCM from 0% to 5% to give tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindoline-2-formate (225 mg, 66%) as a yellow oil.

[0190] To a solution of tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindoline-2-formate (225 mg, 0.3522 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at 25° C. for 30 minutes. LCMS indicated the formation of the required product. The solvent was removed under reduced pressure to give 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindolin-4-yl)-1,2,3,4-tetrahydroquinoline (185 mg, crude) as a yellow oil.

[0191] To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindolin-4-yl)-1,2,3,4-tetrahydroquinoline (185 mg, 0.3434 mmol) in DCM (1 mL) was added TEA (695 mg, 6.868 mmol) and acetyl chloride (270 mg, 3.434 mmol). The reaction mixture was stirred at 25° C. for 50 min. LCMS showed the required product had been formed. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with MeOH in DCM from 0% to 10% to give a yellow solid of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindolin-2-yl)ethan-1-one (90 mg, 45%).

[0192] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl-1-en-1-yl)isoindolin-2-yl)ethan-1-one (90 mg, 0.1550 mmol) in MeOH (30 mL) was added 10% Pd / C (49 mg, 0.0465 mmol). The reaction mixture was stirred at 25° C. for 16 h. LCMS showed the required product had been formed. The reaction mixture was filtered and concentrated in vacuo, and the residue was purified by Pre-HPLC (Column: -Xbridge-C18 150 × 19 × 19 mm, 5 μm Mobile phase: ACN-HO (0.1% FA)) to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl)isoindolin-2-yl)ethan-1-one (30 mg, 33%).

[0193] 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylsulfonyl)cyclohexyl)isoindolin-2-yl)ethan-1-one (30 mg, 0.0515 mmol) was purified by high-performance liquid chromatography (Daicel CHIRALCEL IB-N, 250 mm, inner diameter 30 mm, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M MeOH solution)] = 50 / 40, 80 g / min, 35°C), yellow solids of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-((1s,4s)4-(methylsulfonyl)cyclohexyl)isoindolin-2-yl)ethan-1-one (6.4 mg, 21%) and 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-((1r,4r)4-(methylsulfonyl)cyclohexyl)isoindolin-2-yl)ethan-1-one (14.0 mg, 47%) were obtained. M001299: 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.13 (t, J = 12.8 Hz, 3H), 6.88 (s, 0.25H), 6.74 (s, 0.5H), 6.60 (s, 0.25H), 6.44-6.37 (m, 1H), 4.87-4.25 (m, 4H), 3.86 (s, 3H), 3.55 (d, J = 4.8 Hz, 2H), 3.11 (s, 1H), 2.93 (d, J = 4.4 Hz, 3H), 2.88 (s, 2H), 2.61 (s, 1H), 2.18 (s, 2H), 2.04-1.94 (m, 7H), 1.60-1.50 (m, 4H). M001310: 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.49 (s, 1H), 7.17-7.06 (m, 3H), 6.87 (s, 0.25H), 6.74 (s, 0.5H), 6.60 (s, 0.25H), 6.44-6.37 (m, 1H), 4.87-4.29 (m, 4H), 3.86 (s, 3H), 3.55 (d, J = 4.8 Hz, 2H), 3.31-3.26 (m, 1H), 2.97 (d, J = 4.8 Hz, 3H), 2.88 (s, 2H), 2.82-2.72 (m, 1H), 2.15 (d, J = 12.8 Hz,2H), 2.09-1.97 (m, 7H), 1.91-1.83 (m, 2H), 1.73-1.67 (m, 2H).

[0194] Example 9

[0195] [ka]

[0196] To a solution of 6-chloro-3,4-dihydro-2H-naphthyl-1-one (5.00 g, 0.027 mol) in MeOH (50.0 mL) were added pyridine (2.63 g, 0.033 mol) and O-methylhydroxylamine hydrochloride (2.78 g, 0.03 mol). The reaction solution was stirred at 25 °C under N2 for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE (EA = 0-5%) within 10 min to give (E)-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-methyloxime (5.60 g, 92% yield) as a white oil.

[0197] To a solution of (E)-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-methyloxime (5.6 g, 0.026 mol) in AcOH (50.0 mL) were added N-bromosuccinimide (4.75 g, 0.026 mol) and Pd(OAc) (0.60 g, 0.003 mol). The reaction solution was stirred at 90 °C under microwave irradiation for 0.5 h. The mixture was concentrated, and the residue was washed with NaHCO solution (100 mL) and extracted with DCM (60 mL × 2). The combined organic layer was washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with EA / PE (EA = 0–5%) within 10 min to give (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-methyloxime (6.50 g, 80% yield) as a yellow oil.

[0198] A solution of (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-methyloxime (6.50 g, 0.022 mol) in 1,4-dioxane (15.0 mL) and 6N HCl (70.0 mL) was stirred at 120 °C for 2 h under microwave irradiation. The mixture was concentrated, and the residue was washed with NaHCO solution (100 mL) and extracted with DCM (60 mL × 2). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated to dryness. The residue was purified by silica gel column chromatography eluting with EA / PE (EA = 0-5%) within 10 min to give 8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one (5.10 g, 83% yield) as a yellow oil.

[0199] To a solution of 8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one (5.10 g, 0.019 mol) in EtOH (50.0 mL) and pyridine (10.0 mL) was added hydroxylamine hydrochloride (2.05 g, 0.029 mol). The reaction solution was stirred at 100° C. under microwave irradiation for 1 hour. The mixture was filtered, and the residue was collected to give (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one oxime (4.60 g, 81% yield) as a white solid.

[0200] At 0°C, NaH (2.02 g, 0.050 mol) was added to a solution of (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one oxime (4.60 g, 0.016 mol) in DMF (50.0 mL). The whole mixture was then stirred at 0°C for 0.5 hours, and 4-methylbenzenesulfonyl chloride (3.84 g, 0.020 mol) was added. The mixture was stirred at 25°C for 0.5 hours. The mixture was poured into water, and the whole mixture was extracted with DCM (100 mL x 2). The combined organic phase was washed with brine (50 mL). 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 column chromatography, eluting with PE and THF from 0% to 10% to give a yellow solid, (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-tosyloxime (2.30 g, 27% yield).

[0201] A solution of (E)-8-bromo-6-chloro-3,4-dihydronaphthyl-1(2H)-one O-tosyloxime (2.30 g, 0.005 mol) in TFA (30.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with THF / PE (THF = 0 to 50%) within 15 min to give 9-bromo-7-chloro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (0.91 g, 57% yield) as a yellow oil.

[0202] To a solution of BH3 (1 M in THF, 66.3 mL) was added 9-bromo-7-chloro-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (910 mg, 3.32 mmol) at 25 °C. The reaction mixture was heated to 65 °C and stirred at 65 °C with N2 for 25 hours. The reaction mixture was cooled to ambient temperature and quenched with MeOH until bubbling ceased. Then, an aqueous solution of 4 N HCl was added, and the mixture was heated at 80 °C for 1 hour. The mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (50 mL × 2). The aqueous phase was added with 5 N KOH, the pH was adjusted to 8, and the mixture was extracted with DCM (50 mL × 2). The mixture was concentrated under reduced pressure to give 9-bromo-7-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine (850 mg, 89% yield) as a yellow oil.

[0203] To a solution of 9-bromo-7-chloro-2,3,4,5-tetrahydro-1H-2-benzazepine (850 mg, 3.26 mmol) in THF (20.0 mL) and HO (10.0 mL) was added NaHCO (822 mg, 9.79 mmol) and di-tert-butyl dicarbonate (783 mg, 3.59 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The mixture was 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 silica gel column chromatography eluting with petroleum elution from 0% to 5% EtOAc to afford 9-bromo-7-chloro-1,3,4,5-tetrahydro-2-benzazepine-2-tert-butyl formate (1000 mg, 77% yield) as a colorless oil.

[0204] To a solution of tert-butyl 9-bromo-7-chloro-1,3,4,5-tetrahydro-2-benzazepine-2-formate (300 mg, 0.831 mmol) in 1,4-dioxane (10.0 mL) was added 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (219 mg, 0.831 mmol), Cphos-Pd G3 (67.0 mg, 0.083 mmol), and LHMDS (418 mg, 2.495 mmol). The reaction mixture was heated to 100 °C and stirred with N for 12 hours. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (MeOH from 0 to 10%) for 10 min to give tert-butyl 7-chloro-9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (220 mg, 22% yield) as a yellow solid.

[0205] To a solution of tert-butyl 7-chloro-9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,3,4,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (200 mg, 0.368 mmol) in 1,4-dioxane (10.0 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (187 mg, 0.736 mmol), AcOK (72.0 mg, 0.736 mmol), and XPhos Pd G3 (31.0 mg, 0.036 mmol). The reaction solution was heated to 100 °C and stirred with N2 for 2 h. The mixture was cooled to 25°C and concentrated under reduced pressure to give a black solid: tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (300 mg, 64% yield).

[0206] A solution of tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-1-(4,4,4,5,5-tetramethyl-1,3,3,4,5-tetramethyl-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate) (200 mg, 0.315 mmol) in 1,4-dioxane (6.0 mL) and HO (1.1 mL) was treated with 4-bromo-1-ethylpyridin-2-one (191 mg, 0.945 mmol), KCO (87.0 mg, 0.630 mmol), and XPhos Pd G (27.0 mg, 0.031 mmol). (mmol) was added. The reaction solution was heated to 100°C and stirred with N2 for 3 hours. The mixture was cooled to 25°C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (using 0 to 5% MeOH) within 10 minutes to give a yellow solid: tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate.

[0207] To a solution of tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(1-ethyl-2-oxo-1,2-dihydropyridin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (120 mg, 0.190 mmol) in MeOH (10.0 mL) was added PtO (43.0 mg, 0 mmol). The solution was stirred at 25 °C with H for 12 h. The mixture was filtered to remove solids and concentrated. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (MeOH from 0 to 5%) within 10 min to give a yellow solid tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(1-ethyl-2-oxopiperidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (114 mg, 90% yield).

[0208] A solution of tert-butyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(1-ethyl-2-oxopiperidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (114 mg, 0.179 mmol) in DCM (5.0 mL) and TFA (2.0 mL) was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give 4-(9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)-1-ethylpiperidin-2-one (90.0 mg, 84% yield) as a yellow oil.

[0209] To a solution of 4-(9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)-1-ethylpiperidin-2-one (25.0 mg, 0.046 mmol) in DCM (5.0 mL) was added EtN (14.0 mg, 0.0 mg, 0.140 mmol) and chloro(methoxy)ketone (13.0 mg, 0.140 mmol). The reaction mixture was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (50% to 80% within 8 min using CHCN) to give a white solid, methyl 9-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-7-(1-ethyl-2-oxopiperidin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-formate (4.4 mg, 16% yield). M001260 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.47 (s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.86 - 6.53 (m, 1H), 6.09 (d, J = 48.0 Hz, 1H), 4.85 - 3.91 (m, 2H), 3.85 (s, 3H), 3.69 (s, 1H), 3.54 (d, J = 28.0 Hz, 3H), 3.39 - 3.34 (m, 2H), 3.31 - 3.19 (m, 5H), 3.02 - 2.88 (m, 5H), 2.49 - 2.30 (m, 2H), 2.16 - 1.98 (m, 3H), 1.91 - 1.58 (m, 3H), 1.03 - 0.96 (m, 3H).

[0210] Example 10

[0211] [ka]

[0212] At −10° C., 5-chloro-2-methylbenzoic acid (20 g, 117.24 mmol) was added to cooled concentrated HSO (135 mL). After stirring for 10 minutes, a mixture of concentrated HNO (16.47 g, 261.44 mmol) and concentrated HSO (22 mL) was added dropwise at −10° C. The mixture was stirred at −10° C. for 12 hours, then poured into ice water. The precipitated solid was filtered, washed with water until the pH of the filtrate reached approximately 7, and dried under vacuum to give 5-chloro-2-methyl-3-nitrobenzoic acid (15.5 g, crude) as an off-white solid.

[0213] To a solution of 5-chloro-2-methyl-3-nitro-benzoic acid (15.5 g, 71.90 mmol) in DCM (150 mL) was added oxalyl chloride (18.25 g, 143.79 mmol) and DMF (525.49 mg, 7.19 mmol) dropwise at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction was concentrated in vacuo to give 5-chloro-2-methyl-3-nitro-benzoyl chloride (15.8 g, 67.51 mmol, crude) as a yellow solid.

[0214] To a solution of 5-chloro-2-methyl-3-nitro-benzoyl chloride (15.8 g, 67.51 mmol) in THF (150 mL) was added trimethylsilyldiazomethane (2 M, 135.02 mL) at 0 °C under N2. The mixture was stirred at 25 °C for 12 h. The reaction was concentrated in vacuo to give 1-(5-chloro-2-methyl-3-nitro-phenyl)-2-diazo-ethanone (16 g, crude) as a yellow gel.

[0215] To a solution of TEA (33.78 g, 3.87 mmol) and silver benzoate (9.17 g, 40.06 mmol) in MeOH (60 mL) was added dropwise 1-(5-chloro-2-methyl-3-nitrophenyl)-2-diazo-ethanone (16 g, 66.77 mmol) dissolved in MeOH while stirring at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The mixture was washed with saturated aqueous HCl (1 M) (500 mL) and extracted with EA (600 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by FCC (ISCO®, 40 g SepaFlash® silica column, 0-10% ethyl acetate / petroleum ether gradient elution @ 50 mL / min, petroleum ether / ethyl acetate = 3:1, Rf = 0.7) to give a yellow solid, methyl 2-(5-chloro-2-methyl-3-nitro-phenyl)acetate (12.1 g, 49.66 mmol, 74.37% yield).

[0216] To a solution of methyl 2-(5-chloro-2-methyl-3-nitrophenyl)acetate (12.1 g, 49.66 mmol) in EtOH (100 mL) was added DIBAH (25.94 g, 148.99 mmol) and dissolved in HO (30 mL) at 90 °C. The mixture was stirred at 90 °C for 10 min. The mixture was washed with saturated HO (400 mL) and extracted with EA (600 mL × 3). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by FCC (ISCO®, 40 g SepaFlash® silica column, 0-20% ethyl acetate / petroleum ether gradient elution @ 40 mL / min, petroleum ether / ethyl acetate = 3:1, Rf = 0.4) to give a white solid, methyl 2-(3-amino-5-chloro-2-methyl-phenyl)acetate (3.2 g, 14.98 mmol, 30.16% yield).

[0217] A solution of NaNO (1.14 g, 16.47 mmol) in HO (15 mL) was added to a solution of methyl 2-(3-amino-5-chloro-2-methylphenyl)acetate (3.2 g, 14.98 mmol) in HCl (2 M, 14.98 mL), and ACN (10 mL) was cooled to below 5 °C. After stirring at 0 °C for 45 min, a solution of KI (3.73 g, 22.47 mmol) in HO (15 mL) was added dropwise. The resulting mixture was warmed to 25 °C and stirred for 4 h. The mixture was poured into 150 mL of water and extracted with EA (300 mL × 3). The combined organic layers were concentrated to give the crude product. The crude product was purified by FCC (ISCO®, 20 g SepaFlash® silica column, 0–10% ethyl acetate / petroleum ether gradient elution at 40 mL / min). TLC: petroleum:ethyl acetate=3:1, Rf=0.8) to give a white solid, methyl 2-(5-chloro-3-iodo-2-methyl-phenyl)acetate (3.8 g, 11.71 mmol, 78.18% yield).

[0218] A mixture of methyl 2-(5-chloro-3-iodo-2-methyl-phenyl)acetate (3.8 g, 11.71 mmol), NBS (2.50 g, 14.05 mmol) in CCl (38 mL) was stirred at 0 °C. BPO (567.24 mg, 2.34 mmol) was then added to the mixture. The residue was degassed and purged with N three times, and the mixture was stirred at 85 °C under N atmosphere for 3 h. The mixture was poured into water (500 mL) and extracted with DCM (500 mL × 3). The combined organic layers were concentrated to give the crude product. The crude product was purified by FCC (ISCO®, 40 g SepaFlash® silica column, 0–10% ethyl acetate / petroleum ether gradient elution at 40 mL / min) to give methyl 2-[2-(bromomethyl)-5-chloro-3-iodo-phenyl]acetate (4.1 g, 10.16 mmol, 86.79% yield) as an off-white liquid.

[0219] To a solution of methyl 2-[2-(bromomethyl)-5-chloro-3-iodo-phenyl]acetate (4.1 g, 10.16 mmol) in EtOH (5 mL) at 25 °C was added MeNH (10.52 g, 101.63 mmol). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo, and the crude product was purified by FCC (ISCO®, 40 g SepaFlash® silica column, 0–30% ethyl acetate / petroleum ether gradient elution at 40 mL / min). TLC: petroleum ether:ethyl acetate = 0:1, Rf = 0.5) to give 6-chloro-8-iodo-2-methyl-1,4-dihydroisoquinolin-3-one (2.32 g, 7.22 mmol, 71.00% yield) as an off-white solid.

[0220] 6-Chloro-8-iodo-2-methyl-1,4-dihydroisoquinolin-3-one (500 mg, 1.56 mmol), 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (409.41 mg, 1.56 mmol), CsCO (1.52 g, 4.67 mmol), and toluene (5 mL) were degassed and purged with N three times, and Cphos Pd G (125.39 mg, 0.156 mmol) was added, and the mixture was stirred at 110 °C under N for 1 h. The reaction was concentrated in vacuo. The mixture was poured into 50 mL of water and extracted with EA (100 mL × 3). The combined organic layers were concentrated to give the crude product. The residue was purified by flash silica gel column chromatography (ISCO®, 12 g SepaFlash® silica column, eluting with a 0-5% MeOH / DCM gradient at 30 mL / min) to give 6-chloro-8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-methyl-1,4-dihydroisoquinolin-3-one (160 mg, 0.350 mmol, 22.52% yield) as a yellow oil.

[0221] 6-Chloro-8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-methyl-1,4-dihydroisoquinolin-3-one (50 mg, 0.109 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (24.42 mg), KPO (69.69 mg, 0.328 mmol) and XPhos Pd G (18.53 mg, 0.0219 mmol) in THF / HO (V:V = 5:1) The solution (1 mL) was placed in a microwave tube, and the mixture was stirred at 60 °C in a microwave for 0.5 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EA = 1:1) to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-methyl-6-(1-ethyl-3,6-dihydro-2-pyridin-4-yl)-1,4-dihydroisoquinolin-3-one (35 mg, 0.0676 mmol, 61.79% yield) as a yellow gel.

[0222] A mixture of 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-methyl-6-(1-methyl-3,6-dihydro-1H-pyridin-4-yl)-1,4-dihydroisoquinolin-3-one (35 mg, 0.0676 mmol), Pd / C (30 mg, 10% purity) in MeOH (1 mL) was degassed and purged with H three times, and the mixture was stirred at 25 °C under an H (15 Psi) atmosphere for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The product was then purified by preparative HPLC (Welch Xtimate C). 18The product was further purified using a 150 × 25 mm × 5 mm column (mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions: 5% to 50%). Pure fractions were collected, and volatiles were removed under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to give 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-methyl-6-(1-methyl-4-piperidinyl)-1,4-dihydroisoquinolin-3-one (1.07 mg, 0.00192 mmol, 2.83% yield, 93% purity) as a yellow gel. M001028 1 H NMR (400 MHz, METHANOL-d4) δ 8.49 (br s, 1 H) 7.62 (s, 1 H) 7.49 (s, 1 H) 7.10 - 7.16 (m, 3 H) 6.50 (t, J = 55.41 Hz, 1 H) 6.30 (s, 1 H) 4.54 - 4.63 (m, 1 H) 4.28 - 4.51 (m, 2 H) 3.93 (s, 3 H) 3.60 - 3.72 (m, 3 H) 3.46 - 3.55 (m, 3 H) 3.02 - 3.05 (m, 1 H) 3.00 (s, 3 H) 2.94 - 2.99 (m, 2H) 2.86 - 2.93 (m, 1 H) 2.83 (s, 3 H) 2.07 - 2.20 (m, 4 H) 1.87 - 2.00 (m, 2 H).

[0223] Example 11

[0224] [ka]

[0225] A mixture of 2-bromo-6-iodobenzonitrile (3.9 g, 0.012 mol), methyl propiolate (1.1 g, 0.012 mmol), Pd(PPh3)2Cl2 (0.90 g, 0.0012 mol), and CuI (0.49 g, 0.0025 mol) in DMF (20 mL) and TEA (20 mL) was stirred at 25 °C under N2. The mixture was heated to 50 °C and stirred at this temperature for 2 h. The reaction mixture was cooled to 25 °C, diluted with water (100 mL), and extracted with EtOAc (100 mL × 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / petroleum ether, from 0% to 100% EtOAc within 15 min to give methyl 3-(3-bromo-2-cyanophenyl)propionate (1.5 g, 50% yield) as a yellow solid.

[0226] To a solution of methyl 3-(3-bromo-2-cyanophenyl)propiolate (2 g, 7.57 mmol) in EtOH (20 mL) and THF (20 mL) was added PtO2 (171 mg, 0.75 mmol), successively. The reaction mixture was stirred at 25 °C under a hydrogen atmosphere (balloon) for 2 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give methyl 3-(3-bromo-2-cyanophenyl)propionate (1.5 g, 66% yield) as a yellow solid.

[0227] A mixture of methyl 3-(3-bromo-2-cyanophenyl)propionate (400 mg, 1.49 mmol), 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (314 mg, 1.19 mmol), CsCO (1458 mg, 4.4757 mmol), Pd(dba) (136 mg, 0.14 mmol), and Xantphos (172 mg, 0.29 mmol) in dioxane (10 mL) was stirred at 25 °C under N. The mixture was heated to 100 °C and stirred at this temperature for 10 h. The reaction mixture was cooled to 25 °C, diluted with water (10 mL), and extracted with EtOAc (30 mL × 2). The combined organic phase was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / petroleum ether, from 0% to 100% EtOAc within 15 min to give methyl 3-{2-cyano-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]phenyl}propionate (300 mg, 40% yield), as a yellow solid.

[0228] To a solution of methyl 3-{2-cyano-3-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]phenyl}propionate (150 mg, 0.33 mmol) in MeOH (4 mL) was added Raney Ni (19 mg, 0.33 mmol) at 25 °C. After the addition, the mixture was stirred at 25 °C with H for 2 h. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (CHCN elution from 10% to 70% within 10 min) to give a white solid, 9-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,2,4,5-tetrahydro-2-benzazepin-3-one (10 mg, 7% yield). M001215 1H NMR (400 MHz, DMSO-d6) δ 7.87 - 7.84 (m, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.35 - 7.30 (m, 1H), 7.25 - 7.20 (m, 1H), 7.15 - 7.05 (m, 2H), 6.80 - 6.55 (m, 1H), 6.16 (s, 1H), 4.30 - 4.13 (m, 2H), 3.88 (s, 3H), 3.50 - 3.45 (m, 1H), 3.25 - 3.15 (m, 1H), 3.02 - 2.80 (m, 3H), 2.72 - 2.60 (m, 1H), 2.54 - 2.50 (m, 2H), 2.13 - 2.03 (m, 2H).

[0229] Example 12

[0230] [ka]

[0231] To a solution of 7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (100 mg, 0.380 mmol) and 9-bromo-1,3,4,5-tetrahydro-1-benzazepin-2-one (109 mg, 0.456 mmol) in 1,4-dioxane (15 mL) was added t-BuONa (73.0 mg, 0.760 mmol) and Cphos-Pd G3 (30.6 mg, 0.0379 mmol). The reaction mixture was stirred at 90°C for 16 hours. Water (20 mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (30 mL 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 preparative HPLC (CHCN 45% to 75%) within 9 min to give a white solid, 9-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one (2.40 mg, 1.5% yield). M001236 1 H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.71 (s, 1H), 7.46 (s, 1H), 7.24 (s, 3H), 7.08 (s, 1H), 6.70 (t, J = 55.2 Hz, 1H), 6.19 (s, 1H), 3.85 (s, 3H), 3.60 - 3.46 (m, 2H), 2.90 - 2.83 (m, 2H), 2.77 - 2.71 (m, 2H), 2.25 - 1.97 (m, 6H).

[0232] Example 13

[0233] [ka]

[0234] 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-formate (400 mg, 0.777 mmol) in dioxane (20 mL) was added ethyl 2-cyanoacetate (351 mg, 3.11 mmol), KPO (495 mg, 2.33 mmol), and Xhos-Pd G3 (65.7 mg, 0.0776 mmol) at 25 °C. The reaction mixture was stirred at 25 °C under N for 2 h. The reaction mixture was added to water (20 mL), and the aqueous phase was extracted with ethyl acetate (50 × 2 mL). The combined organic phase was washed with aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0% to 50% EtOAc on petrol to give tert-butyl 6-(1-cyano-2-ethoxy-2-oxoethyl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-formate (440 mg, 95% purity, 91% yield) as a yellow solid.

[0235] Borane-tetrahydrofuran (1 M, 23 mL) was added to a solution of tert-butyl 6-(1-cyano-2-ethoxy-2-oxoethyl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl)-1,3-dihydroisoindole-2-formate (230 mg, 0.389 mol) in THF (35 mL) at 25°C. The reaction mixture was heated to 60°C and stirred with nitrogen gas at 60°C for 5 hours. The reaction mixture was cooled to ambient temperature and quenched with MeOH until bubbling ceased. The mixture was concentrated under reduced pressure. The filtrate was quenched with water (50 mL) and extracted with DCM (30 mL x 2). The combined organic phase was dried over sodium sulfate and filtered to give a white solid of tert-butyl 6-(1-amino-3-hydroxypropan-2-yl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-formate (180 mg, 75% yield).

[0236] To a solution of tert-butyl 6-(1-amino-3-hydroxypropan-2-yl)-4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindole-2-formate (180 mg, 0.0361 mmol) in DCM (60 mL) was added triphosgene (145 mg, 0.488 mmol). The reaction mixture was stirred at 25 °C under N for 5 hours. The mixture was quenched with water (30 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried over sodium sulfate and filtered to give tert-butyl 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(2-oxo-1,3-oxazin-5-yl)-1,3-dihydroisoindole-2-formate (105 mg, 50% yield) as a yellow solid.

[0237] TFA (2.0 mL) was added to a solution of tert-butyl 4-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(2-oxo-1,3-oxazin-5-yl)-1,3-dihydroisoindole-2-formate (105 mg, 0.181 mmol) in DCM (6.0 mL) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 hours. The filtrate was concentrated under reduced pressure to give 5-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-1,3-oxazin-2-one (100 mg, crude) as a yellow oil, which required no further purification and was used directly in the next step.

[0238] To a solution of 5-{7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2,3-dihydro-1H-isoindol-5-yl}-1,3-oxazin-2-one (107 mg, 0.223 mmol) in DCM (10 mL) was added TEA (67.7 mg, 0.670 mmol). The mixture was stirred at 25° C. for 10 minutes. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (CHCN from 28% to 58% within 9 min) to give a white solid of 5-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}-1,3-oxazin-2-one (8.70 mg, 7.5% yield). M001246 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.50 (s, 1H), 7.42 - 7.35 (m, 1H), 7.29 - 7.22 (m, 2H), 7.14 (s, 1H), 6.75 (t, J = 55.2 Hz, 1H), 6.44 - 6.35 (m, 1H), 4.90 - 4.84 (m, 1H), 4.76 - 4.45 (m, 2H), 4.40 - 4.23 (m, 3H), 3.86 (s, 3H), 3.60 - 3.51 (m, 2H), 3.44 - 3.37 (m, 3H), 2.91 - 2.83 (s, 2H), 2.05 - 1.96 (m, 5H).

[0239] To a solution of 5-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}-1,3-oxazin-2-one (20.0 mg, 0.0383 mmol) in THF (6.0 mL) was added dropwise KHMDS (1 M in THF, 0.1 mL, 0.0766 mmol) at −60° C. under N2 atmosphere. After stirring for 10 min, a solution of iodomethane (8.15 mg, 0.0574 mmol) in THF (0.5 mL) was added dropwise at −30° C. under N2 atmosphere. After stirring for an additional 20 min at 10° C., the mixture was quenched with NH4Cl solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (CHCN from 35% to 45% within 8 minutes) to give 5-{2-acetyl-7-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}-3-methyl-1,3-oxazin-2-one (5.00 mg, 23% yield), as a yellow solid. M001238 1H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.50 (s, 1H), 7.30 - 7.22 (m, 2H), 7.14 (s, 1H), 6.75 (t, J = 55.0 Hz, 1H), 6.45 - 6.33 (m, 1H), 4.89 - 4.85 (m, 1H), 4.69 - 4.54 (m, 2H), 4.38 - 4.25 (m, 3H), 3.86 (s, 3H), 3.60 - 3.47 (m, 5H), 2.91 - 2.84 (m, 5H), 2.04 (s, 3H), 2.01 - 1.93 (m, 2H).

[0240] Example 14

[0241] [ka]

[0242] A solution of 1-methoxypiperidin-4-one (500 mg, 3.87 mmol) in THF (15 mL) was cooled to -78 °C, and LDA (2 M, 2.5 mL, 5.03 mmol) was added under N2. The resulting mixture was stirred at the same temperature for 30 minutes and treated with a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (1.80 g, 5.03 mmol) in THF (15 mL). The reaction mixture was stirred again for 30 minutes and allowed to warm to 25 °C. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (60 mL × 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 column chromatography, eluting with 0% to 5% tetrahydrofuran in petroleum to give 1-methoxy-3,6-dihydro-2H-pyridin-4-yl trifluoromethanesulfonate (687 mg, purity 90%, yield 61%) as a colorless oil.

[0243] To a solution of tert-butyl 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-formate (234 mg, 0.377 mmol) and 1-methoxy-3,6-dihydro-2H-pyridin-4-yl trifluoromethanesulfonate (197 mg, 0.754 mmol) in dioxane (8.0 mL) and HO (0.8 mL) was added KCO (156 mg, 1.13 mmol) and XPhos Pd G (32.0 mg, 0.0377 mmol) at 25 °C. The reaction mixture was heated to 100 °C and stirred with nitrogen gas at 100 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM and methanol from 0% to 5% to give tert-butyl 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-methoxy-3,6-dihydro-2H-pyridin-4-yl)-3,4-dihydro-1H-isoquinoline-2-formate (210 mg, purity 90%, yield 83%) as a brown solid.

[0244] To a solution of tert-butyl 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-methoxy-3,6-dihydro-2H-pyridin-4-yl)-3,4-dihydro-1H-isoquinoline-2-formate (120 mg, 0.198 mmol) in MeOH (10 mL) was added Pd / C (21.1 mg, 0.198 mmol). The mixture was stirred at 25 °C under H balloon pressure for 16 hours. The mixture was filtered to remove solids and concentrated. The residue was purified by Prep-HPLC (CHCN from 70% to 95% within 9 min) to give tert-butyl 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-piperidinyl-4-yl)-3,4-dihydro-1H-isoquinoline-2-formate (70 mg, 57% yield) as a white solid. M001274 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 7.46 (s, 1H), 7.11 - 7.00 (m, 3H), 6.69 (t, J = 55.2 Hz, 1H), 6.16 (s, 1H), 4.44 - 4.32 (m, 1H), 4.28 - 4.06 (m, 1H), 3.86 (s, 3H), 3.59 - 3.48 (m, 3H), 3.44 - 3.40 (3, 3H), 3.39 - 3.35 (m, 2H), 2.95 - 2.79 (m, 4H), 2.45 - 2.30 (m, 2H), 2.07 - 1.99 (m, 2H), 1.90 - 1.76 (m, 2H), 1.75 - 1.59 (m, 2H), 1.49 - 1.17 (m, 11H).

[0245] To a solution of tert-butyl 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-methoxypiperidinyl-4-yl)-3,4-dihydro-1H-isoquinoline-2-formate (76.0 mg, 0.125 mmol) in DCM (6.0 mL) was added TFA (2.0 mL) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure to give 7-(difluoromethyl)-1-[6-(1-methoxypiperidinyl-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline (65 mg, 97% yield) as a yellow oil, which was used directly in the next step without further purification.

[0246] To a solution of 7-(difluoromethyl)-1-[6-(1-methoxypiperidinyl-4-yl)-1,2,3,4-tetrahydroisoquinolin-8-yl]-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline (64.0 mg, 0.126 mmol) in DCM (6.0 mL) was added TEA (38.3 mg, 0.378 mmol) and N-methylcarbamoyl chloride (17.7 mg, 0.189 mmol) at 25°C. The mixture was stirred at 25°C for 10 minutes. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over sodium sulfate and filtered. The residue was purified by Prep-HPLC (CHCN from 50% to 60% within 9 min) to give a white solid, 8-[7-(difluoromethyl)-6-(1H-pyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-methoxypiperidinyl-4-yl)-N-methyl-3,4-dihydro-1H-isoquinoline-2-formamide (26.9 mg, 38% yield). M001268 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.69 (t, J = 55.2 Hz, 1H), 6.51 - 6.42 (m, 1H), 6.18 (s, 1H), 4.46 - 4.36 (m, 1H), 4.17 - 4.05 (m, 1H), 3.86 (s, 3H), 3.57 - 3.35 (m, 9H), 3.03 - 2.70 (m, 5H), 2.54 (d, J = 4.0 Hz, 3H), 2.42 - 2.28 (m, 2H), 2.10 - 1.99 (m, 2H), 1.90 - 1.76 (m, 2H), 1.74 - 1.56 (m, 2H).

[0247] Example 15

[0248] [ka]

[0249] Benzoyl peroxide (34.0 mg, 0.140 mmol) was added to a solution of 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-N-methyl-6-(piperidinyl-4-yl)-3,4-dihydro-1H-isoquinoline-2-formamide (50.0 mg, 0.0935 mmol) in THF (2.0 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was purified by preparative TLC (PE / THF=3:7) to give 4-{8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-(methylaminoformyl)-3,4-dihydro-1H-isoquinolin-6-yl}piperidinyl-1-ylbenzoate (20.0 mg, 29% yield) as a white solid.

[0250] To a solution of 4-{8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-2-(methylaminoformyl)-3,4-dihydro-1H-isoquinolin-6-yl}piperidinyl-1-ylbenzoate (20.0 mg, 0.0305 mmol) in MeOH (2 mL) was added K2CO3 (12.7 mg, 0.0915 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 1 hour. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (CHCN 20% to 50%) within 10 min to give a white solid of 8-[7-(difluoromethyl)-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-(1-hydroxypiperidinyl-4-yl)-N-methyl-3,4-dihydro-1H-isoquinoline-2-formamide (4.00 mg, 24% yield). M001276 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.08 (s, 1H), 7.04 (s, 1H), 6.99 (s, 1H), 6.83 - 6.45 (m, 2H), 6.18 (s, 1H), 4.46 - 4.38 (m, 1H), 4.15 - 4.06 (m, 1H), 3.86 (s, 3H), 3.55 - 3.41 (m, 4H), 3.25 - 3.05 (m, 2H), 3.00 - 2.77 (m, 5H), 2.54 (d, J = 4.2 Hz, 3H), 2.45 - 2.33 (m, 2H), 2.10 - 2.00 (m, 2H), 1.85 - 1.40 (m, 4H).

[0251] Example 16

[0252] [ka]

[0253] At 0° C., t-BuOK (1 M THF solution, 1.8 mL, 1.8 mmol) was added to a solution of 4-bromo-1H-pyridin-2-one (200 mg, 1.15 mmol) in THF (8.0 mL). The mixture was stirred at 0° C. for 0.5 hours. Then, at 0° C., a solution of 1-(2-methoxy-5-methylphenyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (526.0 mg, 1.4 mmol) in THF (2.0 mL) was added to the reaction mixture. The mixture was stirred at 0° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with 0% to 50% PE and EtOAc to give 3-(4-bromo-2-oxopyridin-1(2H)-yl)-1-(4-methoxybenzyl)piperidinyl-2,6-dione (300 mg, 64% yield) as a yellow solid.

[0254] 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)-formate (300 mg, 0.57 mmol) in dioxane (4.0 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (288.0 mg, 1.13 mmol), AcOK (167.0 mg, 1.70 mmol), and XPhos Pd G3 (95.9 mg, 0.11 mmol). The mixture was then stirred at 100° C. for 2 h. LCMS indicated that the starting material had been consumed and the required product was detected. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-formate (300 mg, 85% yield) as a yellow oil.

[0255] To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-formate (298.6 mg, 0.48 mmol) in dioxane (5.0 mL) and HO (0.5 mL) was added 3-(4-bromo-2-oxopyridin-1(2H)-yl)-1-(4-methoxybenzyl)piperidinyl-2,6-dione (130.0 mg, 0.32 mmol), KPO (204.3 mg, 0.96 mmol), and XPhos Pd G (54.3 mg, 0.06 mmol). The mixture was then stirred at 100° C. for 2 hours. LCMS indicated that the starting material had been consumed and the required product had been detected. The residue was purified by flash column chromatography, eluting with 0% to 50% PE with EtOAc, and then by flash column chromatography, eluting with 0% to 5% DCM with methanol, to give tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formate (160 mg, 91% yield), as a yellow solid.

[0256] To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-3,4-dihydroisoquinoline-2(1H)-formate (300 mg, 0.37 mmol) in DCM (6.0 mL) was added TFA (2.0 mL). The mixture was then stirred at 25° C. for 0.5 h. LCMS indicated that the starting material had been consumed and the required product was detected. The resulting mixture was concentrated under reduced pressure to give a yellow solid, 3-(4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxopyridin-1(2H)-yl)-1-(4-methoxybenzyl)piperidinyl-2,6-dione (250 mg, 95% yield).

[0257] To a solution of 3-(4-(8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2-oxopyridin-1(2H)-yl)-1-(4-methoxybenzyl)piperidinyl-2,6-dione (200 mg, 0.42 mmol) in DCM (2.0 mL) was added TEA (126.7 mg, 1.3 mmol) and N-methylcarbamoyl chloride (78.1 mg, 0.83 mmol) at 25 °C. The mixture was then stirred at 25 °C for 0.5 h. Water (50 mL) was added to quench the reaction, and the mixture was extracted with DCM (50 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a yellow solid, 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (130 mg, 60% yield).

[0258] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (50 mg, 0.06 mmol) in THF (1.0 mL) was added PtO (14.6 mg, 0.06 mmol) at 25 °C under an atmosphere of H (15 PSI). The mixture was then stirred at 25 °C for 12 h. LCMS indicated that the starting material had been consumed and the required product was detected. After filtration, the filtrate was concentrated under reduced pressure to give a yellow solid, 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1'-(4-methoxybenzyl)-2,2',6'-trioxo-[1,3'-bipiperidinyl]-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (40 mg, 80% yield).

[0259] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1'-(4-methoxybenzyl)-2,2',6'-trioxo-[1,3'-bipiperidinyl]-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (50 mg, 0.06 mmol) in TFA (2.0 mL) was added TfOH (0.2 mL). The mixture was then stirred at 60° C. for 6 hours. The reaction was purified by preparative HPLC, eluting with CH3CN in 0.1% FA / water from 27% to 57% in 7 min to give 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methyl-6-(2,2',6'-trioxo-[1,3'-bipyridin]-4-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (0.9 mg, 3% yield) as a white solid. M001287 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 7.10 (d, J = 11.2 Hz, 3H), 6.70 (t, J = 55.2 Hz, 1H), 6.48 - 6.45 (m, 1H), 6.18 (s, 1H), 4.44 (d, J = 16.8 Hz, 2H), 4.40 - 4.29 (m, 1H), 4.11 (d, J = 16.8 Hz, 2H), 3.86 (s, 3H), 3.57 - 3.51 (m, 2H), 3.50 - 3.42 (m, 2H), 3.40 - 3.35 (m, 2H), 3.30 - 3.16 (m, 2H), 3.16 - 3.05 (m, 2H), 2.97 - 2.77 (m, 5H), 2.55 (d, J = 4.4 Hz, 3H), 2.14 - 1.87 (m, 4H).

[0260] To a solution of 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (50 mg, 0.06 mmol) in TFA (2.0 mL) was added TfOH (0.2 mL). The mixture was then stirred at 60° C. for 6 hours. The reaction was purified by preparative HPLC, eluting with CHCN in 0.1% FA / water from 26% to 56% in 7 min to give a white solid: 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydropyridin-4-yl)-N-methyl-3,4-dihydroisoquinoline-2(1H)-formamide (5.3 mg, 13% yield). M001300 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 7.73 - 7.70 (m, 2H), 7.59 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 7.12 (s, 1H), 6.76 (t, J = 55.1 Hz, 1H), 6.73 (s, 1H), 6.69 - 6.63 (m, 1H), 6.57 - 6.51 (m, 1H), 6.21 (s, 1H), 4.52 (d, J = 17.2 Hz, 2H), 4.17 (d, J = 17.2 Hz, 2H), 3.86 (s, 3H), 3.69 - 3.54 (m, 2H), 3.54 - 3.41 (m, 2H), 3.04 - 2.82 (m, 4H), 2.61 (s, 1H), 2.56 (d, J = 4.4 Hz, 3H), 2.10 - 2.00 (m, 4H).

[0261] Example 17

[0262] [ka]

[0263] To a solution of 1,4-dioxaspiro[4.5]dec-8-ol (10 g, 0.063 mol), 4-DMAP (0.77 g, 0.0063 mol), and TEA (19 g, 0.19 mol) in DCM (200 mL) was added TsCl (18 g, 0.095 mol). The reaction mixture was stirred at 25 °C for 16 h. LCMS indicated the desired product had been formed. The solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 30% EtOAc in PE to give 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (10 g, 48%) as a white solid.

[0264] To a solution of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (5.0 g, 0.02 mol) in EtOH (50 mL) was added sodium methyl sulfate (2.2 g, 0.032 mol). The reaction mixture was stirred at 80 °C for 30 minutes. The solvent was removed under reduced pressure. The solid was dissolved in water and extracted with EtOAc (200 mL × 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE and EA from 0% to 20% to give 8-(methylthio)-1,4-dioxaspiro[4.5]decane (2.2 g, 55%) as a yellow oil.

[0265] To a solution of 8-(methylsulfonyl)-1,4-dioxaspiro[4.5]decane (2.2 g, 5.9 mmol) in HO (5.0 mL) was added PTSA (2.2 g, 11.6 mmol). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was extracted with EtOAc (200 mL). The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE and EA from 0% to 20% to give 4-(methylthio)cyclohexan-1-one (1.2 g, 78%) as a yellow oil.

[0266] To a solution of 4-(methylthio)cyclohexan-1-one (1.2 g, 8.4 mmol) in THF (15 mL) was added LDA (4.5 mL, 2 M THF, 9.0 mmol) at −78° C. The reaction mixture was stirred at the same temperature for 1.0 h, and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (3.2 g, 9.0 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was quenched with NH4Cl(aq) and extracted with EA (200 mL × 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with PE from 0% to 3% EA to give 4-(methylthio)cyclohexyl-1-en-1-yl trifluoromethanesulfonate (0.8 g, 35%) as a pale yellow oil.

[0267] To a solution of tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-formate (1.0 g, 1.6 mmol) and tert-butyl 4-(methylthio)cyclohexyl-1-ene-1-trifluoromethanesulfonate (0.46 g, 1.6 mmol) in dioxane (20 mL) and HO (3 mL) was added Xphos 1 Pd G (0.13 g, 0.16 mmol) and KCO (0.34 g, 2.5 mmol). The reaction mixture was stirred at 100 °C for 2.0 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with 0% to 60% EtOAc in PE to give tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindoline-2-formate (0.50 g, 50%) as a pale yellow solid.

[0268] A solution of tert-butyl 4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindoline-2-formate (0.50 g, 0.80 mmol) in HCl (3.0 mL, 4 M EA) was stirred at 25 °C for 30 min. LCM showed the formation of the target product. The solid was removed under reduced pressure to give 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindol-4-yl)-1,2,3,4-tetrahydroquinoline (0.46 g, crude) as a white solid.

[0269] To a solution of 7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1-(6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindol-4-yl)-1,2,3,4-tetrahydroquinoline (0.46 g, 0.92 mmol) and TEA (0.28 g, 2.7 mmol) in DCM (5.0 mL) was added acetyl chloride (0.14 g, 12.2 mmol), and the reaction mixture was stirred at 25° C. for 30 minutes. The reaction was quenched with water and extracted with DCM (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a white solid: 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindolin-2-yl)ethan-1-one (0.42 g, 86%).

[0270] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl-1-en-1-yl)isoindol-2-yl)ethan-1-one (0.42 g, 0.77 mmol) in MeOH (5.0 mL) was added PtO (0.42 g). The reaction mixture was stirred at 25 °C under H atmosphere for 48 h. The PtO2 was filtered, the solvent removed under reduced pressure, and the residue was purified by preparatory HPLC (CH3CN from 33% to 43% within 2 min) to give 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl)isoindol-2-yl)ethan-1-one (0.1 g, 24%) as a white solid. M001315 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.15 - 7.07 (m, 3H), 6.87 (s, 0.25 H), 6.74 (s, 0.50 H), 6.60 (s, 0.25 H), 6.45 - 6.33 (m, 1H), 4.90 - 4.50 (m, 3H), 4.28 (s, 1H), 3.86 (s, 3H), 3.54 (d, J = 4.8 Hz, 2H), 2.87 (s, 2H), 2.64 - 2.53 (m, 2H), 2.10 - 1.96 (m, 10H), 1.87 (d, J = 11.6 Hz, 2H), 1.60 - 1.47 (m, 2H), 1.38 (d, J = 9.6 Hz, 2H).

[0271] To a solution of 1-(4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-(4-(methylthio)cyclohexyl)isoindol-2-yl)ethan-1-one (90 mg, 0.17 mmol) and ammonium carbamate (19 mg, 0.25 mmol) in MeOH (3.0 mL) was added PIDA (113 mg, 0.35 mmol). The reaction mixture was stirred at 0 °C for 30 min. LCMS showed the formation of the target product. The reaction was quenched with water and extracted with EA (10 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by preparatory HPLC (CHCN from 20% to 35% within 3 min) to give (4-(2-acetyl-7-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)isoindol-5-yl)cyclohexyl)(imino)(methyl)-16-sulfanone (16 mg, 17%) as a pale yellow solid. M001297 1 H NMR (400 MHz, DMSO) δ 7.74 (s, 1H), 7.49 (s, 1H), 7.13 (d, J = 6.0 Hz, 3H), 6.88 (s, 0.25 H), 6.74 (s, 0.50 H), 6.61 (s, 0.25 H), 6.46 - 6.34 (m, 1H), 4.95 - 4.55 (m, 3H), 4.29 (s, 1H), 3.86 (s, 3H), 3.54 (s, 3H), 2.98 (s, 1H), 2.88 (s, 2H), 2.83 (d, J = 4.0 Hz, 3H), 2.58 (s, 1H), 2.21 (s, 2H), 2.05 - 1.90 (m, 7H), 1.65 - 1.45 (m, 4H).

[0272] Example 18

[0273] [ka]

[0274] 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)-formate (120 mg, 226.83 μmol) in DCM (4 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated to give compound 2 (120 mg, 221.02 μmol, 97.4% yield, TFA) in the form of a yellow solid.

[0275] To a solution of 1-((8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)piperidinyl-3-methyl formate (50 mg, 75.34 μmol, TFA) in DCM (3 mL) was added TEA (22.87 mg, 226.01 μmol) and carbamoyl chloride (17.61 mg, 188.34 μmol). The mixture was stirred at 15 °C for 16 h. The mixture was extracted with DCM (10 mL) and washed with brine (5 mL). The organic layer was dried over NaSO, filtered, and concentrated to give compound 4 (40 mg, 65.93 μmol, 87.5% yield) as a yellow oil.

[0276] 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)-formate (0.7 g, 1.32 mmol), potassium ethylenetrifluoroborate (265.86 mg, 1.98 mmol), Pd(dba) (121.17 mg, 132.32 μmol), s-Phos (108.64 mg, 264.64 μmol), and t-BuONa (381.49 mg, 3.97 mmol) in dioxane (10 mL) was degassed and purged with N three times, and the mixture was stirred at 100 °C under N for 16 h. 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 (petroleum ether / ethyl acetate 100% to 70%) to give compound 6 (593 mg, 1.14 mmol, 86.3% yield) as a yellow oil.

[0277] To a solution of tert-butyl 8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrrol-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-6-vinyl-3,4-dihydroisoquinoline-2(1H)-formate (593 mg, 1.14 mmol) in HO (2 mL) and THF (8 mL) was added KOsO (21.71 mg, 114.12 μmol), the mixture was cooled to 0 °C, and NaIO (488.19 mg, 2.28 mmol, 126.47 μL, 2 eq) was added, heated to 15 °C, and stirred for 16 h. 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 (petroleum ether / ethyl acetate 100% to 30%) to give compound 7 (451 mg, 864.65 μmol, 75.8% yield) as a yellow oil.

[0278] To a solution of 1-((8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)piperidinyl-3-methyl formate (50 mg, 75.34 μmol, TFA) in DCM (3 mL) was added TEA (22.87 mg, 226.01 μmol) and carbamoyl chloride (17.61 mg, 188.34 μmol). The mixture was stirred at 15 °C for 16 h. The mixture was extracted with DCM (10 mL) and washed with brine (5 mL). The organic layer was dried over Na SO , filtered, and concentrated to give compound 6 (40 mg, 65.93 μmol, 87.5% yield, crude) as a yellow oil.

[0279] To a solution of 1-((8-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-2-(methylaminoformyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)piperidinyl-3-methylformate (40 mg, 65.93 μmol) in MeOH (2 mL) and HO (1 mL) was added LiOH (4.74 mg, 197.79 μmol). The mixture was stirred at 15 °C for 0.5 h. The mixture was concentrated to give the crude product, which was purified by prep-HPLC (FA) to give a gray solid M001015 (3.25 mg, 5.48 μmol, 8.3% yield). M001015 1 H NMR (400MHz, CD3Cl) δ 8.23 ​​(br s, 1H), 7.72 (s, 1H), 7.47 (s, 1H), 7.34 -6.96 (m, 3H), 6.88 - 6.09 (m, 1H), 6.18 (s, 1H), 4.56 - 4.07 (m, 3H), 3.85 (s, 3H),3.01 - 2.63 (m, 8H), 2.59 - 2.53 (m, 6H), 2.42 - 2.28 (m, 2H), 2.18 - 1.89 (m, 4H),1.83 - 1.51 (m, 2H), 1.45 - 1.30 (m, 1H).

[0280] Example 19

[0281] [ka]

[0282] Phenylboronic acid (19.38 mg, 158.92 μmol), 6-chloro-4-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-N-methylisoindoline-2-formamide (50 mg, 105.95 μmol), XPhos Pd G3 (8.97 mg, 10.59 μmol), and K3PO4 (67.47 mg, 317.84 μmol) were dissolved in THF (2 mL) and HO (0.5 mL) and placed in a microwave tube. The tube was heated in a microwave oven at 60 °C for 1 h. The mixture was extracted with EtOAc (10 mL) and washed with brine (5 mL × 2). The organic layer was dried over NaSO, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100% to 0%) to give a yellow solid M001120 (3.66 mg, 7.13 μmol, 6.7% yield). M001120 1 H NMR (400MHz, DMSO-d6) δ 7.75 (s, 1H), 7.69 (br d, J = 7.70 Hz, 2H), 7.56 (s,1H), 7.48-7.51 (m, 2H), 7.44-7.47 (m, 1H), 7.33-7.41 (m, 1H), 7.14 (s, 1H), 6.60-6.91 (m, 1H), 6.29-6.46 (m, 2H), 4.68 (br s, 2H), 4.26-4.47 (m, 2H), 3.85 (s, 3H), 3.63 (br s, 1H), 2.86-2.93 (m, 2H), 2.55-2.63 (m, 4H), 1.98-2.09 (m, 2H).

[0283] Example 20

[0284] [ka]

[0285] To a solution of 6-bromo-7-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (600 mg, 2.30 mmol) and 3-(methoxymethyl)-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (635 mg, 2.52 mmol) in dioxane (20 mL) and HO (2.0 mL) was added KCO (949 mg, 6.87 mmol) and Pd(dppf)Cl (168 mg, 0.230 mmol). The reaction mixture was stirred at 100 °C under N for 2 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL × 2). The combined organic phase was washed with aqueous NaCl (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 0% to 30% EtOAc on petroleum to give 7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-1,2,3,4-tetrahydroquinoline (700 mg, 85% yield) as a yellow oil.

[0286] To a solution of 7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-1,2,3,4-tetrahydroquinoline (797 mg, 2.59 mmol) and tert-butyl (6-chloro-4-iodo-1,3-dihydroisoindol-2-yl)formate (1974 mg, 5.19 mmol) in dioxane (60 mL) was added t-BuONa (748 mg, 7.78 mmol) and XPhos Pd G3 (219 mg, 0.259 mmol) at 25 °C. The reaction mixture was stirred at 90 °C for 16 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL × 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 column chromatography, eluting with PE in THF from 0% to 25% to give tert-butyl {6-chloro-4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}formate (1.01 g, 66% yield), as a brown solid.

[0287] To a solution of tert-butyl {6-chloro-4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}formate (200 mg, 0.357 mmol) and 2-(1-methylphenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (167 mg, 0.536 mmol) in 10:1 THF / HO (11 mL) was added KPO (227 mg, 1.07 mmol) and XPhos Pd G (60.4 mg, 0.0714 mmol) at 25 °C. The reaction mixture was stirred at 60 °C under N for 2 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (80 mL × 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 column chromatography, eluting with petroleum THF from 0% to 60% to give tert-butyl {4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}formate (113 mg, 44% yield), as a brown solid.

[0288] TFA (2.0 mL) was added to a solution of tert-butyl {4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}formate (113 mg, 0.159 mmol) in DCM (6.0 mL) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure to give 7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-1-{6-[2-(1-methylphenoxy)pyridin-4-yl]-2,3-dihydro-1H-isoindol-4-yl}-3,4-dihydro-2H-quinoline (120 mg, 92% yield) as a brown oil, which required no further purification and was used directly in the next step.

[0289] To a solution of 7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-1-{6-[2-(1-methylphenoxy)pyridin-4-yl]-2,3-dihydro-1H-isoindol-4-yl}-3,4-dihydro-2H-quinoline (97.0 mg, 0.159 mmol) in DCM (5.0 mL) was added TEA (48.4 mg, 0.478 mmol) and acetyl chloride (18.8 mg, 0.239 mmol). The reaction mixture was stirred at 25 °C for 10 minutes. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (50 mL × 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 column chromatography, eluting with methanol in DCM from 0% to 5% to give 1-{4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}ethanone (71.0 mg, 62% yield) as a yellow solid.

[0290] To a solution of 1-{4-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}vinyl (99.0 mg, 0.155 mmol) in MEOH (8.0 mL) was added PtO (34.5 mg, 0.152 mmol). The mixture was stirred at 25 °C under H balloon pressure for 16 h. The mixture was filtered to remove solids and concentrated. The residue was purified by Prep-HPLC (CHCN from 40% to 70% within 10 min) to give 4-{2-acetyl-7-[7-(difluoromethyl)-6-[3-(methoxymethyl)-1-methylpyrazol-4-yl]-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidinyl-2-one (15.1 mg, 18% yield) as a white solid. M001206 1 H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.52 (m, 2H), 7.25 - 7.14 (m, 2H), 7.09 - 7.03 (m, 1H), 6.65 (d, J = 55.4 Hz, 1H), 6.45 - 6.35 (m, 1H), 4.90 - 4.84 (m, 1H), 4.74 - 4.50 (m, 2H), 4.37 - 4.27 (m, 1H), 4.18 (s, 2H), 3.84 (s, 3H), 3.62 - 3.54 (m, 2H), 3.22 - 3.17 (m, 4H), 3.14 - 3.02 (m, 2H), 2.90 - 2.84 (m, 2H), 2.37 - 2.30 (m, 2H), 2.05 - 1.87 (m, 7H).

[0291] Example 21

[0292] [ka]

[0293] To a solution of 7-bromo-1,2,3,4-tetrahydroquinoline (2.0 g, 0.0094 mol) and cyclopropylborinediol (1.6 g, 0.019 mol) in toluene / water (11 mL) was added K3PO4 (6.0 g, 0.028 mol), tricyclohexylphosphine (0.3 g, 0.0009 mol), and Pd(OAc)2 (0.2 g, 0.0009 mol). The mixture was stirred at 100 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (from 0% to 20% EtOAc within 15 min) to give 7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.2 g, 66% yield) as a yellow gel.

[0294] To a solution of 7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.1 g, 0.0062 mol) in ACN (20 mL) was added N-bromosuccinimide (1.2 g, 0.0065 mol) at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether, with 0% to 30% EtOAc in 20 min to give 6-bromo-7-cyclopropyl-1,2,3,4-tetrahydroquinoline (1.3 g, 74% yield), a yellow liquid.

[0295] To a solution of 6-bromo-7-cyclopropyl-1,2,3,4-tetrahydroquinoline (0.9 g, 0.0054 mol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.1 g, 0.0054 mmol) in dioxane / water (22 mL) was added K2CO3 (1.5 g, 0.011 mol) and Pd(dppf)Cl2 (0.3 g, 0.0003 mmol). The mixture was stirred at 90 °C for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EtOAc / petroleum ether, from 0% to 50% EtOAc within 20 min to give 7-cyclopropyl-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (0.7 g, 64% yield), as a yellow gel.

[0296] To a solution of 7-cyclopropyl-6-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (300 mg, 3.2 mmol) and tert-butyl (6-chloro-4-iodo-1,3-dihydroisoindol-2-yl)formate (1322 mg, 3.5 mmol) in dioxane (30 mL) was added Cphos-Pd G3 (509 mg, 0.63 mmol) and t-BuONa (607 mg, 6.3 mmol). The mixture was stirred at 90° C. for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether, eluting from 0% to 50% EtOAc within 15 min to give tert-butyl {6-chloro-4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}formate (400 mg, 23% yield) as a yellow gel.

[0297] To a solution of tert-butyl {6-chloro-4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-2-yl}formate (200 mg, 0.40 mmol) and 2-(1-methylphenoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (247 mg, 0.79 mmol) in dioxane / water (11 mL) was added KCO (252 mg, 1.2 mmol) and X-Phos Pd G (67 mg, 0.079 mmol). The mixture was stirred at 90 °C for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether, eluting from 0% to 50% EtOAc within 15 min to give tert-butyl {4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}formate (100 mg, 35% yield) as a yellow gel.

[0298] A mixture of tert-butyl {4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}formate (100 mg, 0.15 mmol) in DCM / TFA (6 mL) was stirred for 0.1 hours at 25° C. The mixture was concentrated under reduced pressure to give 7-cyclopropyl-1-{6-[2-(1-methylphenoxy)pyridin-4-yl]-2,3-dihydro-1H-isoindol-4-yl}-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline (80 mg, 85% yield) as a yellow gel.

[0299] To a solution of 7-cyclopropyl-1-{6-[2-(1-methylphenoxy)pyridin-4-yl]-2,3-dihydro-1H-isoindol-4-yl}-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinoline (80 mg, 0.14 mmol) and triethanolamine (44 mg, 0.43 mmol) in DCM (10 mL) was added acetyl chloride (23 mg, 0.29 mmol). The mixture was stirred at 25° C. for 0.1 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether, with EtOAc eluting from 0% to 50% within 10 min to give 1-{4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}ethenone (70 mg, 73% yield) as a yellow gel.

[0300] To a solution of 1-{4-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-6-[2-(1-methylphenoxy)pyridin-4-yl]-1,3-dihydroisoindol-2-yl}vinyl (70 mg, 0.12 mmol) in MeOH (5 mL) was added PtO (27 mg, 0.12 mmol). The mixture was stirred at 25 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparatory HPLC, eluting with 40% to 50% CHCN in water within 10 min, to give 4-{2-acetyl-7-[7-cyclopropyl-6-(1-methylpyrazol-4-yl)-3,4-dihydro-2H-quinolin-1-yl]-1,3-dihydroisoindol-5-yl}piperidinyl-2-one (30 mg, 49% yield) as a white solid. M001219 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.14-7.01 (m, 2H), 7.02 (s, 1H), 5.88-5.82 (m,, 1H), 4.85 (s, 1H), 4.64 (s, 1H), 4.59 (s, 1H), 4.26 (s, 1H), 3.85 (s, 3H), 3.49 (d, J = 5.2 Hz, 2H), 3.20 (s, 2H), 3.07 (s, 1H), 2.79-2.78 (m, 2H), 2.36 - 2.29 (m, 2H), 2.04 (d, J = 5.2 Hz, 1H), 2.00 - 1.92 (m, 4H), 1.87-1.84 (m, 3H), 0.77 - 0.69 (m, 2H), 0.21 - 0.13 (m, 2H).

[0301] Example 22

[0302] [ka]

[0303] To a stirred solution of 2-bromo-4-fluorobenzaldehyde (5.0 g, 0.024 mol) in HSO (30.0 mL) was added nitric acid (1.71 g, 0.027 mol) at 0 °C. The reaction mixture was heated to 25 °C and stirred at that temperature for 2 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (50 mL × 2). The combined organic phase was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure to give 2-bromo-4-fluoro-5-nitrobenzenecarbaldehyde (5.6 g, 78% yield) as a yellow solid.

[0304] To a stirred solution of 2-bromo-4-fluoro-5-nitrobenzenecarbaldehyde (1.5 g, 0.006 mol) in DCM (20.0 mL) was added DAST (1.93 g, 0.012 mol) at 0 °C. The reaction mixture was heated to 25 °C and stirred at this temperature for 12 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0% to 5% EtOAc) within 10 min to give 1-bromo-2-(difluoromethyl)-5-fluoro-4-nitrobenzene (1.4 g, 78% yield) as a yellow solid.

[0305] To a solution of 1-bromo-2-(difluoromethyl)-5-fluoro-4-nitrobenzeneformic acid (1.4 g, 0.005 mol) in EtOH (20.0 mL) and HO (5.0 mL) was added Fe (1.45 g, 0.026 mol) and NH Cl (2.78 g, 0.052 mol). The reaction mixture was heated to 90 °C and stirred at this temperature for 2 h. The mixture was cooled to 25 °C, filtered to remove solids, and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (0% to 5% EtOAc) within 10 min to give 4-bromo-5-(difluoromethyl)-2-fluoroaniline (0.85 g, 62% yield) as a white solid.

[0306] To a solution of 4-bromo-5-(difluoromethyl)-2-fluoroaniline (850 mg, 3.54 mmol) in 1,4-dioxane (15.0 mL) and HO (2.0 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (884 mg, 4.24 mmol), KCO (979 mg, 7.08 mmol), and Pd(dppf)Cl (259 mg, 0.354 mmol). The reaction mixture was heated to 100 °C and stirred at this temperature with N for 10 hours. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (from 0% to 20% EtOAc) within 10 min to give 5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)aniline (790 mg, 88% yield) as a white solid.

[0307] To a solution of 5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)aniline (500 mg, 2.07 mmol) in 1,4-dioxane (10.0 mL) was added tert-butyl 8-bromo-6-chloro-3,4-dihydro-1H-isoquinoline-2-formate (719 mg, 2.07 mmol), t-BuONa (398 mg, 4.14 mmol), and Cphos-Pd G3 (167 mg, 0.207 mmol). The reaction mixture was heated to 90 °C and stirred at this temperature with N for 12 hours. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (MeOH from 0 to 10%) within 10 min to give tert-butyl 6-chloro-8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-3,4-dihydroisoquinoline-2(1H)-formate (780 mg, 45% yield) as a yellow solid.

[0308] To a solution of tert-butyl 6-chloro-8-(5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-3,4-dihydroisoquinoline-2(1H)-formate (150 mg, 0.295 mmol) in THF (6.0 mL) and HO (1.0 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (139 mg, 0.591 mmol), KPO (188 mg, 0.887 mmol), and XPhos Pd G (25.0 mg, 0.029 mmol). The reaction solution was heated to 80 °C and stirred at this temperature with N for 12 hours. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH / DCM (MeOH from 0 to 10%) for 10 min to give tert-butyl 8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-formate (150 mg, 83% yield) as a yellow solid.

[0309] To a solution of tert-butyl 8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-formate (150 mg, 0.258 mmol) in DCM (5.0 mL) was added TFA (1.0 mL). The solution was stirred at 25° C. for 1 hour. The mixture was concentrated under reduced pressure to give 5-(8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methylpyridin-2(1H)-one (110 mg, 84% yield) as a yellow oil.

[0310] To a solution of 5-(8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-1,2,3,4-tetrahydroisoquinolin-6-yl)-1-methylpyridin-2(1H)-one (110 mg, 0.229 mmol) in DCM (5.0 mL) was added EtN (70.0 mg, 0.688 mmol) and N-methylcarbamoyl chloride (64.0 mg, 0.688 mmol). The reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (CHCN was purified from 25% to 55% within 8 min) to give a white solid c (80.0 mg, 65% yield). M001239 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 2.0 Hz, 1H), 7.87 (s, 1H), 7.71 - 7.68 (m, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 12.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.06 - 6.75 (m, 2H), 6.48 - 6.43 (m, 2H), 4.43 (s, 2H), 3.88 (s, 3H), 3.55 - 3.52 (m, 2H), 3.47 (s, 3H), 2.84 (s, 2H), 2.59 (d, J = 4.0 Hz, 3H).

[0311] To a solution of 8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methyl-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (70 mg, 0.130 mmol) in MeOH (6.0 mL) was added PtO (30.0 mg, 0.130 mmol). The solution was stirred at 25 °C with H for 12 h. The mixture was filtered to remove solids and concentrated. The residue was purified by Prep-HPLC (CHCN from 25% to 55% within 9 min) to give 8-((5-(difluoromethyl)-2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-N-methyl-6-(1-methyl-6-oxopiperidin-3-yl)-3,4-dihydroisoquinoline-2(1H)-formamide (42.5 mg, 50% yield) as a white solid. M001232 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.34 (d, J = 12.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.05 - 6.76 (m, 3H), 6.49 - 6.41 (m, 1H), 4.39 (s, 2H), 3.89 (s, 3H), 3.52 - 3.49 (m, 2H), 3.32 - 3.24 (m, 2H), 3.05 - 2.99 (m, 1H), 2.79 - 2.76 (m, 5H), 2.59 (d, J = 4.0 Hz, 3H), 2.36 - 2.22 (m, 2H), 1.97 - 1.82 (m, 2H).

[0312] [Table 2]

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[0377] Biological Activity Example 1 22RV1 or vCap cells were cultured in RPMI-1640 medium (RPMI-1640 supplemented with 10% fetal bovine serum and 100 units of penicillin / streptomycin double antibody per mL) and placed in a cell culture incubator at 37°C and 5% CO. 5 × 10 cells in the logarithmic growth phase were cultured. 3Cells were seeded into 96-well cell culture plates at a density of 100 μL per well and cultured overnight. Different concentrations of active compounds dissolved in DMSO were added to the plates to a final concentration of 0.5% DMSO. The positive control was 1% TweeN20, and the negative control was 0.5% DMSO. After 72 hours of culture, an equal volume of CellTiter-Glo was added to each well. The plates were shaken to mix for 2 minutes and then incubated at room temperature for 10 minutes. Fluorescence signals were then read using a microplate reader. Data were analyzed and graphed using Prism 7.0. Values ​​shown are mean ± SEM (n = 2). The negative control was 0% inhibition, and the positive control was 100% inhibition. The formula for calculating the inhibition rate is as follows: % inhibition rate = (Icompound - IZPE) / (IHPE - IZPE) × 100, where Icompound is the signal value of the compound group, IHPE is the signal value of the 100% inhibition group, and IZPE is the signal value of the negative control group. The X axis represents the compound concentration (μM), and the Y axis represents % inhibition. Note, A<1 μM, 1 μM <B。

[0378] [Table 3]

[0379] JPEG2025529942000136.jpg229169

[0380] JPEG2025529942000137.jpg229169

[0381] JPEG2025529942000138.jpg229169

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[0385] The biochemical activity of EP300 regulators was measured using the Ep300 AlphaLISA® Detection Kit. The principle of this assay is based on the enzymatic transfer of an acetyl group from acetyl-coenzyme A to a specific lysine residue in a biotinylated peptide substrate. After incubating the compounds with EP300, they were incubated with an antibody specifically binding to the acetylated peptide and receptor beads that bind to the acetylated peptide, followed by incubation with streptavidin-labeled donor beads. Alpha counts were read, and the data were analyzed using Prism 7.0 to calculate the IC50. The values ​​shown are mean ± SEM (N=2).

[0386] The biochemical activity of CBP preparations was measured using the CBP AlphaLISA® Detection Reagent Kit. The principle of this assay is based on the binding of the CBP bromodomain to an acetylated histone substrate. After incubating the compound with CBP and the biotinylated substrate for 30 minutes, acceptor beads were added and incubated for 15 minutes. Donor beads were then added and incubated for another 15 minutes. Alpha counts were then read and the data analyzed using Prism 7.0 to calculate IC50 values. The values ​​shown are means ± SEM (n = 2). A<10 nM, B>10 nM.

[0387] [Table 4]

[0388] The above are illustrative examples of the embodiments of the technical solution of the present disclosure. It should be understood that the scope of the claims of the present disclosure is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the scope of the spirit and principles of the present disclosure should be included within the scope of the claims.

Claims

1. A compound of formula I and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, crystalline polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, 【Chemical 1】 Among them, n=0, 1, 2, m=0, 1, 2, 3, p=0, 1, 2, 3, 4, 5, q=0, 1, 2, X 1 , X 2 , X 3 , X 4 are each independently selected from C or N, Each R 1 are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 1 C substituted with a 1-12 Alkyl group, C 1-12 an alkoxy group, and —(C═O)R; The R is C 1-12 Alkyl group, C 1-12 Alkoxy group, NH 2 -, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 3-12 cycloalkyl groups, Each R 1 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 selected from alkoxy groups, Each R 2 are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 selected from alkoxy groups, R 2 ' is H, halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 2 C substituted with a 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 Cycloalkyl groups, C 1-12 selected from alkyl groups, Each R 2 a are the same or different and independently represent H, oxo (=O), halogen, COOH, OH, unsubstituted or optionally one, two or more R 2 NH substituted with b 2 , C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkylthio group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 Cycloalkyl groups, C 6-14 Aryl C(=O)-, 5-14 membered heteroaryl C(=O)-, 3-14 membered heterocyclyl C(=O)-, C 3-12 CycloalkylC(=O)-, C 1-12 AlkylS(=O) 2 -, C 1-12 AlkylS(=O)-, C 1-12 AlkylS(=O)(=NH)-, C 3-12 CycloalkylS(=O) 2 -, C 1-12 Alkyl-C(=O)-NH-, C 1-12 Alkyl-S(=O) 2 -NH-, Each R 2 b's are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, R 3 H, halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 3 C substituted with a 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC (=O), N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 cycloalkyl groups, Each R 3 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 3 C substituted with b 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, Each R 3 b's are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, R 4 H, halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 4 C substituted with a 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC (=O), N,N-diC 1-12 Alkylaminocarbonyl group, C 6-14 Aryl groups, 5-14 membered heteroaryl groups, 3-14 membered heterocyclyl groups, C 3-12 cycloalkyl groups, Each R 4 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 4 C substituted with b 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 alkyl-NHC(=O)-, and N,N-diC alkylaminocarbonyl groups; Each R 4 b's are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 alkylamino groups, Each R 5 are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 5 C substituted with a 1-12 Alkyl group, C 1-12 selected from alkoxy groups, Each R 5 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 selected from alkoxy groups, R 6 H, halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 6 C substituted with a 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC (=O), N,N-diC 1-12 alkylaminocarbonyl groups, Each R 6 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, R 7 H, halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally one, two or more R 7 C substituted with a 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 Alkyl-NHC (=O), N,N-diC 1-12 alkylaminocarbonyl groups, Each R 7 a are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, or R 6 is R 7 together with R to form a 5- to 14-membered heteroaryl group, a 3- to 14-membered heterocyclyl group that is unsubstituted or optionally substituted with one, two or more R, and the 5- to 14-membered heteroaryl group, the 3- to 14-membered heterocyclyl group contains at least one N atom; Each Rsa may be the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, unsubstituted or optionally substituted with one, two or more Rsb 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 Alkylamino group, C 1-12 AlkylC(=O)-, C 1-12 AlkoxyC(=O)-, C 1-12 Alkyl-NHC(=O)-, N,N-diC 1-12 alkylaminocarbonyl groups, Each Rsb may be the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-12 Alkyl group, C 1-12 Alkoxy group, C 1-12 Alkyl-NH-, N,N-diC 1-12 The compound of formula I, and its racemates, stereoisomers, tautomers, isotopic derivatives, nitrogen oxides, solvates, crystalline polymorphs, metabolites, esters, prodrugs or pharmaceutically acceptable salts thereof, are selected from the group consisting of alkylamino groups.

2. In the above formula I, 【Chemistry 2】 The part has the following structure: 【Chemistry 3】 The compound of formula I according to claim 1, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of

3. Each R 1 are identical or different and independently represent oxo (=O), C 1-6 Alkyl group, C 1-6 an alkoxy group, and —(C═O)R, wherein R is C 1-6 Alkyl group, C 1-6 Alkoxy group, NH 2 -, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl groups, A compound of formula I according to claim 1 or 2, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof.

4. R 2 ' is H, Cl, unsubstituted or optionally one, two or more R 2 C substituted with a 6-10 Aryl groups, 5-9 membered heteroaryl groups, 3-12 membered heterocyclyl groups, C 3-8 Cycloalkyl groups, C 1-3 alkyl groups, said heterocyclyl groups containing 1 to 4 heteroatoms selected from N, O and S; Preferably, R 2 ' is H, Cl, unsubstituted or optionally one, two or more R 2 The following structure substituted with a 【Chemistry 4】 Selected from More preferably, R 2 ' is the following structure 【Chemistry 5】 Selected from Preferably, R 2 a is H, halogen (e.g., F), methyl group, ethyl group, oxo (=O), methoxy group, OH, COOH, 【Chemistry 6】 CH 3 C(=O)-, -CH 2 CHF 2 , -CH 2 CF 3 , -Cbz, -Boc, amino group, methylamino group, dimethylamino group, methylthio group, 【Chemistry 7】 -CH 2 CN、 【Chemistry 8】 The compound of formula I according to any one of claims 1 to 3, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of

5. R 3 is H, unsubstituted or optionally one, two or more R 3 C substituted with a 1-6 Alkyl group, C 1-6 Alkoxy group, C 3-8 cycloalkyl groups, and each R 3 a are the same or different and independently represent halogen, CN, NH 2 , COOH, and OH; R 4 is unsubstituted or optionally substituted with one, two or more R 4 a 5-6 membered heteroaryl group (e.g., a pyrazolyl group) substituted with 4 a are identical or different and are independently unsubstituted or optionally substituted with one, two or more R 4 C substituted with b 1-6 Alkyl group, C 1-6 Alkoxy group, N,N-diC 1-6 alkylaminocarbonyl groups, and each R 4 b's are the same or different and independently represent oxo (=O), halogen, CN, NH 2 , COOH, OH, C 1-6 Alkyl group, C 1-6 selected from alkoxy groups, Preferably, R 4 teeth 【Chemistry 9】 Selected from Each R 5 are the same or different and independently represent H, halogen, C 1-6 Alkyl group, C 1-6 selected from alkoxy groups, Preferably, R 6 H, halogen, C 1-6 Alkyl group, C 1-6 alkoxy groups, preferably R 6 is H, Preferably, R 7 H, halogen, C 1-6 Alkyl group, C 1-6 alkoxy groups, preferably R 7 is F, More preferably, R 6 and R 7 together with R to form a 5- or 6-membered heteroaryl group or a 5- or 6-membered heterocyclyl group which is unsubstituted or optionally substituted with one, two or more R Most preferably, R 6 and R 7 and the following structure, unsubstituted or optionally substituted with one, two or more Rsa: 【Chemistry 10】 The compound of formula I according to any one of claims 1 to 4, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, characterized in that it forms

6. The formula I may further include the structure shown in formula I-1 below: 【Chemistry 11】 Selected from Among them, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 7 , R, n, m, p, q are as defined in any one of claims 1 to 5, R 1 ' is R 1 and Preferably, R 1 ' is oxo (=O), C 1-6 Alkyl group, C 1-6 an alkoxy group, and —(C═O)R, wherein R is C 1-6 Alkyl group, C 1-6 Alkoxy group, NH 2 -, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl groups, Preferably, R 1 ' is H, CH 3 , -C(=O)CH 3 , -C(=O)OCH 3 , -C(=O)OCH 2 CH 3 , -C(=O)OCH(CH 3 ) 3 , C.H. 3 NHC(=O)-, CH 3 CH 2 NHC(=O)-, NH 2 C(=O)-, cyclopropyl-C(=O)-, Preferably, R 1 ' is -(C=O)CH 3 and Preferably, the formula I further comprises the structure shown in the following formula II, formula III, or formula IV: 【Chemistry 12】 Selected from In the formula II, formula III and formula IV, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 2 ', R 3 , R 4 , R 5 , R 6 , R 7 , R, n, m, p, q are as defined in any one of claims 1 to 5, Preferably, the formula I further comprises the structure shown in the following formula IIa or IIIa: 【Chemistry 13】 Selected from In the formula IIa and formula IIIa, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 2 ', R 3 , R 4 , R 5 6. The compound of formula I according to any one of claims 1 to 5, characterized in that R, n, m, p, and q are as defined in the compound of formula (I), and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

7. Exemplary specific compounds of the compound of formula (I) are characterized as follows: 【Table 1】 A compound of formula I according to any one of claims 1 to 6, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 7, and its racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug, or pharmaceutically acceptable salt thereof.

9. the pharmaceutical composition comprises a second therapeutic agent; The second therapeutic agent may be selected from drugs commonly used to treat cancer, heart disease, metabolic disease, inflammatory disease, fibrotic disease, and viral infections. Preferably, the class of second therapeutic agents may include androgen receptor antagonists such as enzalutamide, and inhibitors of CYP17A1 (17α-hydroxylase / C17,20 lyase) such as abiraterone, and cytotoxic chemotherapeutic agents such as docetaxel. The class of therapeutic agents used to treat lung cancer includes cytotoxic chemotherapeutic agents such as cisplatin, carboplatin, and docetaxel. The class of therapeutic agents used to treat bladder cancer includes cytotoxic chemotherapeutic agents such as cisplatin, carboplatin, and docetaxel.

9. The pharmaceutical composition of claim 8, wherein the second therapeutic agent comprises a cytotoxic chemotherapy agent such as gemcitabine or cisplatin, or an immunotherapy such as BCG vaccine (BCG), and the class of the second therapeutic agent may further be selected from immune checkpoint inhibitors such as pembrolizumab, nivolumab, atezolizumab or ipilimumab, PARP (poly ADP-ribose polymerase) inhibitors such as olaparib, and CDK4 / 6 (cyclin-dependent kinase 4 and 6) inhibitors, and preferably the second therapeutic agent can be used in combination with a KRAS inhibitor or the like.

10. Use of a compound of formula I according to any one of claims 1 to 7, or a racemate, stereoisomer, tautomer, isotopic derivative, nitrogen oxide, solvate, crystalline polymorph, metabolite, ester, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 8 or 9, in the manufacture of a medicament for preventing and / or treating a disease or condition mediated by CBP and / or EP300.

11. The disease or condition mediated by CBP and / or EP300 is selected from cancer, heart disease, metabolic disease, inflammatory disease, fibrodegenerative disease, and viral infection, and 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, and the prostate cancer may be, for example, castration-resistant prostate cancer (CRPC), the lung cancer may be, for example, non-small cell lung cancer or small cell lung cancer, and the lymphoma may be selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, and the like. The use according to claim 10.

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