Compounds and their uses

Abstract

The present disclosure features compounds useful for treating BAF complex-associated disorders.

Description

[Technical Field]

[0001] The present invention relates to compounds useful for modulating the BRG1 or BRM-associated factor (BAF) complex. In particular, the present invention relates to compounds useful for treating disorders associated with BAF complex function. [Background technology]

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which such gene expression occurs. The human switch / sucrose non-fermentable (SWI / SNF) chromatin remodeling complex, also known as the BAF complex, contains two SWI2-like ATPases, known as BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in several cancer tumors and is required for cancer cell proliferation. The potential global transcriptional activator SNF2L2 and / or BRM, also known as the ATP-dependent chromatin remodeler SMARCA2, are encoded by the SMARCA2 gene on chromosome 9 and have been shown to be essential for tumor cell growth in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and / or BRM leads to downstream effects in cells, including cell cycle arrest and tumor suppression. Summary of the Invention

[0003] The present invention features compounds useful for modulating the BAF complex. In some embodiments, the compounds are useful for treating disorders associated with alterations in the BAF complex, such as disorders associated with alterations in one or both of the BRG1 and BRM proteins. The compounds of the present invention can be used alone or in combination with other pharmaceutically active agents to treat such disorders.

[0004] In one aspect, the present invention provides a compound having the structure: [ka] (In the formula, R 1 is absent, H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and [ka] is a 5- or 6-membered heteroarylene; R 2 and R 5 each is independently H or optionally substituted C1-C6 alkyl; R 3 is H or optionally substituted C-C alkyl, and R 4 is H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl, or R 3 and R 4 together with the carbon atom to which each is attached form an optionally substituted C3-C6 cycloalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 is independently an optionally substituted C1-C6 alkyl; Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or [ka] and A is an optionally substituted C6-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, -O-, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 heteroalkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C2-C6 heteroalkynylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, optionally substituted C2-C9 heteroarylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is H, halogen, cyano, optionally substituted C-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl), or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, [ka] is a 6-membered heteroarylene. In some embodiments, [ka] is a five-membered heteroarylene.

[0006] In some embodiments, [ka] teeth, [ka] wherein each of X, Y, and Z is independently N or CH.

[0007] In some embodiments, the compound of formula A has the structure of formula I: [ka] wherein each of X, Y, and Z is independently N or CH; R 1 is H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and R 2 , R 3 , and R 5 each is independently H or optionally substituted C1-C6 alkyl; R 4 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 each is independently an optionally substituted C1-C6 alkyl; Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or [ka] and A is an optionally substituted C6-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, -O-, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C6 alkenylene, optionally substituted C2-C6 heteroalkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C2-C6 heteroalkynylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, optionally substituted C2-C9 heteroarylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is H, halogen, cyano, optionally substituted C-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl), or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, X, Y, and Z are CH; X is N and Y and Z are CH; Z is N and X and Y are CH; Y is N and X and Z are CH; X is CH and Y and Z are N; Z is CH and X and y are N; Y is CH and X and Z are N; or X, Y, and Z are N.

[0009] In some embodiments, the compound of Formula I has the structure of Formula Ia: [ka] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound of Formula I has the structure of Formula Ib: [ka] or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound of Formula I has the structure of Formula Ic: [ka] or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound of formula I has the structure of formula Id: [ka] or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, [ka] teeth, [ka] wherein X' is O or S, Y' is N or CH, and Z' is N or CH.

[0014] In some embodiments, the compound of formula A has the structure of formula II: [ka] (In the formula, W' is C or N; X' is O, S, or N-CH3; Y' is N or CH; Z' is N or CH; R 1 is absent, H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and R2 , R 3 , and R 5 each is independently H or optionally substituted C1-C6 alkyl; R 4 is H, optionally substituted C1-C6 alkyl, or optionally substituted C1-C6 heteroalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 each is independently an optionally substituted C1-C6 alkyl; Het is optionally substituted 5-membered heteroarylene, optionally substituted 6-membered heteroarylene, or [ka] and A is an optionally substituted C6-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, -O-, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C1-C6 alkenylene, optionally substituted C2-C6 heteroalkenylene, optionally substituted C2-C6 alkynylene, optionally substituted C2-C6 heteroalkynylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, optionally substituted C2-C9 heteroarylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is H, halogen, cyano, optionally substituted C-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, X' is O, Y' is CH, and Z' is N; X' is S, Y' is CH, and Z' is N; X' is O, Y' is N, and Z' is CH; X' is S, Y' is N, and Z' is CH; X' is O, Y' is N, and Z' is N; or X' is S, Y' is N, and Z' is N.

[0016] In some embodiments, the compound of Formula II has the structure of Formula IIa: [ka] or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the compound of Formula II has the structure of Formula IIb: [ka] or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, R 2 is H.

[0019] In some embodiments, R 5 is H. In other embodiments, R 5 is optionally substituted C1-C6 alkyl, for example, methyl.

[0020] In some embodiments, R 3 is H. In some embodiments, R 3 is optionally substituted C1-C6 alkyl, e.g., R 3 is methyl.

[0021] In a further embodiment, R 4 is H. In other embodiments, R 4is optionally substituted C1-C6 alkyl, for example, methyl, tert-butyl, isopropyl, isobutyl, or tert-pentyl. 4 is optionally substituted C1-C6 heteroalkyl, for example, [ka] In some embodiments, R 4 teeth, [ka] is.

[0022] In some embodiments, R 3 is H and R 4 teeth, [ka] is.

[0023] In some embodiments, R 3 and R 4 together with the carbon atom to which each is attached form an optionally substituted C3-C6 cycloalkyl.

[0024] In some embodiments, R 3 and R 4 together with the carbon atom to which each is attached form a C3-C6 cycloalkyl.

[0025] In some embodiments, R 3 and R 4 together with the carbon atoms to which they are attached, [ka] Form.

[0026] In some embodiments, Het is an optionally substituted 5-membered heteroarylene.

[0027] In some embodiments, Het is [ka] In a further embodiment, Het is [ka] is.

[0028] In some embodiments, Het is an optionally substituted 6-membered heteroarylene.

[0029] In some embodiments, Het is [ka] is.

[0030] In some embodiments, Het is [ka] is.

[0031] In some embodiments, L is absent. In some embodiments, L is -O-. In some embodiments, L is an optionally substituted C1-C6 alkylene, for example, L is [ka] In further embodiments, L is an optionally substituted C1-C6 heteroalkylene, for example, L is [ka] In some embodiments, L is optionally substituted C1-C6 alkenylene, for example, [ka] In further embodiments, L is an optionally substituted C2-C6 heteroalkenylene. In other embodiments, L is an optionally substituted C2-C6 alkynylene, for example, L is [ka] In still other embodiments, L is an optionally substituted C2-C6 alkynylene, for example, L is [ka] In some embodiments, L is an optionally substituted C2-C9 heterocyclylene, for example, L is [ka] In further embodiments, L is an optionally substituted C2-C9 heterocyclylC1-C6 alkylene, for example, L is [ka] In other embodiments, L is an optionally substituted C2-C9 heteroarylene. In yet other embodiments, L is an optionally substituted C2-C9 heteroarylC1-C6 alkylene.

[0032] In some embodiments, A is an optionally substituted C-C 10 Arylenes, for example: [ka] is.

[0033] In other embodiments, A is an optionally substituted C2-C9 heteroarylene, such as [ka] is.

[0034] In further embodiments, A is an optionally substituted C2-C9 heterocyclylene, such as [ka] [ka] is.

[0035] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0036] In some embodiments, B is H. In other embodiments, B is cyano. In further embodiments, B is an optionally substituted C-C 10 Aryl, for example [ka] In still further embodiments, B is optionally substituted C2-C9 heterocyclyl, such as [ka] [ka] [ka] In some embodiments, R 9a , R 9b , R 9c , and R 9d each independently represents H, halogen, hydroxyl, optionally substituted C 1-6 Alkyl, or optionally substituted C 1-6 In other embodiments, X is O or C(R 10 ) 2; y can be 0, 1, 2, 3, 4, 5, 6, 7, or 8; each R 10 are independently H, halogen, cyano, amino, hydroxyl, allyl, heteroaryl, optionally substituted C alkyl, optionally substituted C 1-6 heteroalkyl, or two of which combine with the carbon to which they are attached to form C=O.

[0037] In some embodiments, B is morpholino. In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0038] In still other embodiments, B is an optionally substituted C2-C9 heteroaryl, such as [ka] [ka] In a further embodiment, B is an optionally substituted C3-C 10 Cycloalkyl, for example [ka] is.

[0039] In certain embodiments, R 1 is H. In other embodiments, R 1 is optionally substituted C1-C6 acyl, e.g., acetyl. In a further embodiment, R 1 is optionally substituted C1-C6 alkyl, for example, methyl, tert-butyl, isopropyl, or [ka] In yet another embodiment, R 1 is optionally substituted C1-C6 heteroalkyl, for example, [ka] In some embodiments, R 1 is an optionally substituted C2-C9 heterocyclyl, for example, [ka] is.

[0040] In a further embodiment, R 1 is -SO2R 6 In some embodiments, R 6 is optionally substituted C1-C6 alkyl, e.g., methyl, isopropyl, or [ka] In some embodiments, R 6 is -NR 7 R 8In some embodiments, R 7 is methyl. In some embodiments, R 8 is methyl.

[0041] In some embodiments, the compound is any one of compounds 1-827 in Table 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of any one of compounds 1-421 in Table 1.

[0042] In some embodiments, the compound is any one of compounds 1-156 in Table 1. In other embodiments, the compound is any one of compounds 157-421 in Table 1. In some embodiments, the compound is any one of compounds 422-827 in Table 1.

[0043] In some embodiments, the compound is any one of compounds 1-776 in Table 1. In some embodiments, the compound is any one of compounds 777-819 in Table 1. In some embodiments, the compound is any one of compounds 820-827 in Table 1.

[0044] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

[0045] In another aspect, the invention features a pharmaceutical composition including any one of the above compounds and a pharmaceutically acceptable excipient.

[0046] In another aspect, the invention features a method for reducing the activity of a BAF complex in a cell, the method including contacting the cell with an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof.

[0047] In some embodiments, the cells are cancer cells.

[0048] In another aspect, the invention features a method of treating a BAF complex-associated disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof.

[0049] In some embodiments, the BAF complex-associated disorder is cancer.

[0050] In a further aspect, the invention features a method of inhibiting a BRM, the method comprising contacting a cell with an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof. In some embodiments, the cell is a cancer cell.

[0051] In another aspect, the invention features a method of inhibiting BRG1, the method including contacting a cell with an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof. In some embodiments, the cell is a cancer cell.

[0052] In a further aspect, the invention features a method of inhibiting BRM and BRG1, the method including contacting a cell with an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof. In some embodiments, the cell is a cancer cell.

[0053] In another aspect, the invention features a method for treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof.

[0054] In some embodiments, the disorder associated with BRG1 loss-of-function mutation is cancer.In other embodiments, the subject is determined to have a BRG1 loss-of-function disorder, for example, is determined to have a BRG1 loss-of-function cancer (for example, is determined to comprise cancer cells that have loss of BRG1 function).

[0055] In another aspect, the invention features a method of inducing apoptosis in a cell, the method including contacting the cell with an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof. In some embodiments, the cell is a cancer cell.

[0056] In a further aspect, the invention features a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the aforementioned compounds or pharmaceutical compositions thereof.

[0057] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

[0058] In some embodiments of any of the aforementioned methods, the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

[0059] In some embodiments of any of the foregoing methods, the cancer is a drug-resistant cancer or has failed to respond to prior therapy (e.g., vemurafenib, dacarbazine, CTLA4 inhibitors, PD1 inhibitors, interferon therapy, BRAF inhibitors, MEK inhibitors, radiation therapy, temozolimide, irinotecan, CAR-T therapy, Herceptin, Perjeta, tamoxifen, Xeloda, docetaxol, platinum agents such as carboplatin, taxanes such as paclitaxel and docetaxel, ALK inhibitors, MET inhibitors, Alimta, Abraxane, Adriamycin®, gemcitabine, Avastin, Halaven, neratinib, PARP inhibitors, ARN810, mTOR inhibitors, topotecan, Gemzar, VEGFR2 inhibitors, folate receptor antagonists, demcizumab, fosbretabulin, or PDL1 inhibitors).

[0060] In some embodiments of any of the aforementioned methods, the cancer has, or is determined to have, a BRG1 mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is homozygous. In some embodiments of any of the aforementioned methods, the cancer does not have, or is determined to not have, an epidermal growth factor receptor (EGFR) mutation. In some embodiments of any of the aforementioned methods, the cancer does not have, or is determined to not have, an anaplastic lymphoma kinase (ALK) driver mutation. In some embodiments of any of the aforementioned methods, the cancer has, or is determined to have, a KRAS mutation. In some embodiments of any of the aforementioned methods, the BRG1 mutation is in the ATPase catalytic domain of the protein. In some embodiments of any of the aforementioned methods, the BRG1 mutation is a deletion at the C-terminus of BRG1.

[0061] In another aspect, the present disclosure provides a method for treating a BAF-related disorder (e.g., cancer or viral infection) in a subject in need thereof, comprising contacting a cell with an effective amount of any of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the disorder is a retrovirus belonging to the Retroviridae family, e.g., lentivirus (e.g., human immunodeficiency virus (HIV) and deltaretrovirus (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II))), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., human papillomavirus (HPV), E1), Parvoviridae (e.g., parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), Togaviridae (e.g., rubella virus). In some embodiments, the disorder is rhesus coffinii, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas.

[0062] In another aspect, the disclosure provides a method for treating a viral infection in a subject in need thereof, comprising administering to the subject an effective amount of any of the aforementioned compounds, or pharmaceutically acceptable salts thereof, or any of the aforementioned pharmaceutical compositions. In some embodiments, the viral infection is caused by a virus selected from the Retroviridae family, e.g., lentiviruses (e.g., human immunodeficiency virus (HIV) and deltaretroviruses (e.g., human T-cell leukemia virus I (HTLV-I), human T-cell leukemia virus II (HTLV-II)), Hepadnaviridae family (e.g., hepatitis B virus (HBV)), Flaviviridae family (e.g., hepatitis C virus (HCV)), Adenoviridae family (e.g., human adenovirus), Herpesviridae family (e.g., human cytomegalovirus (HCMV), Epstein-Barr virus, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2), human herpesvirus 6 (HHV-6), herpesvirus K*, CMV, varicella-zoster virus), Papillomaviridae family (e.g., human papillomavirus (HPV), HPV E1), Parvoviridae (e.g., parvovirus B19), Polyomaviridae (e.g., JC virus and BK virus), Paramyxoviridae (e.g., measles virus), or Togaviridae (e.g., rubella virus).

[0063] In another aspect, the invention features a method of treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0064] In another aspect, the invention features a method for reducing tumor growth of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer, the method comprising administering to a subject an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0065] In another aspect, the invention features a method of inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, the method comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0066] In another aspect, the invention features a method of inhibiting metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject, the method comprising administering an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0067] In another aspect, the invention features a method for reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer cells, the method comprising contacting the cells with an effective amount of any of the foregoing compounds or pharmaceutical compositions thereof.

[0068] In some embodiments of any of the above aspects, the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is in the subject.

[0069] In some embodiments of any of the above aspects, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, an effective amount of a compound reduces the level and / or activity of BRG1 by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0070] In some embodiments, an effective amount of a compound reduces BRG1 levels and / or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more). In some embodiments, an effective amount of a compound reduces BRG1 levels and / or activity by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0071] In some embodiments of any of the above aspects, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 50% (e.g., 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference. In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%).

[0072] In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 12 hours (e.g., 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, 24 hours, 30 hours, 36 hours, 48 ​​hours, 72 hours, or more). In some embodiments, an effective amount of a compound reduces the level and / or activity of a BRM by at least 5% (e.g., 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) compared to a reference for at least 4 days (e.g., 5 days, 6 days, 7 days, 14 days, 28 days, or more).

[0073] In some embodiments, the subject has cancer. In some embodiments, the cancer expresses BRG1 and / or BRM protein, and / or the cell or subject has been identified as expressing BRG1 and / or BRM. In some embodiments, the cancer expresses BRG1 protein, and / or the cell or subject has been identified as expressing BRG1. In some embodiments, the cancer expresses BRM protein, and / or the cell or subject has been identified as expressing BRM. In some embodiments, the cancer is melanoma (e.g., uveal melanoma, mucosal melanoma, or cutaneous melanoma). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is a hematological cancer, e.g., multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia (e.g., T-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia), diffuse large cell lymphoma, or non-Hodgkin's lymphoma. In some embodiments, the cancer is breast cancer (e.g., ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer). In some embodiments, the cancer is bone cancer (e.g., Ewing's sarcoma). In some embodiments, the cancer is renal cell carcinoma (e.g., microphthalmia transcription factor (MITF) family translocation renal cell carcinoma (tRCC)). In some embodiments, the cancer is metastatic (e.g., the cancer has spread to the liver). Metastatic cancers may include cells that exhibit migration and / or migratory cell invasion, and / or may include cells that exhibit endothelial recruitment and / or angiogenesis. In other embodiments, the migrating cancer is a cell migration cancer. In yet other embodiments, the cell migration cancer is a non-metastatic cell migration cancer. Metastatic cancers may be cancers that spread by seeding on the surfaces of the peritoneum, pleura, pericardium, or subarachnoid space. Alternatively, metastatic cancers may be cancers that spread via the lymphatic system or hematogenously.In some embodiments, the effective amount of the agent that decreases the level and / or activity of BRG1 and / or BRM is an amount effective to inhibit metastatic colonization of the liver by cancer.

[0074] In some embodiments, the cancer harbors a mutation in GNAQ. In some embodiments, the cancer harbors a mutation in GNA11. In some embodiments, the cancer harbors a mutation in PLCB4. In some embodiments, the cancer harbors a mutation in CYSLTR2. In some embodiments, the cancer harbors a mutation in BAP1. In some embodiments, the cancer harbors a mutation in SF3B1. In some embodiments, the cancer harbors a mutation in EIF1AX. In some embodiments, the cancer harbors a TFE3 translocation. In some embodiments, the cancer harbors a TFEB translocation. In some embodiments, the cancer harbors a MITF translocation. In some embodiments, the cancer harbors an EZH2 mutation. In some embodiments, the cancer harbors a SUZ12 mutation. In some embodiments, the cancer harbors an EED mutation.

[0075] In some embodiments, the method further comprises administering to the subject or contacting the cells with an anti-cancer therapy, such as a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation. In some embodiments, the anti-cancer therapy is a chemotherapeutic or cytotoxic agent, such as an antimetabolite, a mitotic inhibitor, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an anti-neoplastic agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulatory agent, a Janus-related kinase inhibitor, a phosphinositide 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

[0076] In some embodiments, the compounds of the present invention are used in combination with another anti-cancer therapy used to treat uveal melanoma, such as surgery, a MEK inhibitor, and / or a PKC inhibitor. For example, in some embodiments, the method further comprises performing surgery before, after, or simultaneously with the administration of the compound of the present invention. In some embodiments, the method further comprises administering a MEK inhibitor and / or a PKC inhibitor before, after, or simultaneously with the administration of the compound of the present invention.

[0077] In some embodiments, the anti-cancer therapy and the compound of the invention are administered within 28 days of each other, each together in an amount effective to treat the subject.

[0078] In some embodiments, the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation, hi some embodiments, the subject or cancer has and / or has been identified as having a BRM loss-of-function mutation.

[0079] In some embodiments, the cancer is resistant to one or more chemotherapeutic or cytotoxic agents (e.g., the cancer has been determined to be resistant to a chemotherapeutic or cytotoxic agent, such as by a genetic marker, or is likely to be resistant to a chemotherapeutic or cytotoxic agent, e.g., a cancer that has failed to respond to a chemotherapeutic or cytotoxic agent). In some embodiments, the cancer has failed to respond to one or more chemotherapeutic or cytotoxic agents. In some embodiments, the cancer is resistant to or has failed to respond to dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp100, a CTLA-4 inhibitor (e.g., ipilimumab), a PD-1 inhibitor (e.g., nivolumab or pembrolizumab), a PD-L1 inhibitor (e.g., atezolizumab, avelumab, or durvalumab), a mitogen-activated protein kinase (MEK) inhibitor (e.g., selumetinib, binimetinib, or tametinib), and / or a protein kinase C (PKC) inhibitor (e.g., sotrastaurin or IDE196).

[0080] In some embodiments, the cancer is resistant to or has not responded to previously administered therapeutic agents used to treat uveal melanoma, such as MEK inhibitors or PKC inhibitors. For example, in some embodiments, the cancer is resistant to or has not responded to mitogen-activated protein kinase (MEK) inhibitors (e.g., selumetinib, binimetinib, or tametinib) and / or protein kinase C (PKC) inhibitors (e.g., sotrastaurin or IDE196).

[0081] chemical terms The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0082] For any of the chemical definitions below, a number following an atomic symbol indicates the total number of atoms of that element present at a particular chemical moiety. As understood, other atoms, such as H atoms, or substituents described herein, may be present as needed to satisfy valences. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with groups defined herein, references to the number of carbon atoms include divalent carbons in acetal and ketal groups, but do not include carbonyl carbons in acyl, ester, carbonate, or carbamate groups. References to the number of oxygen, nitrogen, or sulfur atoms in heteroaryl groups include only those atoms that form part of the heterocyclic ring.

[0083] The term "acyl," as used herein, represents an H or alkyl group attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, trifluoroacetyl, propionyl, and butanoyl. Exemplary unsubstituted acyl groups contain 1 to 6, 1 to 11, or 1 to 21 carbons.

[0084] The term "alkyl," as used herein, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms).

[0085] Alkylene is a divalent alkyl group. The term "alkenyl," as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon double bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0086] The term "alkynyl," as used herein, alone or in combination with other groups, refers to a straight-chain or branched hydrocarbon residue having a carbon-carbon triple bond and having 2 to 20 carbon atoms (e.g., 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 carbon atoms).

[0087] The term "amino" as used herein refers to -N(R N1 )2(in the formula, each R N1 are independently H, OH, NO2, N(R N2 )2, SO2OR N2 , SO2R N2 , SOR N2 , an N-protecting group, alkyl, alkoxy, aryl, arylalkyl, cycloalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), and these enumerated R N1 Each of the groups may be optionally substituted; or two R N1 combine to form an alkylene or heteroalkylene, and each R N2 are independently H, alkyl, or aryl). The amino groups of the present invention include unsubstituted amino (i.e., —NH) or substituted amino (i.e., —N(R N1 )2).

[0088] The term "aryl," as used herein, refers to an aromatic mono- or polycarbocyclic radical of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2-dihydronaphthyl, indanyl, and 1H-indenyl. An "arylene" is a divalent aryl group.

[0089] The term "arylalkyl," as used herein, refers to an alkyl group substituted with an aryl group. Exemplary unsubstituted arylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C-C alkyl, C-C 10 Aryl, C1-C 10 Alkyl C6-C 10 Aryl, or C1-C 20 Alkyl C6-C 10 aryl), for example, benzyl and phenethyl. In some embodiments, alkyl and aryl can each be further substituted with 1, 2, 3, or 4 substituents, as defined herein for each group.

[0090] The term "azido" as used herein refers to an -N3 group.

[0091] The term "bridged polycycloalkyl," as used herein, refers to a bridged polycyclic group of 5 to 20 carbons containing 1 to 3 bridges.

[0092] The term "cyano," as used herein, refers to a --CN group.

[0093] The term "carbocyclyl," as used herein, refers to a non-aromatic C-C 12 It refers to a monocyclic, bicyclic, or tricyclic structure in which the rings are formed by carbon atoms. Carbocyclyl structures include cycloalkyl groups and unsaturated carbocyclyl radicals.

[0094] The term "cycloalkyl," as used herein, refers to a saturated non-aromatic monovalent mono- or polycarbocyclic radical of 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

[0095] The term "halo," as used herein, means a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0096] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, a heteroalkyl group can be further substituted with one, two, three, or four substituents as described herein for an alkyl group. An example of a heteroalkyl group, as used herein, is "alkoxy," which refers to alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group. The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, a heteroalkenyl group can be further substituted with one, two, three, or four substituents as described herein for an alkenyl group. An example of a heteroalkenyl group, as used herein, is "alkenoxy," which refers to alkenyl-O-. A heteroalkenylene is a divalent heteroalkenyl group. The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. In some embodiments, heteroalkynyl groups can be further substituted with one, two, three, or four substituents described herein for alkynyl groups. An example of a heteroalkynyl group, as used herein, is "alkynoxy," which refers to alkynyl-O-. Heteroalkynylene is a divalent heteroalkynyl group.

[0097] The term "heteroaryl," as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. A "heteroarylene" is a divalent heteroaryl group.

[0098] The term "heteroarylalkyl," as used herein, refers to an alkyl group substituted with a heteroaryl group. Exemplary unsubstituted heteroarylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C1-C6 alkyl, C2-C9 heteroaryl, C1-C 10 alkyl C2-C9 heteroaryl, or C1-C 20 In some embodiments, alkyl and heteroaryl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0099] The term "heterocyclyl," as used herein, refers to a mono- or polycyclic radical having 3 to 12 atoms having at least one non-aromatic ring containing 1, 2, 3, or 4 ring atoms selected from N, O, or S, and no aromatic rings containing N, O, or S atoms. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, thiomorpholinyl, furyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1,3-dioxanyl. A "heterocyclene" is a divalent heterocyclyl group.

[0100] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclyl group. Exemplary unsubstituted heterocyclylalkyl groups include those having 7 to 30 carbons (e.g., 7 to 16 or 7 to 20 carbons, e.g., C1-C6 alkyl, C2-C9 heterocyclyl, C1-C 10 alkyl C2-C9 heterocyclyl, or C1-C 20 alkylC2-C9 heterocyclyl). In some embodiments, alkyl and heterocyclyl can each be further substituted with 1, 2, 3, or 4 substituents as defined herein for each group.

[0101] The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with an --OH group.

[0102] The term "hydroxyl," as used herein, refers to an --OH group.

[0103] The term "N-protecting group," as used herein, refers to those groups intended to protect an amino group against unwanted reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999).N-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries, such as protected or unprotected D,L, or D,L-amino acids, such as alanine, thiamin ... isine, and phenylalanine; sulfonyl-containing groups, such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-20-dimethoxybenzyloxycarbonyl, dibenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl These include, but are not limited to, aryl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and silyl groups such as trimethylsilyl.Preferred N-protecting groups are alloc, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0104] The term "nitro," as used herein, refers to the group --NO.sub.2.

[0105] The term "oxo" as used herein refers to the group ═O.

[0106] The term "thiol," as used herein, refers to an --SH group.

[0107] Alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl (e.g., cycloalkyl), aryl, heteroaryl, and heterocyclyl groups can be substituted or unsubstituted. If substituted, typically 1 to 4 substituents will be present unless otherwise specified. Substituents include, for example, alkyl (e.g., unsubstituted and substituted, where the substituents include any of the groups described herein, e.g., aryl, halo, hydroxy), aryl (e.g., substituted and unsubstituted phenyl), carbocyclyl (e.g., substituted and unsubstituted cycloalkyl), halo (e.g., fluoro), hydroxyl, heteroalkyl (e.g., substituted and unsubstituted methoxy, ethoxy, or thioalkoxy), heteroaryl, heterocyclyl, amino (e.g., NH or mono- or dialkylamino), azido, cyano, nitro, oxo, sulfonyl, or thiol. The aryl, carbocyclyl (eg, cycloalkyl), heteroaryl, and heterocyclyl groups can also be substituted with alkyl (unsubstituted and substituted, for example, arylalkyl (eg, substituted and unsubstituted benzyl)).

[0108] The compounds of the present invention may have one or more asymmetric carbon atoms and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g., racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Optically active forms can be obtained, for example, by resolution of racemates, asymmetric synthesis, or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). That is, some of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are most commonly pairs of stereoisomers whose mirror images are not superimposable because they contain asymmetrically substituted carbon atoms that act as chiral centers. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms and represent the arrangement of substituents around one or more chiral carbon atoms. Enantiomers of a compound can be prepared by separating the enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and separation methods based thereon. Suitable techniques and / or methods for separating enantiomers of compounds described herein from racemic mixtures can be readily determined by those skilled in the art. A "racemate" or "racemic mixture" refers to a compound containing two enantiomers, such that such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light. A "geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon-carbon double bond can be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. "R", "S", "S*", "R*", "E", "Z", "cis", and "trans" indicate the configuration relative to the core molecule.Some of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation around a single bond, where the steric strain barrier to rotation is high enough to allow for separation of the conformers. The compounds of the present invention can be prepared as individual isomers by isomer-specific synthesis or resolved from an isomeric mixture. Traditional resolution techniques include using an optically active acid to form a salt of the free base of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free base), using an optically active amine to form a salt of the acid form of each isomer of the isomeric pair (followed by fractional crystallization and regeneration of the free acid), using an optically pure acid, amine, or alcohol to form an ester or amide of each isomer of the isomeric pair (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either the starting material or the final product using a variety of well-known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight pure relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure by weight. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity is the ratio of the weight of an enantiomer to the weight of that enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the weight of all diastereomers. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction relative to other stereoisomers.When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by mole fraction. Percent purity by mole fraction is the ratio of moles of an enantiomer to moles of its enantiomer to moles of its optical isomer. Similarly, percent purity by mole fraction is the ratio of moles of a diastereomer to moles of its diastereomer to moles of its isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and the compound has at least one chiral center, the name or structure should be understood to encompass any enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or a mixture enriched in one enantiomer relative to the corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry and has two or more chiral centers, the name or structure should be understood to encompass a diastereomer free of the other diastereomer, several diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0109] The compounds of the present disclosure also include all isotopes of atoms occurring in intermediate or final compounds. "Isotopes" refer to atoms having the same atomic number but different mass numbers due to different numbers of neutrons in the nucleus. For example, isotopes of hydrogen include tritium and deuterium.

[0110] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful due to their ease of preparation and detectability. Additionally, heavier isotopes, such as deuterium (i.e., 2 Substitution with H may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosing requirements) due to greater metabolic stability. In some embodiments, one or more hydrogen atoms may be 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 Replaced by C-enriched carbon. Positron-emitting isotopes, e.g., 15 O. 13 N, 11 C, and 18F is useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. The preparation of isotopically labeled compounds is known to those skilled in the art. For example, isotopically labeled compounds can be prepared following procedures similar to those disclosed for the compounds of the present invention described herein, usually by using isotopically labeled reagents instead of non-isotopically labeled reagents.

[0111] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in this disclosure; other suitable methods and materials known in the art may also be used. Materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0112] definition In this application, unless otherwise clear from the context, (i) the term "a" may be understood to mean "at least one," (ii) the term "or" may be understood to mean "and / or," and (iii) the terms "comprising" and "including" may be understood to encompass the listed components or steps, whether presented by themselves or together with one or more additional components or steps.

[0113] As used herein, the terms "about" and "approximately" refer to values ​​that are within 10% of the stated value. For example, the term "about 5 nM" indicates a range of 4.5 to 5.5 nM.

[0114] As used herein, the term "administration" refers to the administration of a composition (e.g., a compound or a preparation comprising a compound described herein) to a subject or system. Administration to an animal subject (e.g., a human) can be by any suitable route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, intraintestinal, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intratumor, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal, and intravitreal.

[0115] As used herein, the term "BAF complex" refers to the BRG1 or HBRM-associated factor complex in human cells.

[0116] As used herein, the term "BAF complex-associated disorder" refers to a disorder caused by or affected by the level of activity of the BAF complex.

[0117] As used herein, the term "BRG1 loss-of-function mutation" refers to a mutation in BRG1 that results in a protein with reduced activity (e.g., at least a 1% reduction in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% reduction in BRG1 activity). Exemplary BRG1 loss-of-function mutations include, but are not limited to, homozygous BRG1 mutations and deletions at the C-terminus of BRG1.

[0118] As used herein, the term "BRG1 loss-of-function disorder" refers to a disorder (e.g., cancer) that exhibits a decrease in BRG1 activity (e.g., at least a 1% decrease in BRG1 activity, e.g., a 2%, 5%, 10%, 25%, 50%, or 100% decrease in BRG1 activity).

[0119] The term "cancer" refers to conditions caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.

[0120] As used herein, "combination therapy" or "administered in combination" means that two (or more) different agents or treatments are administered to a subject as part of a defined treatment regimen for a particular disease or condition. The treatment regimen defines the dosage and periodicity of administration of each agent so that the effects of the separate agents on the subject overlap. In some embodiments, delivery of two or more agents is simultaneous or concurrent, and the agents may be co-formulated. In some embodiments, two or more agents are not co-formulated but are administered in a sequential manner as part of a prescribed regimen. In some embodiments, administration of two or more agents or treatments in combination results in a greater reduction in symptoms or other parameters associated with the disorder than is observed when one agent or treatment is delivered alone or in the absence of the other. The effect of the two treatments may be partially additive, fully additive, or greater than additive (e.g., synergistic). Sequential or substantially simultaneous administration of each therapeutic agent may be achieved by any appropriate route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents may be administered by the same route or by different routes, for example, a first therapeutic agent of the combination may be administered by intravenous injection, while a second therapeutic agent of the combination may be administered orally.

[0121] "Determining the level" of a protein or RNA refers to detecting the protein or RNA by methods known in the art, either directly or indirectly. "Directly determining" means performing a process to obtain a physical entity or value (e.g., performing an assay or test on a sample, or "analyzing a sample" as that term is defined herein). "Indirectly determining" refers to receiving a physical entity or value from another organization or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Methods for measuring protein levels typically include, but are not limited to, Western blotting, immunoblotting, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, immunofluorescence, surface plasmon resonance, chemiluminescence, fluorescence polarization, phosphorescence, immunohistochemistry, matrix-assisted laser desorption / ionization time-of-flight (MALDI-TOF) mass spectrometry, liquid chromatography (LC)-mass spectrometry, microcytometry, microscopy, fluorescence-activated cell sorting (FACS), and flow cytometry, as well as assays based on protein properties, including, but not limited to, enzymatic activity or interaction with other protein partners. Methods for measuring RNA levels are known in the art and include, but are not limited to, quantitative polymerase chain reaction (qPCR) and Northern blot analysis.

[0122] A "decreased level" or "increased level" of protein or RNA refers to a decrease or increase, respectively, in protein or RNA levels as compared to a reference (e.g., about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500% or more decrease or increase; more than about 10%, more than about 15%, more than about 20% as compared to a reference). , greater than about 50%, greater than about 75%, greater than about 100%, or greater than about 200% decrease or increase; less than about 0.01 fold, less than about 0.02 fold, less than about 0.1 fold, less than about 0.3 fold, less than about 0.5 fold, less than about 0.8 fold, or less; or greater than about 1.2 fold, greater than about 1.4 fold, greater than about 1.5 fold, greater than about 1.8 fold, greater than about 2.0 fold, greater than about 3.0 fold, greater than about 3.5 fold, greater than about 4.5 fold, greater than about 5.0 fold, greater than about 10 fold, greater than about 15 fold, greater than about 20 fold, greater than about 30 fold, greater than about 40 fold, greater than about 50 fold, greater than about 100 fold, greater than about 1000 fold, or more decrease or increase). Protein levels can be expressed as mass / volume (eg, g / dL, mg / mL, μg / mL, ng / ml) or as a percentage of total protein in the sample.

[0123] "Reducing the activity of BAF complex" means reducing the level of the activity or downstream effect associated with BAF complex.A non-limiting example of reducing the activity of BAF complex is Sox2 activation.The activity level of BAF complex can be measured by any method known in the art, for example, by the method described in Kadoch et al.Cell, 2013, 153, 71-85, which is incorporated herein by reference.

[0124] As used herein, the term "inhibiting BRM" refers to inhibiting or reducing the level or activity of the ATPase catalytic binding domain or bromodomain of a protein. BRM inhibition can be determined using methods known in the art, such as a BRM ATPase assay, a nanoDSF assay, or a BRM luciferase cellular assay.

[0125] As used herein, the term "LXS196," also known as IDE196, refers to a compound having the structure: [ka] or a pharmaceutically acceptable salt thereof.

[0126] The term "pharmaceutical composition," as used herein, refers to a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient and suitable for administration to a mammal, e.g., a human. Typically, pharmaceutical compositions are manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, in unit dosage form for oral administration (e.g., tablets, capsules, caplets, gelcaps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as a particulate-free sterile solution in a solvent system suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0127] As used herein, a "pharmaceutically acceptable excipient" refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving an active compound) that has substantially non-toxic and non-inflammatory properties in patients. Excipients can include, for example, antiadhesives, antioxidants, binders, coating agents, compression aids, disintegrants, dyes (colorants), softeners, emulsifiers, fillers (diluents), film-forming or coating agents, flavors, fragrances, glidants (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinol palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0128] As used herein, the term "pharmaceutically acceptable salt" refers to any pharmaceutically acceptable salt of a compound, e.g., any compound of Formula I. Pharmaceutically acceptable salts of any of the compounds described herein may include those that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues without undue toxicity, irritation, or allergic response, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0129] The compounds of the present invention may have ionizable groups so that they can be prepared as pharmaceutically acceptable salts. These salts may be acid addition salts, including inorganic or organic acids, or salts may be prepared from inorganic or organic bases when the compounds of the present invention are in acidic form. Frequently, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, Representative salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.

[0130] "Reference" refers to any useful reference used to compare protein or RNA levels. A reference can be any sample, standard, standard curve, or level used for comparison purposes. A reference can be a normal reference sample or reference standard or level. A "reference sample" can be, for example, a control, e.g., a predetermined negative control value such as a "normal control," or a previous sample collected from the same subject; a sample from a normal healthy subject, such as normal cells or normal tissue; a sample (e.g., cell or tissue) from a subject without a disease; a sample from a subject diagnosed with a disease but not yet treated with a compound of the present invention; a sample from a subject being treated with a compound of the present invention; or a sample of purified protein or RNA (e.g., any of those described herein) with a known normal concentration. A "reference standard or level" refers to a value or numerical value derived from a reference sample. A "normal control value" is a predetermined value indicating a non-disease state, for example, a value expected in a healthy control subject. Typically, a normal control value is expressed as a range ("between X and Y"), a high threshold ("below X"), or a low threshold ("above X"). A subject having a measured value within the range of normal control values ​​for a particular biomarker is typically referred to as "within normal limits" for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject without a disease or disorder (e.g., cancer); a subject treated with a compound of the present invention. In a preferred embodiment, the reference sample, standard, or level is matched to the subject sample by at least one of the following criteria: age, weight, sex, disease stage, and general health. A standard curve of purified protein or RNA levels, such as any of those described herein, within the normal reference range can also be used as a reference.

[0131] As used herein, the term "subject" refers to any organism to which a composition in accordance with the present invention can be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals, such as mice, rats, rabbits, non-human primates, and humans). A subject can be a human or animal seeking or in need of treatment, requesting treatment, undergoing treatment, will undergo treatment in the future, or under the care of a professional trained in a particular disease or condition.

[0132] As used herein, the terms "treat," "treated," or "treating" refer to a therapeutic procedure or any measure whose purpose is to delay (attenuate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; a decrease in the severity of the condition, disorder, or disease; a stabilized (i.e., non-worsening) state of the condition, disorder, or disease; a delay in the onset of or slowing of the progression of the condition, disorder, or disease; an improvement (whether partial or total) in the condition, disorder, or disease state or remission; an improvement in at least one measurable physical parameter not necessarily discernible by the patient; or an improvement or amelioration of the condition, disorder, or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. The compounds of the present invention can also be used to "prophylactically treat" or "prevent" a disorder, for example, in subjects at increased risk of developing the disorder.

[0133] As used herein, the terms "variant" and "derivative" are used interchangeably and refer to natural, synthetic, and semi-synthetic analogs of compounds, peptides, proteins, or other substances described herein. Variants or derivatives of compounds, peptides, proteins, or other substances described herein may retain or improve the biological activity of the original substance.

[0134] The details of one or more embodiments of the invention are set forth in the specification below. Other features, objects, and advantages of the invention will be apparent from the description and claims. [Brief explanation of the drawings]

[0135] [Figure 1] 1 is a graph showing the inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (Compound A). [Figure 2A] 1 is a graph showing the inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (Compound A), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 2B] 1 is a graph showing the inhibition of cell proliferation of the uveal melanoma cell line MP41 by a BRG1 / BRM inhibitor (Compound A), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 3] 1 is a graph showing the inhibition of cell proliferation of several cancer cell lines by a BRG1 / BRM inhibitor (compound 67). [Figure 4] 1 is a graph showing the area under the curve (AUC) calculated from dose-response curves for cancer cell lines treated with a BRG1 / BRM inhibitor (compound 67). [Figure 5] 1 is a graph showing the inhibition of cell proliferation of uveal melanoma and non-small cell lung cancer cell lines by a BRG1 / BRM inhibitor (compound 67). [Figure 6A] 1 is a graph showing the inhibition of cell proliferation of uveal melanoma cell line 92-1 by a BRG1 / BRM inhibitor (compound 67), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 6B] 1 is a graph showing the inhibition of cell proliferation of the uveal melanoma cell line MP41 by a BRG1 / BRM inhibitor (compound 67), a MEK inhibitor (selumetinib), and a PKC inhibitor (LXS196). [Figure 7A]1 is a graph showing the inhibition of cell proliferation of parental and PKC inhibitor-refractory uveal melanoma cell lines by a PKC inhibitor (LXS196). [Figure 7B] 1 is a graph showing the inhibition of cell proliferation of parental and PKC inhibitor-refractory uveal melanoma cell lines by a BRG1 / BRM inhibitor (compound 67). [Figure 8A] 1 is a graph showing the inhibition of tumor growth in mice implanted with a uveal melanoma cell line by a BRG1 / BRM inhibitor (compound 320). [Figure 8B] FIG. 1 is a diagram of tumor size from mice implanted with a uveal melanoma cell line and dosed with a BRG1 / BRM inhibitor (compound 320). [Figure 8C] 1 is a graph showing changes in body weight of mice transplanted with a uveal melanoma cell line and administered a BRG1 / BRM inhibitor (compound 320). DETAILED DESCRIPTION OF THE INVENTION

[0136] The present disclosure features compounds useful for inhibiting BRG1 and / or BRM. These compounds can be used to regulate the activity of the BAF complex, for example, to treat BAF-related disorders, such as cancer. Exemplary compounds described herein include compounds having a structure according to Formula A: [ka] (In the formula, R 1 is H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and [ka] is a 5- or 6-membered heteroarylene, and R 2 , R 3 , and R 5is independently H or optionally substituted C-C alkyl, and R 4 is H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 are independently optionally substituted C-C alkyl, Het is optionally substituted 5- or 6-membered heteroarylene, and A is optionally substituted C-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, —O—, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is H, halogen, cyano, optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl) or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula I: [ka] wherein each of X, Y, and Z is independently N or CH; 1 is hydrogen, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and R 2 , R 3 , and R 5is independently H or optionally substituted C-C alkyl, and R 4 is hydrogen, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 each independently is an optionally substituted C-C alkyl, Het is a 5- or 6-membered heteroarylene, Het is a 5- or 6-membered heteroarylene, and A is an optionally substituted C-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, —O—, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is hydrogen, halogen, cyano, optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl) or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of Formula II: [ka] wherein X' is O or S, Y' is N or CH, Z' is N or CH, and R 1 is H, optionally substituted C1-C6 acyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or -SO2R 6 and R2 , R 3 , and R 5 is independently H or optionally substituted C-C alkyl, and R 4 is H, optionally substituted C-C alkyl, or optionally substituted C-C heteroalkyl; R 6 is optionally substituted C1-C6 alkyl or -NR 7 R 8 and R 7 and R 8 each independently is an optionally substituted C-C alkyl, Het is a 5- or 6-membered heteroarylene, and A is an optionally substituted C-C 10 arylene, optionally substituted C2-C9 heterocyclylene, or optionally substituted C2-C9 heteroarylene; L is absent, —O—, optionally substituted C1-C6 alkylene, optionally substituted C1-C6 alkenylene, optionally substituted C1-C6 heteroalkylene, optionally substituted C2-C9 heterocyclylC1-C6 alkylene, or optionally substituted C2-C9 heteroarylC1-C6 alkylene; B is H, halogen, cyano, optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 cycloalkyl, optionally substituted C2-C9 heterocyclyl, or optionally substituted C2-C9 heteroaryl) or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, the compound is any one of compounds 1-827 in Table 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of any one of compounds 1-421 in Table 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of any one of compounds 1-156 in Table 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has the structure of any one of compounds 157-421 in Table 1. In some embodiments, the compound is any one of compounds 422-827 in Table 1.

[0140] In some embodiments, the compound is any one of compounds 1-776 in Table 1. In some embodiments, the compound is any one of compounds 777-819 in Table 1. In some embodiments, the compound is any one of compounds 820-827 in Table 1.

[0141] Other embodiments, and exemplary methods for synthesis of the production of these compounds, are described herein.

[0142] Pharmaceutical use The compounds described herein are useful in the methods of the present invention and, without being bound by theory, are believed to exert their ability to modulate the level, status, and / or activity of the BAF complex, i.e., by inhibiting the activity of BRG1 and / or BRM proteins within the BAF complex in mammals. BAF complex-associated disorders include, but are not limited to, BRG1 loss-of-function mutation-associated disorders.

[0143] Aspects of the invention relate to methods of treating a disorder associated with a BRG1 loss-of-function mutation, e.g., cancer (e.g., non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary site, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer) in a subject in need thereof. In some embodiments, the compound is administered in an amount and for a time effective to result in one or more (e.g., two or more, three or more, four or more) of: (a) decreased tumor size, (b) decreased tumor growth rate, (c) increased tumor cell death, (d) decreased tumor progression, (e) decreased number of metastases, (f) decreased metastasis rate, (g) reduced tumor recurrence, (h) increased subject survival, or (i) increased subject progression-free survival.

[0144] Cancer treatment can result in a reduction in tumor size or volume.For example, after treatment, tumor size is reduced by 5% or more (for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to its size before treatment.Tumor size can be measured by any reproducible means of measurement.For example, tumor size can be measured as the diameter of the tumor.

[0145] Cancer treatment can also lead to a reduction in the number of tumors.For example, after treatment, the number of tumors is reduced by 5% or more (for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment.The number of tumors can be measured by any reproducible means of measurement, for example, the number of tumors can be measured by counting the tumors visible to the naked eye or under a certain magnification (for example, 2x, 3x, 4x, 5x, 10x or 50x).

[0146] Cancer treatment can result in a decrease in the number of metastatic nodules in other tissues or organs away from the primary tumor site.For example, after treatment, the number of metastatic nodules decreases by 5% or more (for example, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) compared to the number before treatment.The number of metastatic nodules can be measured by any reproducible means of measurement.For example, the number of metastatic nodules can be measured by counting the metastatic nodules that can be seen with the naked eye or at a certain magnification (for example, 2x, 10x, or 50x).

[0147] Cancer treatment can result in an increase in the average survival time of a population of subjects treated according to the present invention compared to a population of untreated subjects.For example, the average survival time increases by more than 30 days (more than 60 days, 90 days, or 120 days).The increase in the average survival time of a population can be measured by any reproducible means.The increase in the average survival time of a population can be measured, for example, by calculating the average length of survival for a population after the start of treatment with a compound of the present invention.The increase in the average survival time of a population can also be measured, for example, by calculating the average length of survival for a population after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0148] Cancer treatment can also result in a reduction in the mortality rate of a treated population of subjects compared to an untreated population.For example, the mortality rate is reduced by more than 2% (for example, more than 5%, 10%, or 25%).The reduction in mortality rate of a treated population of subjects can be measured by any reproducible means, for example, by calculating the average number of disease-related deaths per unit time for a population after the start of treatment with a pharmaceutically acceptable salt of the present invention.The reduction in mortality rate of a population can also be measured, for example, by calculating the average number of disease-related deaths per unit time for a population after the completion of the first round of treatment with a pharmaceutically acceptable salt of the present invention.

[0149] Exemplary cancers that can be treated by the present invention include, but are not limited to, non-small cell lung cancer, small cell lung cancer, colon cancer, bladder cancer, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, and penile cancer.

[0150] Combination preparations and their uses The compounds of the present invention may be combined with one or more therapeutic agents, particularly those that treat or prophylactically treat any of the cancers described herein.

[0151] Combination therapy The compounds of the present invention can be used alone or in combination with additional therapeutic agents, such as other drugs for treating cancer or related symptoms, or in combination with other types of treatment for treating cancer. In combined treatment, the dosage of one or more therapeutic compounds can be reduced from the standard dosage when administered alone. For example, the dosage can be empirically determined from the drug combination and sequence, or can be estimated by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6, 2005). In this case, the dosage of the compounds when combined should provide a therapeutic effect.

[0152] In some embodiments, the second therapeutic agent is a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in the treatment of cancer). These include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione-substituted ureas, methylhydrazine derivatives, adrenocortical suppressants, corticosteroids, progestins, estrogens, antiestrogens, androgens, antiandrogens, and gonadotropin-releasing hormone analogs. Also included are 5-fluorouracil (5-FU), leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. Non-limiting examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metuledopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); Cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosurea, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicins, particularly calicheamicin gamma and calicheamicin omegal (see, e.g., Agnew, Chem. Intl. Ed Engl. 33:183-186 (1994)), dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6 -diazo-5-oxo-L-norleucine, Adriamycin® (doxorubicin including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, chelamycin, rodorubicin, streptomycin glynn, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifur Lysine, enocitabine, floxuridine; androgens, e.g., calsterone, dromostalon propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diazicon; elfomitine;Elliptinium acetate; epothilones; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidynin; maytansinoids, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraelin; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine, trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidine); urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as Taxol® paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), ABraxane®, a cremophor-free albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and Taxotere® doxetaxel (Rhone-Poulenc Rorer, Antony, France), chlorambucil; Gemzar® gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes, e.g., cisplatin, oxaliplatin, carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; Navelbine® vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; Xeloda; ibandronate; irinotecan (e.g., CPT-11), topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids, e.g., retinoic acid; capecitabine;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Two or more chemotherapeutic agents may be used in a cocktail administered in combination with the first therapeutic agent described herein. Suitable dosing regimens for combination chemotherapy are known in the art and are described, for example, in Saltz et al. (1999) Proc ASCO 18:233a and Douillard et al. (2000) Lancet 355:1041-7.

[0153] In some embodiments, the second therapeutic agent is a therapeutic agent that is a biologic, such as a cytokine (e.g., an interferon or an interleukin (e.g., IL-2)) used in the treatment of cancer. In some embodiments, the biologic is an anti-angiogenic agent, e.g., an anti-VEGF agent, e.g., bevacizumab (Avastin®). In some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, fully human antibody, Fc fusion protein, or functional fragment thereof), that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important to cancer. Such medications include Rituxan (rituximab); Zenapax (daclizumab); Simulect (basiliximab); Synagis (palivizumab); Remicade (infliximab); Herceptin (trastuzumab); Mylotarg (gemtuzumab ozogamicin); Campath (alemtuzumab); Zevalin (ibritumomab tiuxetan); Humira (adalimumab); Xolair (omalizumab); Bexxar (tositumomab-I-131); Raptiva (efalizumab); Erbitux (cetuximab); Avastin (bevacizumab); Tysabri (natalizumab); Actemra (tositumomab-I-131); Antibody-drug conjugates include: silizumab; Vectibix (panitumumab); Lucentis (ranibizumab); Soliris (eculizumab); Cimzia (certolizumab pegol); Simponi (golimumab); Ilaris (canakinumab); Stelara (ustekinumab); Arzerra (ofatumumab); Prolia (denosumab); Numax (motavizumab); ABThrax (raxibacumab); Benlysta (belimumab); Yervoy (ipilimumab); Adcetris (brentuximab vedotin); Perjeta (pertuzumab); Kadcyla (Ado-trastuzumab emtansine), and Gazyva (obinutuzumab). Antibody-drug conjugates are also included.

[0154] The second agent can be a therapeutic agent that is a non-drug treatment, for example, the second therapeutic agent is radiation therapy, cryotherapy, hyperthermia, and / or surgical removal of tumor tissue.

[0155] The second agent can be a checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, e.g., a monoclonal antibody). The antibody can be, for example, humanized or fully human. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, such as an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA4 antibody, e.g., ipilimumab / Yervoy or tremelimumab). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PD-1 (e.g., nivolumab / Opdivo®; pembrolizumab / Keytruda®; pidilizumab / CT-011). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of PDL1 (e.g., MPDL3280A / RG7446; MEDI4736; MSB0010718C; BMS936559). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or Fc fusion or small molecule inhibitor) of PDL2 (e.g., a PDL2 / Ig fusion protein, e.g., AMP224). In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or small molecule inhibitor) of B7-H3 (e.g., MGA271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a B-7 family ligand, or a combination thereof.

[0156] In any of the combination embodiments described herein, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent can be administered immediately, up to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, up to 5 hours, up to 6 hours, up to 7 hours, up to 8 hours, up to 9 hours, up to 10 hours, up to 11 hours, up to 12 hours, up to 13 hours, 14 hours, up to 16 hours, up to 17 hours, up to 18 hours, up to 19 hours, up to 20 hours, up to 21 hours, up to 22 hours, up to 23 hours, up to 24 hours, or up to 1-7 days, 1-14 days, 1-21 days, or 1-30 days before or after the second therapeutic agent.

[0157] Pharmaceutical Compositions The compounds of the present invention are preferably formulated into pharmaceutical compositions for administration to mammals, preferably humans, in a biologically compatible form suitable for administration in vivo. Thus, in one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention in admixture with a suitable diluent, carrier, or excipient.

[0158] The compounds of the present invention can be used in the form of free base, salt, solvate, and prodrug. All forms are within the scope of the present invention. According to the method of the present invention, the described compounds or their salts, solvates, or prodrugs can be administered to patients in various forms depending on the selected administration route, as will be understood by those skilled in the art. The compounds of the present invention can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via patch, pump, or transdermal administration, and pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration can be by continuous infusion over a selected period of time.

[0159] The compounds of the present invention can be administered orally, for example, using an inert diluent or an assimilable edible carrier, or they can be enclosed in hard or soft shell gelatin capsules, or they can be compressed into tablets, or they can be incorporated directly with food. For oral therapeutic administration, the compounds of the present invention can be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, and wafers. The compounds of the present invention can also be administered parenterally. Solutions of the compounds of the present invention can be prepared in water suitably mixed with a surfactant, such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, as well as in oils. Under ordinary conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003, 20th ed.) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be sufficiently fluid for easy administration via syringe. Compositions for nasal administration can conveniently be formulated as aerosols, drops, gels, and powders. Aerosol formulations typically comprise a solution or fine suspension of an active agent in a physiologically acceptable aqueous or non-aqueous solvent and are usually provided in single or multiple doses in a sealed container, which may take the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container may be an integrated dispensing device, such as a single-dose nasal inhaler or aerosol dispenser, fitted with a metering valve intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it contains a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon.Aerosol dosage forms may also take the form of a pump atomizer. Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, gelatin, and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter. The compounds described herein can be administered intratumorally, for example, by intratumoral injection. Intratumoral injection is a direct injection into the tumor vasculature and is specifically intended for separate, accessible solid tumors. Local, regional, or systemic administration may also be appropriate. The compounds described herein can be advantageously administered by administering an injection or multiple injections to the tumor, for example, spaced about 1 cm apart. In the case of surgical intervention, the present invention can be used preoperatively, such as to subject inoperable tumors to resection. Continuous administration can also be applied, where appropriate, by, for example, implanting a catheter into the tumor or tumor vasculature.

[0160] The compounds of the invention can be administered to animals, for example, humans, alone or in combination with pharmaceutically acceptable carriers described herein, the proportions being determined by the solubility and chemical properties of the compound, the chosen route of administration, and standard pharmaceutical practice.

[0161] Dosage The dosage of the compounds of the present invention and / or compositions containing the compounds of the present invention can vary depending on many factors, such as the pharmacodynamic properties of the compound; the mode of administration; the age, health, and weight of the recipient; the nature and severity of the symptoms; the frequency of treatment and, if present, the type of concurrent treatment; and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compounds of the present invention can be initially administered at a suitable dosage, which can be adjusted as necessary depending on the clinical response. Satisfactory results can usually be obtained when administered to humans at a daily dosage of, for example, between 0.05 mg and 3000 mg (measured as solid form). Dose ranges include, for example, between 10 and 1000 mg (e.g., 50 and 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0162] Alternatively, the dosage can be calculated using the patient's body weight. For example, the dose of the compound or pharmaceutical composition thereof administered to the patient can be in the range of 0.1 to 100 mg / kg (e.g., 0.1 to 50 mg / kg, 0.25 to 25 mg / kg). In exemplary, non-limiting embodiments, the dose can be in the range of 0.5 to 5.0 mg / kg (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg / kg) or 5.0 to 20 mg / kg (e.g., 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg). [Example]

[0163] The following abbreviations are used throughout the examples below: [Table 2-1] [Table 2-2] [Table 2-3]

[0164] Example 1. Preparation of N-(2-((4-(3-(2-((dimethylamino)methyl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 1) [ka] Step 1: Preparation of 4-(3-bromophenyl)thiazol-2-amine (Intermediate B) [ka] To a mixture of 1-(3-bromophenyl)ethanone (473 g, 2.38 mol, 313.25 mL) and thiourea (361.78 g, 4.75 mol) was added I2 (603.14 g, 2.38 mol, 478.68 mL, 1 equiv.). The mixture was stirred at 110 °C for 16 h. After cooling, the reaction mixture was triturated with MTBE (5 L) and then filtered to remove all unreacted iodine and acetophenone. The filter cake was placed in ice water (4 L) and treated with 25% NH3.H2O to a pH of approximately 9-10. The suspension was stirred at 25 °C for 15 min, then filtered and washed with water (1 L) to give a wet solid. The wet solid was dissolved in EtOAc (4 L) and washed with saturated NaHCO3 (1 L × 2) and brine (1 L). The EtOAc layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with PE / EA=100:1 (4 L) at 25° C. for 3 hours, then the suspension was filtered, the filter cake was washed with PE (1 L) and dried in vacuo to give intermediate B (450 g, 1.69 mol, 71.20% yield, 95.93% purity) as a pink solid. LCMS (ESI) m / z [M+H + ] = 254.9; 1H NMR (400 MHz, DMSO-d6) δ 7.98-7.97 (m, 1H), 7.80-7.77 (m, 1H), 7.43-7.42 (m, 1H), 7.34 - 7.30 (m, 1H), 7.15 (s, 1H), 7.10 (s, 2H).

[0165] Step 2: Preparation of tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (Intermediate D) [ka] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (82.40 g, 470.34 mmol), HATU (178.84 g, 470.34 mmol), and DIEA (151.97 g, 1.18 mol, 204.81 mL) in DCM (1000.00 mL) was added Intermediate B (100.00 g, 391.95 mmol), and the mixture was stirred at 30 °C for 16 h. The reaction mixture was washed with saturated citric acid (500 mL × 4) and brine (500 mL), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (200.0 mL), filtered, and dried in vacuo to give Intermediate D (100 g, 241.89 mmol, 61.71% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 413.8. 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.09 - 8.09 (m, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.76 (s, 1H), 7.52 - 7.49 (m, 1H), 7.41 - 7.37 (m, 1H), 7.16 - 7.13 (m, 1H), 3.87 - 3.81 (m, 2H), 1.39 (s, 9H).

[0166] Step 3: Preparation of 2-amino-N-(4-(3-bromophenyl)thiazol-2-yl)acetamide (Intermediate E) [ka] A mixture of intermediate D (10 g, 24.25 mmol) in HCl / dioxane (100 mL) was stirred at 30° C. for 2 hours. The reaction mixture was concentrated in vacuo to give intermediate E (8.4 g, crude, HCl) as a white solid, which was used directly for the next step. LCMS (ESI) m / z [M+H] + = 313.8.

[0167] Step 4: Preparation of N-(2-((4-(3-bromophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Intermediate G) [ka] To a solution of intermediate E (8.4 g, 24.09 mmol, HCl), 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (5.47 g, 28.91 mmol) in DCM (100 mL) was added HATU (10.99 g, 28.91 mmol) and DIEA (18.68 g, 144.56 mmol, 25.18 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was then filtered and washed with MTBE (50 mL × 2) to obtain a filter cake, which was dried in vacuo to obtain intermediate G (10 g, 20.58 mmol, 85.43% yield) as a white solid, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 484.8. 1H NMR (400 MHz, DMSO-d6) δ 12.40 - 12.35 (m, 1H), 8.69 - 8.66 (m, 1H), 8.11 -8.10 (m, 1H), 7.92 -7.90 (m, 1H), 7.85 -7.84 (m, 1H), 7.78 (s, 1H), 7.53 -7.51 (m, 1H), 7.42 - 7.38 (m, 1H), 7.32 - 7.30 (m, 1H), 6.78 - 6.77 (m, 1H), 4.14 (d, J = 6.0 Hz,2H), 3.57 (s, 3H).

[0168] Step 5: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Intermediate I) [ka] To a solution of intermediate G (1.5 g, 3.10 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.18 g, 4.65 mmol) in dioxane (15 mL) was added Pd(dppf)Cl (227.07 mg, 310.33 μmol) and KOAc (913.69 mg, 9.31 mmol). The mixture was then stirred at 80 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered through silica gel, and concentrated to give a residue. The residue was triturated with a solution of PE:EA (1:1, 20 mL), filtered, and concentrated in vacuo to give Intermediate I (6.5 g, 12.00 mmol, 96.71% yield) as a brown solid. LCMS (ESI) m / z [M+H] + = 531.2; 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.67 (t, J = 6.0 Hz, 1H), 8.29 (s, 1H), 8.01 (br d, J = 7.6 Hz, 1H), 7.84 (s,1H), 7.65 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.31 (t, J = 2.8 Hz, 1H), 6.78 (d, J = 1.6 Hz, 1H), 4.14 (d, J= 6.0 Hz, 2H), 3.57 (s, 3H), 1.31 (s, 12H).

[0169] Step 6: Preparation of N-(2-((4-(3-(2-((dimethylamino)methyl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 1) [ka] To a mixture of 1-(4-bromo-2-pyridyl)-N,N-dimethyl-methanamine (30 mg, 139.48 μmol), Intermediate I (88.78 mg, 167.37 μmol), and KPO (118.42 mg, 557.91 μmol) in dioxane (1.5 mL) / HO (0.2 mL) was added 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.09 mg, 13.95 μmol), and the reaction mixture was stirred at 100° C. under N for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.05% ammonia hydroxide v / v)-acetonitrile]; B%: 22%-52%) and lyophilized to give compound 1 (12.36 mg, 22.49 μmol, 16.12% yield, 98% purity) as a yellow solid. LCMS (ESI) m / z [M+H] += 539.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.45(s, 1H), 8.70-8.59 (m, 2H), 8.28 (s, 1H), 8.01 (d, J=8 Hz, 1H), 7.85-7.74 (m, 4H), 7.66-7.58 (m, 2H), 7.32-7.31 (m, 1H), 6.79-6.77 (m, 1H), 4.15(d, J=5.6 Hz, 2H), 3.68 (s, 2H), 3.57 (s, 3H), 2.29 (s, 6H).

[0170] Example 2. Preparation of 1-isopropyl-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 2) [ka] Step 1: Preparation of methyl 1-isopropyl-1H-pyrrole-3-carboxylate (Intermediate C) [ka] To a solution of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol) in DMF (10 mL) was added NaH (239.74 mg, 5.99 mmol, 60% purity) at 25 °C. The mixture was then stirred at this temperature for 1 h, followed by the addition of 2-iodopropane (679.29 mg, 4.00 mmol, 399.58 μL). The resulting mixture was stirred at this temperature for 1 h, then quenched with NH4Cl (3 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate C (0.49 g, 1.22 mmol, 30.43% yield) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 168.1.

[0171] Step 2: Preparation of 1-isopropyl-1H-pyrrole-3-carboxylic acid (Intermediate D) [ka] To a solution of intermediate C (200 mg, 1.20 mmol) in MeOH (1 mL) and HO (3 mL) was added NaOH (96.00 mg, 2.40 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo and then purified by reverse phase (FA conditions) and concentrated under reduced pressure to remove acetonitrile. The residue was then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give intermediate D (68 mg, 435.89 μmol, 36.32% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 154.2; 1 H NMR (400 MHz, DMSO-d6) δ 11.79-11.48 (m, 1H), 7.44-7.42 (m, 1H), 6.89-6.87 (m, 1H), 6.35 (dd, J = 2.0, 2.8 Hz, 1H), 4.39-4.24 (m, 1H), 1.41-1.34 (m, 6H).

[0172] Step 3: Preparation of 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-amine (Intermediate H) [ka] To a solution of 4-(3-bromophenyl)thiazol-2-amine (20 g, 78.39 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (21.90 g, 86.23 mmol), and Pd(dppf)Cl (2 g, 2.73 mmol) in dioxane (300 mL) was added KOAc (23.08 g, 235.17 mmol) under N, and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude Intermediate H (23.69 g, crude) as a brown solid, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 303.2.

[0173] Step 4: Preparation of 4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-amine (Intermediate J) [ka] To a solution of intermediate H (23 g, 76.11 mmol), 3-bromo-1-methyl-pyrazole (12.25 g, 76.11 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (3 g, 4.60 mmol) in dioxane (200 mL) and water (50 mL), KPO (48.47 g, 228.33 mmol) was added, and the mixture was stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 3:1 to 2:1) and concentrated under reduced pressure to give intermediate J (15 g, 58.52 mmol, 76.89% yield) as a gray solid. LCMS (ESI) m / z [M+H] + = 257.1; 1H NMR (400 MHz, DMSO-d6) δ 8.25-8.24 (m, 1H), 7.73-7.63 (m, 3H), 7.38-7.34 (m, 1H), 7.08-6.06 (m, 3H), 6.69-6.68 (m, 1H), 3.89 (s, 3H).

[0174] Step 5: Preparation of tert-butyl (2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate L) [ka] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (4.10 g, 23.41 mmol), DIEA (6.05 g, 46.82 mmol, 8.15 mL), and HATU (8.90 g, 23.41 mmol) in DCM (40 mL) was added intermediate J (4 g, 15.61 mmol), and the mixture was stirred at 30 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give intermediate L (2 g, 4.44 mmol, 28.45% yield) as a brown solid. LCMS (ESI) m / z [M+H] + =414.1.

[0175] Step 6: Preparation of 2-amino-N-(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)acetamide (Intermediate E) [ka] A solution of intermediate L (2 g, 4.84 mmol) in 4 M HCl / dioxane (20 mL) was stirred at 30° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (50.0 mL), then filtered and concentrated under reduced pressure to give intermediate E (2 g, crude, HCl salt) as a brown solid. LCMS (ESI) m / z [M+H] +=313.9;1H NMR (400 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.51 (s, 3H), 8.39 (s, 1H), 7.82-7.72 (m, 4H), 7.47-7.43 (m, 1H), 6.74-6.73 (m, 1H), 3.93-3.90 (m, 5H).

[0176] Step 7: Preparation of 1-isopropyl-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 2) [ka] A mixture of intermediate D (65 mg, 424.34 μmol), intermediate E (199.47 mg, 636.51 μmol), HOBt (114.68 mg, 848.69 μmol), EDCI (162.69 mg, 848.69 μmol), and DIEA (164.53 mg, 1.27 mmol, 221.74 μL) in DMF (2 mL) was degassed and purged with N2 three times, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase (basic conditions) and lyophilized to give compound 2 (64 mg, 142.69 μmol, 33.62% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 449.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.39 (s, 1H), 8.18-8.16 (m, 1H), 7.83-7.68 (m, 4H), 7.48-7.40 (m, 2H), 6.88-6.86 (m, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.48 (dd, J = 2.0, 2.8 Hz, 1H), 4.32 (m, 1H), 4.10 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 1.39 (d, J = 6.8 Hz, 6H).

[0177] Example 3. Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxamide (Compound 3) [ka] Step 1: Preparation of (Z)-ethyl 3-(dimethylamino)-2-isocyanoacrylate (Intermediate C) [ka] To a solution of ethyl 2-isocyanoacetate (1 g, 8.84 mmol, 970.87 μL) in EtOH (10 mL) was added 1,1-dimethoxy-N,N-dimethyl-methanamine (2.11 g, 17.68 mmol, 2.35 mL) dropwise at 0 °C, and the mixture was stirred at 30 °C under N for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 30 / 1 to 10:1) and concentrated to give Intermediate C (1 g, crude) as a brown oil. LCMS (ESI) m / z [M+H] + =169.2. 1 H NMR (400 MHz, methanol-d4) δ 7.34-7.31 (s, 1H), 4.20-4.13 (m, 2H), 3.31-3.24 (m, 6H), 1.29-1.25 (m, 3H).

[0178] Step 2: Preparation of ethyl 1-(tert-butyl)-1H-imidazole-4-carboxylate (Intermediate D) [ka] A mixture of intermediate C (1 g, 5.95 mmol) and 2-methylpropan-2-amine (1.30 g, 17.84 mmol, 1.87 mL) was stirred at 140 °C for 24 h. The reaction mixture was concentrated to give a residue. The crude product was purified by reverse-phase HPLC (0.1% NH H O). The solution was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na SO , and filtered. The filtrate was concentrated to give intermediate D (200 mg, 847.00 μmol, 14.25% yield) as a yellow oil. LCMS (ESI) m / z [M+H] + = 197.3.

[0179] Step 3: Preparation of 1-(tert-butyl)-1H-imidazole-4-carboxylic acid (Intermediate E) [ka] To a solution of intermediate D (80 mg, 407.65 μmol) in HO (1 mL) and EtOH (1 mL) was added NaOH (16.30 mg, 407.65 μmol), and the mixture was stirred at 30° C. for 2 h. The reaction mixture was concentrated in vacuo to give intermediate E (60 mg, crude) as a yellow solid, which was used directly for the next step. LCMS (ESI) m / z [M+H] + = 169.1.

[0180] Step 4: Preparation of tert-butyl (2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate I) [ka] To a solution of 3-(2-aminothiazol-4-yl)benzonitrile (7 g, 34.78 mmol) and 2-(tert-butoxycarbonylamino)acetic acid (9.14 g, 52.17 mmol) in pyridine (140 mL) was added EDCI (20.00 g, 104.35 mmol), and the mixture was stirred at 30 °C for 2 h. The reaction mixture was concentrated to give a residue. The residue was poured into aqueous citric acid (200 mL), and the solution was stirred at 30 °C for 30 min. The mixture was extracted with EtOAc (100 mL × 3), and the combined organic layers were washed with brine (200 mL), dried over Na SO , and filtered. The filtrate was concentrated to give a residue. The residue was triturated with EtOAc (20 mL), then filtered and dried in vacuo to give Intermediate I (6.6 g, 15.98 mmol, 45.93% yield) as a white solid. LCMS (ESI) m / z [M+H-56] + = 303.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.39-12.31 (m, 1H), 8.34-8.29 (m, 1H), 8.25-8.18 (m, 1H), 7.88-7.84 (m, 1H), 7.81-7.76 (m, 1H), 7.70-7.62 (m, 1H), 7.24-7.12 (m, 1H), 3.94-3.80 (m, 2H), 1.48-1.32 (m, 9H).

[0181] Step 5: Preparation of 2-amino-N-(4-(3-cyanophenyl)thiazol-2-yl)acetamide (Intermediate F) [ka] A mixture of intermediate I (6.6 g, 18.19 mmol) in HCl / dioxane (70 mL) was stirred at 30° C. for 2 hours. The reaction mixture was concentrated to give a residue. The residue was triturated with MTBE (10 mL), then filtered and dried in vacuo to give intermediate F (6.1 g, crude, HCl salt) as a white solid. LCMS (ESI) m / z [M+H] + = 258.9. 1H NMR (400 MHz, methanol-d₄) δ 8.27 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.60-7.56 (m, 1H), 4.02 (s, 2H).

[0182] Step 6: Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-imidazole-4-carboxamide (compound 3) [ka] To a solution of intermediate E (60 mg, 356.73 μmol) and intermediate F (52.58 mg, 178.37 μmol, HCl salt) in DCM (2 mL) was added HATU (81.38 mg, 214.04 μmol) and DIEA (115.26 mg, 891.83 μmol, 155.34 μL), and the mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 22%-52%) and lyophilized to give compound 3 (33.52 mg, 82.06 μmol, 46.01% yield) as a white solid. LCMS (ESI) m / z [M+H] + =409.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.32 (s, 1H), 8.23-8.21 (m, 2H), 7.89-7.86 (m, 3H), 7.78 (d, J=7.6 Hz, 1H), 7.67-7.63 (m, 1H), 4.17 (d, J=6.0 Hz, 2H), 1.53 (s, 9H).

[0183] Example 4. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 4) [ka] Step 1: Preparation of tert-butyl 1H-pyrrole-3-carboxylate (Intermediate C) [ka] To a mixture of 1H-pyrrole-3-carboxylic acid (500 mg, 4.50 mmol) in toluene (15 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (3.66 g, 18.00 mmol, 4.32 mL) dropwise within 20 min at 80 °C. The reaction mixture was stirred at 80 °C for 10 min. The reaction mixture was cooled to room temperature (30 °C), diluted with EtOAc (40 mL), washed with HO (60 mL), and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column (NH.HO condition) and lyophilized to give intermediate C (450 mg, 2.69 mmol, 59.80% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.52 (br s, 1H), 7.37-7.35 (m, 1H), 6.74-6.72 (m, 1H), 6.62-6.60 (m, 1H), 1.56 (s, 9H).

[0184] Step 2: Preparation of tert-butyl 1-(methylsulfonyl)-1H-pyrrole-3-carboxylate (Intermediate E) [ka] To a solution of intermediate C (620 mg, 3.71 mmol) in THF (25 mL) was added KHMDS (1 M, 7.42 mL) slowly at 0 °C under N. The reaction mixture was stirred at 0 °C under N for 30 min. Methanesulfonyl chloride (509.71 mg, 4.45 mmol, 344.40 μL) was then added slowly to the reaction mixture at 0 °C under N. The reaction mixture was warmed to 30 °C and stirred at 30 °C under N for 16 h. The reaction mixture was poured slowly into HO (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography (NH.HO conditions) to give intermediate E (510 mg, 2.01 mmol, 54.19% yield) as a yellow solid. LCMS (ESI) m / z[M+Na] + =268.2. 1 H NMR (400 MHz, CDCl3) δ 7.65-7.64 (m, 1H), 7.09-7.08 (m, 1H), 6.72-6.71 (m, 1H), 3.21 (s, 3H), 1.56 (s, 9H).

[0185] Step 3: Preparation of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (Intermediate F) [ka] To a solution of intermediate E (560 mg, 2.28 mmol) in DCM (25 mL) was added TFA (3.85 g, 33.77 mmol, 2.5 mL) slowly at 30° C. The reaction mixture was stirred at 30° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (FA condition) to give intermediate F (310 mg, 1.57 mmol, 68.57% yield) as a white solid. LCMS (ESI) m / z [M+H] + =190.0. 1H NMR (400 MHz, methanol-d4) δ 7.77-7.76 (m, 1H), 7.24-7.22 (m, 1H), 6.71-6.70 (m, 1H), 3.37 (s, 3H).

[0186] Preparation of 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide (Intermediate G) [ka] Step 4: Preparation of 4-[3-(4-pyridyl)phenyl]thiazol-2-amine (Intermediate J) [ka] To a solution of 4-(3-bromophenyl)thiazol-2-amine (10 g, 39.20 mmol), 4-pyridylboronic acid (14.45 g, 117.59 mmol), and KCO (16.25 g, 117.59 mmol) in dioxane (120 mL) and water (30 mL) was added Pd(dppf)Cl (1 g, 1.37 mmol) under N, and the mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with water (500 mL), extracted with EtOAc (500 mL), and concentrated under reduced pressure to give a residue. The residue was purified by crystallization from DCM / MTBE = 1:20 (200 mL) and filtered to give intermediate J (9.5 g, 36.33 mmol, 92.69% yield) as a brown solid. LCMS (ESI) m / z [M+H] + = 254.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J=6.0 Hz, 2H), 8.19 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.68 (d,J=8.0 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.21 (s, 1H), 7.11 (s, 2H).

[0187] Step 5: Preparation of tert-butyl N-[2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]carbamate (Intermediate L) [ka] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (9.85 g, 56.25 mmol), HATU (21.39 g, 56.25 mmol), and DIPEA (14.54 g, 112.51 mmol) in DCM (200 mL) was added Intermediate C (9.5 g, 37.50 mmol, 1 equiv.), and the mixture was stirred at 30° C. for 16 h. A precipitate formed. The reaction mixture was filtered to give a yellow solid. The crude product was triturated with EtOAc (300 mL) and MeOH (50 mL) and dried in vacuo to give Intermediate L (11 g, 25.89 mmol, 69.03% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 411.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.32 (br s, 1H), 8.69 - 8.67 (m, 2H), 8.30 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.83 (s, 1H), 7.80 - 7.76 (m, 3H), 7.64 - 7.60 (m, 1H), 7.20 - 7.15 (m, 1H), 3.88 (d, J=6.4 Hz, 2H), 1.44 (s, 9H).

[0188] Step 6: Preparation of 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide (Intermediate G) [ka] To a solution of intermediate L (11 g, 26.80 mmol) in MeOH (20 mL) was added 4 M HCl / EtOAc (20 mL). The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by trituration with EtOAc (200 mL) and MTBE (50 mL) and dried in vacuo to give intermediate G (12 g, HCl salt) as a pale yellow solid. LCMS (ESI) m / z [M+H] + = 311.3. 1 H NMR (400 MHz, methanol-d4) δ8.92 (d, J=6.8 Hz, 2H), 8.52 - 8.47 (m, 3H), 8.22 (d, J=8.0 Hz, 1H), 7.94 (m, J=8.4 Hz, 1H), 7.75 - 7.66 (m, 2H), 4.04 (s, 2H).

[0189] Step 7: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 4) [ka] To a mixture of intermediate F (248.74 mg, 1.31 mmol) in DCM (15 mL) was added DIPEA (708.01 mg, 5.48 mmol, 954.19 μL), HATU (624.88 mg, 1.64 mmol), and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide (380 mg, 1.10 mmol, HCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 13 h. The reaction mixture was filtered, and the filter cake was washed with DCM (50 mL) and MeOH (20 mL) to give a yellow solid (600 mg). The yellow solid was triturated with EtOH (50 mL) at 30° C. for 15 min and filtered to give a yellow solid (270 mg). The yellow solid was triturated with MeCN (20 mL) and 10 drops of TFA at 30° C. for 20 min and filtered to give compound 4 (257.10 mg, 419.77 μmol, 38.31% yield, TFA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 481.9; 1 H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 8.85 (d, J=5.2 Hz, 2H), 8.71-8.69 (m, 1H), 8.40 (s, 1H), 8.13-8.08 (m, 3H), 7.89-7.84 (m, 3H), 7.68-7.64 (m, 1H), 7.33-7.31 (m, 1H), 6.78-6.77 (m, 1H), 4.15 (d, J=5.6 Hz, 2H), 3.58 (s, 3H).

[0190] Example 5. Preparation of (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-phenylthiazol-2-yl)amino)butan-2-yl)-1H-pyrrole-3-carboxamide (Compound 5) [ka] Step 1: Preparation of (S)-tert-butyl (4-(methylthio)-1-oxo-1-((4-phenylthiazol-2-yl)amino)butan-2-yl)carbamate (Intermediate C) [ka] To a solution of (2S)-2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (5.0 g, 20.05 mmol) in DCM (20.0 mL) was added EEDQ (6.20 g, 25.07 mmol), and then 4-phenylthiazol-2-amine (2.95 g, 16.71 mmol) was added to the mixture. The mixture was stirred at 25 °C for 3 h. 10% citric acid (800.0 mL) was added, and the reaction mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 50 / 1 to 8:1) to give Intermediate C (5.8 g, 14.23 mmol, 85.16% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 408.0;ee%=100%.

[0191] Step 2: Preparation of (S)-2-amino-4-(methylthio)-N-(4-phenylthiazol-2-yl)butanamide (Intermediate D) [ka] To a solution of intermediate C (5.8 g, 14.23 mmol) in DCM (20.0 mL) was added TFA (4.0 mL). The mixture was stirred at 10° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DCM. The crude product intermediate D (7 g, crude, TFA salt) was lyophilized and used in the next step as a white solid without further purification. LCMS (ESI) m / z [M+H] + = 307.9;ee%=100%.

[0192] Step 3: Preparation of (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-phenylthiazol-2-yl)amino)butan-2-yl)-1H-pyrrole-3-carboxamide (compound 5) [ka] To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (300 mg, 1.59 mmol) and intermediate D (487.50 mg, 1.59 mmol) in DCM (10 mL) was added DIPEA (614.81 mg, 4.76 mmol, 828.59 μL), EDCI (455.97 mg, 2.38 mmol), and HOBt (321.39 mg, 2.38 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column (FA conditions) and lyophilized to give compound 5 (507.03 mg, 1.05 mmol, 66.35% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 478.9; 1 H NMR (400 MHz, methanol-d4) δ 7.93-7.85 (m, 3H), 7.42-7.35 (m, 3H), 7.30 (d, J=7.2 Hz, 1H), 7.28-7.24 (m, 1H), 6.84-6.82 (m, 1H), 4.90-4.88 (m, 1H), 3.36 (s, 3H), 2.73-2.57 (m, 2H), 2.31-2.11 (m, 5H);ee%=100%.

[0193] Example 6. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 6) [ka] Step 1: Preparation of tert-butyl (2-((4-bromothiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate C) [ka] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (14.68 g, 83.78 mmol) and 4-bromothiazol-2-amine (10 g, 55.85 mmol) in pyridine (150 mL) was added EDCI (53.54 g, 279.27 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc = 1:0 to 0:1) to give a solid. The solid was triturated with MTBE (20 mL), filtered, and dried in vacuo to give intermediate C (8 g, 21.65 mmol, 38.77% yield) as a white solid. LCMS (ESI) [M+H] + = 336.1 / 338.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.59 - 6.56 (m, 1H), 3.84 (d, J = 6.4 Hz, 2H), 1.39 (s, 9H).

[0194] Step 2: Preparation of 2-amino-N-(4-bromothiazol-2-yl)acetamide (Intermediate D) [ka] A solution of intermediate C (5 g, 14.87 mmol) in HCl / dioxane (4 M, 50 mL) was stirred at 25° C. for 2 h. The reaction mixture was filtered and the solid was dried in vacuo to give intermediate D (4.2 g, HCl salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 236.2 / 238.2.

[0195] Step 3: Preparation of N-(2-((4-bromothiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Intermediate F) [ka] A solution of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (1.67 g, 8.81 mmol), DIEA (2.85 g, 22.01 mmol), and HATU (4.19 g, 11.01 mmol) in DCM (20 mL) was stirred at 25 °C for 5 minutes. Intermediate D (2 g, 7.34 mmol) was then added at 25 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was filtered to give a brown solid. The solid was triturated with DCM (5 mL), then dissolved in DMSO (5 mL), repurified by reverse-phase HPLC (FA), concentrated, extracted with EtOAc (20 mL × 2), and the combined organic layers were dried over anhydrous NaSO and concentrated to give Intermediate F (550 mg, 1.31 mmol, 17.83% yield) as a white solid. LCMS (ESI) [M+H] + =407.1 / 409.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (br s, 1H), 8.69 - 8.67 (m, 1H), 7.83 - 7.83 (m, 1H), 7.33 - 7.28 (m, 2H), 6.76 - 6.75 (m, 1H), 4.10 (d, J = 5.8 Hz, 2H), 3.57 (s, 3H).

[0196] Step 4: Preparation of 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]pyridine (Intermediate G) [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmol) and 4-fluoropyridine (375.28 mg, 2.81 mmol, 1.09 equiv., HCl) in DMF (5 mL) was added CsCO (1.68 g, 5.15 mmol). The mixture was then stirred at 100 °C for 16 h. The reaction mixture was diluted with brine (10 mL) and then extracted with EtOAc (5 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give intermediate G (1.5 g, crude) as a yellow oil, which was used directly in the next step. LCMS (ESI) [M+H] + = 272.1.

[0197] Step 5: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(1-(pyridin-4-yl)-1H-pyrazol-4-yl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 6) [ka] To a solution of intermediate F (100 mg, 245.54 μmol) and intermediate G (332.86 mg, 1.23 mmol) in dioxane / HO (4 / 1) (5 mL) was added KPO (156.36 mg, 736.62 μmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (32.01 mg, 49.11 μmol). The mixture was stirred at 75 °C under N for 16 h. HO (0.5 mL) was added to the mixture, causing a yellow solid to precipitate from the mixture. The solid was filtered to obtain the crude product. The crude product was purified by reverse phase (0.1% FA condition) and lyophilized to give compound 6 (11.15 mg, 20.62 μmol, 8.40% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 472.3; 1H NMR (400 MHz, DMSO-d6) δ 12.41 (br s, 1H), 8.98 (s, 1H), 8.68-8.66 (m, 3H), 8.22 (s, 1H), 7.90-7.88 (m, 2H), 7.85-7.84 (m, 1H), 7.41 (s, 1H), 7.32-7.32(m, 1H), 6.78-6.78 (m, 1H), 4.22-4.07 (m, 2H), 3.66-3.50 (m, 3H).

[0198] Example 7. Preparation of 1-(tert-butyl)-N-(2-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 7) [ka] Step 1: Preparation of N-(2-((4-bromothiazol-2-yl)amino)-2-oxoethyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide (Intermediate D) [ka] To a solution of 1-tert-butylpyrrole-3-carboxylic acid [prepared according to the method in Example 34] (73.62 mg, 440.29 μmol) in DCM (4 mL) was added EDCI (105.50 mg, 550.36 μmol), DIEA (189.68 mg, 1.47 mmol, 255.63 μL), and HOBt (74.37 mg, 550.36 μmol). 2-Amino-N-(4-bromothiazol-2-yl)acetamide [prepared according to the method in Example 6] (100 mg, 366.90 μmol, HCl salt) was then added. The mixture was stirred at 25° C. for 2 hours. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (EtOAc / petroleum ether gradient) and concentrated to give intermediate D (120 mg, 303.55 μmol, 82.73% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 387.0.

[0199] Step 2: Preparation of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one (Intermediate H) [ka] A mixture of 7-bromo-2-methyl-isoquinolin-1-one (300 mg, 1.26 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (351.98 mg, 1.39 mmol), KOAc (371.00 mg, 3.78 mmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (82.12 mg, 126.01 μmol) in dioxane (4 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 80 °C for 2 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate H (300 mg, crude) as a yellow solid, which was used for the next step without further purification. LCMS (ESI) m / z [M+H] + = 286.2.

[0200] Step 3: Preparation of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (Intermediate E) [ka] To a solution of intermediate H (80 mg, 280.56 μmol) in MeOH (5 mL) was added Pd / C (10 mg, 280.56 μmol, 10% purity). The mixture was stirred under H (15 psi) at 25° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give intermediate E (70 mg, crude) as a white solid, which was used for the next step without further purification. LCMS (ESI) m / z [M+H] + = 287.8.

[0201] Step 4: Preparation of 1-(tert-butyl)-N-(2-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 7) [ka] A mixture of N-(2-((4-bromothiazol-2-yl)amino)-2-oxoethyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide (50 mg, 129.78 μmol), Intermediate E (48.45 mg, 168.71 μmol), KPO (82.64 mg, 389.34 μmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (16.92 mg, 25.96 μmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 80° C. for 2 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.05% ammonia hydroxide v / v)-acetonitrile]; B%: 28%-58%) and lyophilized to give compound 7 (7 mg, 15.04 μmol, 11.59% yield) as a white solid. LCMS (ESI) m / z [M+H] + =466.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.17-8.14 (m, 1H), 7.98-7.95 (m, 1H), 7.65 (s, 1H), 7.52-7.50 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.97-6.95 (m, 1H), 6.47-6.46 (m, 1H), 4.09 (d, J=5.6 Hz, 2H), 3.58-3.55 (m, 2H), 3.04-2.98 (m, 5H), 1.50 (s, 9H).

[0202] Example 8. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 8) [ka] Step 1: Preparation of N-(2-((4-(3-bromophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide (Intermediate C) [ka] To a solution of 2-amino-N-[4-(3-bromophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 1) (2.09 g, 5.98 mmol, HCl salt) in DCM (20 mL) were added EDCI (1.72 g, 8.97 mmol), DIEA (3.86 g, 29.90 mmol, 5.21 mL), and HOBt (1.21 g, 8.97 mmol). The mixture was stirred at 25° C. for 30 minutes, and then 1-tert-butylpyrrole-3-carboxylic acid [prepared according to the method in Example 34] (1 g, 5.98 mmol) was added at 25° C. and stirred for 16 hours. The mixture was cooled to 25° C. and concentrated under reduced pressure at 40° C. The residue was poured into ice water (20 mL). The aqueous phase was extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1:0, 0:1) and concentrated to give intermediate C (1.5 g, 3.25 mmol, 54.36% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =463.0; 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 8.24-8.17 (m, 1H), 8.12 (d, J = 1.6 Hz, 1H), 7.95-7.88 (m, 1H), 7.78 (s, 1H), 7.57-7.49 (m, 2H), 7.41 (s, 1H), 6.99-6.97 (m, 1H), 6.48-6.47 (m, 1H), 4.13-4.07 (m, 2H), 1.50 (s, 9H).

[0203] Step 2: Preparation of 1-(tert-butyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Intermediate E) [ka] A mixture of Intermediate C (500 mg, 1.08 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (825.59 mg, 3.25 mmol), Pd(dppf)Cl (158.59 mg, 216.74 μmol), and KOAc (319.08 mg, 3.25 mmol) in dioxane (5 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 80 °C for 4 h. The mixture was cooled to 25 °C and concentrated in vacuo at 40 °C. The residue was poured into ice water (10 mL). The aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10 / 1, 0 / 1) and concentrated to give intermediate E (500 mg, 973.57 μmol, 89.84% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 509.4.

[0204] Step 3: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 8) [ka] To a mixture of 1-(3-bromopyrazol-1-yl)-2-methyl-propan-2-ol (50 mg, 228.23 μmol) and Intermediate E (116.04 mg, 228.23 μmol) in dioxane (1.2 mL) and HO (0.3 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (29.75 mg, 45.65 μmol) and KPO (145.34 mg, 684.69 μmol) under N at 25° C. The reaction mixture was heated to 75° C. and stirred at 75° C. for 2 h. The mixture was cooled to 25° C. and concentrated under reduced pressure at 40° C. The residue was poured into ice water (10 mL). The aqueous phase was extracted with EtOAc (10 mL × 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (FA) and lyophilized to give compound 8 (20.86 mg, 39.67 μmol, 17.38% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =521.3; 1 HNMR (400 MHz, methanol-d₄) δ 8.39–8.30 (m, 1H), 7.87–7.79 (m, 1H), 7.75–7.67 (m, 2H), 7.60–7.56 (m, 1H), 7.46–7.40 (m, 2H), 6.98–6.93 (m, 1H), 6.73–6.67 (m, 1H), 6.60–6.54 (m, 1H), 4.27–4.20 (m, 2H), 4.18–4.12 (m, 2H), 1.57 (s, 9H), 1.22 (s, 6H).

[0205] Example 9. Preparation of N-(2-((4-(3-(2-aminopyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 9) [ka] Step 1: Preparation of N-(2-((4-(3-(2-aminopyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 9) [ka] To a solution of N-(2-((4-(3-bromophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide [prepared according to the method in Example 1] (50 mg, 96.26 μmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (31.78 mg, 144.40 μmol) in dioxane (2 mL) and HO (0.2 mL) was added KPO (61.30 mg, 288.79 μmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.55 mg, 19.25 μmol) under N. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into water (5 mL), and the solution was extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 15%-36%) to give compound 9 (4.95 mg, 9.97 μmol, 10.36% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 497.1. 1H NMR (400 MHz, DMSO-d6) δ 12.78-12.43 (m, 1H), 8.69-8.67 (m, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.99 (d, J=5.6 Hz,1H), 7.98 (s, 1H), 7.85-7.83 (m, 1H), 7.75 (s, 1H), 7.56-7.55 (m, 2H), 7.30 (s, 1H), 6.81 (dd, J=1.6, 5.4 Hz, 1H), 6.77 (d, J=1.6 Hz, 1H), 6.73 (s, 1H), 5.98 (s, 2H), 4.14 (d, J=6.0 Hz, 2H), 3.56 (s, 3H).

[0206] Example 10. Preparation of N-(2-((4-(3-cis-2,6-dimethylmorpholino)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 10) [ka] Step 1: Preparation of tert-butyl (2-((4-(3-cis-2,6-dimethylmorpholino)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate C) [ka] A mixture of tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (400 mg, 970.17 μmol) (prepared according to the method in Example 1), cis-2,6-dimethylmorpholine (167.61 mg, 1.46 mmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium, ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (77.07 mg, 97.02 μmol), and t-BuONa (279.71 mg, 2.91 mmol) in dioxane (4 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 60 °C for 12 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 10-60% ethyl acetate / petroleum ether gradient) and concentrated in vacuo to give Intermediate C (200 mg, 362.77 μmol, 37.39% yield) as a yellow oil. LCMS (ESI) m / z [M+H] + = 447.3.

[0207] Step 2: Preparation of 2-amino-N-(4-(3-cis-2,6-dimethylmorpholino)phenyl)thiazol-2-yl)acetamide (Intermediate D) [ka] To a solution of intermediate C (180 mg, 403.08 μmol) in MeOH (2 mL) was added HCl / dioxane (2 mL). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give intermediate D (160 mg, crude, HCl salt) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 347.2.

[0208] Step 3: Preparation of N-(2-((4-(3-cis-2,6-dimethylmorpholino)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 10) [ka] To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (47.43 mg, 250.71 μmol) in DMF (2 mL) was added EDCI (60.08 mg, 313.39 μmol), DIEA (108.01 mg, 835.71 μmol, 145.57 μL), and HOBt (42.35 mg, 313.39 μmol), followed by the addition of intermediate D (80 mg, 208.93 μmol, HCl salt). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.075% TFA)-acetonitrile]; B%: 30%-60%) and lyophilized to give compound 10 (40 mg, 60.79 μmol, 29.10% yield, TFA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 518.3. 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.67-8.65 (m, 1H), 7.84 (s, 1H), 7.61 (s, 1H), 7.44 (s, 1H), 7.36-7.30 (m, 2H), 7.29-7.24 (m, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.79-6.75 (m, 1H), 4.13 (d, J=5.6 Hz, 2H), 3.78-3.67 (m, 2H), 3.62 (d, J=11.0 Hz, 2H), 3.57 (s, 3H), 2.32-2.25 (m, 2H), 1.17 (d, J=6.0 Hz, 6H);ee%=100%.

[0209] Example 11. Preparation of (S)—N-(2-((4-(3-(3-methoxypiperidin-1-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 11) [ka] Step 1: Preparation of (S)-tert-butyl 3-methoxypiperidine-1-carboxylate (Intermediate B) [ka] To a solution of tert-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol) in THF (20 mL) was added NaH (794.91 mg, 19.87 mmol, 60% purity) at 0 °C and stirred at 0 °C for 30 min. Then, MeI (2.12 g, 14.91 mmol, 927.95 μL) was added to the mixture and stirred at 25 °C for 2 h. The mixture was poured into aqueous NH4Cl (80 mL) and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (25 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give Intermediate B (2.14 g, crude) as a dark brown oil, which was used in the next step without further purification. LCMS (ESI) m / z [M+Na] + = 237.9.

[0210] Step 2: Preparation of (S)-3-Methoxypiperidine (Intermediate C) [ka] A solution of intermediate B (1.78 g, 8.27 mmol) in HCl / dioxane (4 M, 12.82 mL) was stirred for 1 h at 25° C. The reaction mixture was concentrated in vacuo to give intermediate C (1.2 g, crude, HCl salt) as a dark brown solid, which was used in the next step without further purification.

[0211] 1 H NMR (400 MHz, methanol-d4) δ 3.63 (s, 1H), 3.39 (s, 3H), 3.27 (s, 1H), 3.22-3.12 (m, 2H), 3.05-3.00 (m, 1H), 2.01-1.94 (m, 2H), 1.76-1.66 (m, 2H).

[0212] Step 3: Preparation of (S)-tert-butyl (2-((4-(3-(3-methoxypiperidin-1-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate D) [ka] A mixture of tert-butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (prepared according to the method in Example 1) (250 mg, 606.35 μmol), Intermediate C (137.92 mg, 909.53 μmol, HCl salt), t-BuONa (233.08 mg, 2.43 mmol), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium, ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (48.17 mg, 60.64 μmol) in dioxane (5 mL) was degassed and purged with N three times, and then the mixture was stirred under N at 70 °C for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (45 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 20 / 1 to 1:1) and concentrated in vacuo to give intermediate D (340 mg, 723.30 μmol, 59.64% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 447.5.

[0213] Step 4: Preparation of (S)-2-amino-N-(4-(3-(3-methoxypiperidin-1-yl)phenyl)thiazol-2-yl)acetamide (Intermediate E) [ka] A mixture of intermediate D (300 mg, 671.80 μmol) in HCl / dioxane (4 M, 3 mL) was stirred under N for 0.5 h at 25° C. The reaction mixture was concentrated in vacuo to give intermediate E (300 mg, crude, HCl salt) as a brown solid, which was used directly in the next step.

[0214] Step 5: Preparation of (S)—N-(2-((4-(3-(3-methoxypiperidin-1-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 11) [ka] To a solution of intermediate E (60 mg, 156.70 μmol, HCl salt), 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (35.57 mg, 188.04 μmol), and DIEA (101.26 mg, 783.48 μmol, 136.46 μL) in DCM (2 mL) was added HOBt (25.41 mg, 188.04 μmol) and EDCI (90.12 mg, 470.09 μmol), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 20%-40%) and lyophilized to give compound 11 (88.55 mg, 140.19 μmol, 89.47% yield, TFA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 518.4. 1H NMR (400MHz, DMSO-d6) δ 8.12-8.00 (m, 2H), 7.83 (s, 1H), 7.62-7.51 (m, 3H), 7.28-7.27 (m, 1H), 6.81-6.80 (m, 1H), 4.26 (s, 2H), 3.80-3.72 (m, 3H), 3.64-3.59 (m, 1H), 3.55-3.51 (m, 1H), 3.48 (s, 3H), 3.38 (s, 3H), 2.28-2.20 (m, 1H), 2.04-1.99 (m, 1H), 1.95-1.87 (m, 2H);ee%=100%.

[0215] Example 12. Preparation of N-(2-((4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 12) [ka] Step 1: Preparation of 7-bromo-1-methylquinolin-2(1H)-one (Intermediate B) [ka] To a solution of 7-bromo-1H-quinolin-2-one (500 mg, 2.23 mmol) in DMF (5 mL) was added NaH (107.11 mg, 2.68 mmol, 60% purity) at 0 °C and stirred at 0 °C for 0.5 h. Then MeI (610 mg, 4.30 mmol, 267.54 μL) was added at 0 °C and stirred at 25 °C for 1.5 h. The reaction mixture was quenched by the addition of water (2 mL), then diluted with EtOAc (15 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give intermediate B (400 mg, 1.68 mmol, 75.29% yield) as a brown solid, which was used directly for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 9.6 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46-7.44 (m, 1H), 6.65 (d, J = 9.2 Hz, 1H), 3.60 (s, 3H).

[0216] Step 2: Preparation of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2(1H)-one (Intermediate D) [ka] To a solution of Intermediate B (400 mg, 1.68 mmol) in dioxane (5 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (639.96 mg, 2.52 mmol), KOAc (494.67 mg, 5.04 mmol), and Pd(dppf)Cl (122.93 mg, 168.01 μmol). The mixture was stirred at 80 °C for 2 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 20 / 1 to 1:1) and concentrated to give intermediate D (204 mg, 715.43 μmol, 42.58% yield) as a white solid. LCMS (ESI) m / z [M+H] + =286.3; 1 H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.69-7.65 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 9.6 Hz, 1H), 3.80 (s, 3H), 1.39 (s, 12H).

[0217] Step 3: Preparation of tert-butyl (2-((4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate F) [ka] To a mixture of tert-butyl N-[2-[(4-bromothiazol-2-yl)amino]-2-oxo-ethyl]carbamate (prepared according to the method in Example 6) (160 mg, 475.90 μmol), Intermediate D (203.55 mg, 713.85 μmol), and KPO (303.05 mg, 1.43 mmol) in dioxane (3 mL) and HO (0.6 mL), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (31.02 mg, 47.59 μmol) was added, degassed, and purged with N three times. The mixture was then stirred under a N atmosphere at 80° C. for 2 h. The residue was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE: EtOAc = 1:1 to 0:1) and concentrated to give Intermediate F (140 mg, 336.90 μmol, 70.79% yield) as a pale yellow solid. LCMS (ESI) m / z [M+H] + =415.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 7.97 (s, 1H), 7.90-7.88 (m, 2H), 7.80-7.73 (m, 2H), 7.16-7.13 (m, 1H), 6.59 (d, J = 9.6 Hz, 1H), 3.86 (d, J = 6.4 Hz, 2H), 3.66 (s, 3H), 1.38 (s, 9H).

[0218] Step 4: Preparation of 2-amino-N-(4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)thiazol-2-yl)acetamide (Intermediate G) [ka] To a solution of intermediate F (40 mg, 96.51 μmol) in dioxane (0.5 mL) was added HCl / dioxane (4 M, 241.27 μL). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give intermediate G (35 mg, crude, HCl salt) as a yellow solid, which was used directly in the next step. LCMS (ESI) m / z [M+H] + =315.0.

[0219] Step 5: Preparation of N-(2-((4-(1-methyl-2-oxo-1,2-dihydroquinolin-7-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 12) [ka] To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (22.65 mg, 119.72 μmol) in DMF (0.5 mL) was added EDCI (28.69 mg, 149.65 μmol), HOBt (20.22 mg, 149.65 μmol), DIEA (38.68 mg, 299.30 μmol, 52.13 μL), and Intermediate G (35 mg, 99.77 μmol, HCl salt). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with saturated brine (5 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.05% ammonia hydroxide v / v)-acetonitrile]; B%: 10%-40%) and lyophilized to give compound 12 (12.98 mg, 26.30 μmol, 26.36% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 486.0; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.06-7.98 (m, 1H), 7.95-7.73 (m, 5H), 7.31 (s, 1H), 6.78 (s, 1H), 6.60 (d, J = 9.2 Hz, 1H), 4.13 (d, J = 4.4 Hz, 2H), 3.68 (s, 3H), 3.57 (s, 3H).

[0220] Example 13. Preparation of N-(2-((4-(3-(2-((2-(dimethylamino)-2-oxoethyl)(methyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 13) [ka] 1-Methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (75 mg, 141.40 μmol) and 2-[( To a mixture of [4-bromo-2-pyridyl)-methyl-amino]-N,N-dimethylacetamide (38.48 mg, 141.40 μmol), EtN (42.92 mg, 424.19 μmol, 59.04 μL) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.22 mg, 14.14 μmol) were added under N at 30 °C. The reaction mixture was heated to 70 °C and stirred at 70 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (neutral conditions) to give compound 13 (39.01 mg, 64.90 μmol, 45.90% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 596.2. 1 H NMR (400 MHz, DMSO-d 67) δ 12.41 (br s, 1H), 8.73-8.61 (m, 1H), 8.21 (s, 1H), 8.12 (d, J=5.2 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.85 (s, 1H), 7.80 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.61-7.52 (m, 1H), 7.36-7.27 (m, 1H), 6.92-6.83 (m, 2H), 6.79-6.77 (m, 1H), 4.51 (s, 2H), 4.15 (d, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.12-3.00 (m, 6H), 2.81 (s, 3H).

[0221] Example 14. Preparation of 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylic acid (Compound 14) [ka] Step 1: Preparation of tert-butyl 2-(4-bromopyridin-2-yl)acetate (Intermediate B) [ka] To a solution of 4-bromo-2-methyl-pyridine (1.4 g, 8.14 mmol) in THF (20 mL) was added LDA (2 M, 4.88 mL) dropwise at −70° C. After the addition, the mixture was stirred at this temperature for 1 h. Then, BocO (1.95 g, 8.95 mmol, 2.06 mL) was added dropwise at −70° C. The resulting mixture was stirred at 25° C. for 11 h. The reaction mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over NaO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give intermediate B (500 mg, 1.84 mmol, 22.58% yield) as a yellow oil.1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 5.4 Hz, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 1.8, 5.4 Hz, 1H), 3.74 (s, 2H), 1.47 (s, 9H).

[0222] Step 2: Preparation of tert-butyl 1-(4-bromopyridin-2-yl)cyclopropanecarboxylate (Intermediate D) [ka] To a solution of intermediate B (450 mg, 1.65 mmol) in DMF (5 mL) was added NaH (198.43 mg, 4.96 mmol, 60% purity) at 25 °C. After the addition, the mixture was stirred at this temperature for 1 h, and then 1,2-dibromoethane (621.28 mg, 3.31 mmol, 249.51 μL) was added dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give intermediate D (400 mg, 1.34 mmol, 81.13% yield) as a yellow oil. LCMS (ESI) m / z [M+H-56] + = 242.0.

[0223] Step 3: Preparation of tert-butyl 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylate (Intermediate F) [ka] A mixture of Intermediate D (200 mg, 670.75 μmol), 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (391.36 mg, 737.83 μmol), KPO (427.14 mg, 2.01 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (43.72 mg, 67.08 μmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N three times, then the mixture was stirred at 80° C. under a N atmosphere for 12 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with NaCl (10 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give intermediate F (200 mg, 321.69 μmol, 47.96% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 622.4.

[0224] Step 4: Preparation of 1-(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)cyclopropanecarboxylic acid (compound 14) [ka] A mixture of intermediate F (100 mg, 160.84 μmol), TFA (183.39 mg, 1.61 mmol, 119.09 μL) in DCM (1 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25 °C for 1 h. The mixture was concentrated to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give compound 14 (43 mg, 76.02 μmol, 47.27% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 566.4;1 H NMR (400 MHz, DMSO-d6) δ 12.66-12.27 (m, 1H), 8.72-8.70 (m, 1H), 8.57 (d, J = 5.4 Hz, 1H), 8.28 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.88-7.83 (m, 3H), 7.76 (d, J = 8.2 Hz, 1H), 7.65-7.57 (m, 2H), 7.32 (dd, J = 2.4, 3.4 Hz, 1H), 6.78 (dd, J= 1.6, 3.4 Hz, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.58 (s, 3H), 1.61-1.46 (m, 4H).

[0225] Example 15. Preparation of 2-(methyl(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)amino)acetic acid (Compound 15) and N-(2-((4-(3-(2-(methyl(2-(methylamino)-2-oxoethyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 16) [ka] Step 1: Preparation of 2-(methyl(4-(3-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)amino)acetic acid (Compound 15) [ka] A solution of 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (100 mg, 188.53 μmol) and 2-[ To a mixture of [(4-bromo-2-pyridyl)-methyl-amino]-N-methylacetamide (48.66 mg, 188.53 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.29 mg, 18.85 μmol) and EtN (57.23 mg, 565.59 μmol, 78.72 μL) were added under N at 30 °C. The reaction mixture was heated to 70 °C and stirred at 70 °C for 2 h under N. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (FA conditions) to give compound 15 (60 mg, 97.62 μmol, 51.78% yield, FA salt) as a green solid. This product was a hydrolysis by-product. LCMS (ESI) m / z [M+H] + = 569.1; 1 H NMR (400 MHz, DMSO-d6) δ 8.70-8.67 (m, 1H), 8.22 (s, 1H), 8.15 (d, J=5.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.88-7.80 (m, 2H), 7.69 (d, J=7.6 Hz, 1H), 7.60-7.54 (m, 1H), 7.35-7.30 (m, 1H), 6.97-6.85 (m, 2H), 6.79-6.77 (m, 1H), 4.29 (s, 2H), 4.15 (d, J=6.0 Hz, 2H), 3.57 (s, 3H), 3.21-3.06 (m, 2H).

[0226] Step 2: Preparation of N-(2-((4-(3-(2-(methyl(2-(methylamino)-2-oxoethyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 16) [ka] To a mixture of compound 101 (60 mg, 97.62 μmol, FA salt) in DMF (1 mL) was added EDCI (28.07 mg, 146.43 μmol), HOBt (19.78 mg, 146.43 μmol), DIPEA (63.08 mg, 488.10 μmol, 85.01 μL), and methanamine (31.84 mg, 471.58 μmol, 35.78 μL, HCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 14 h. The reaction mixture was filtered to give a black solution. The black solution was purified by reverse-phase column chromatography (neutral conditions) to give compound 16 (26.92 mg, 44.88 μmol, 45.97% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 582.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.69-8.66 (m, 1H), 8.21 (s, 1H), 8.15 (d, J=5.6 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.86-7.84 (m, 1H), 7.79 (s, 1H), 7.78-7.73 (m, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.33-7.31 (m, 1H), 6.95-6.92 (m, 1H), 6.87 (s, 1H), 6.79-6.77 (m, 1H), 4.20 (s, 2H), 4.16 (d, J=6.0 Hz, 2H), 3.57 (s, 3H), 3.13 (s, 3H), 2.60 (d, J=4.8 Hz, 3H).

[0227] Example 16. Preparation of N-(2-((4-(3-(2-((dimethylamino)methyl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 17) [ka] To a solution of 4-bromo-2-methyl-1H-imidazole (30 mg, 186.34 μmol) and 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (98.84 mg, 186.34 μmol) in dioxane (2 mL) / HO (0.2 mL) was added KPO (118.66 mg, 559.01 μmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.14 mg, 18.63 μmol) under N. The mixture was stirred at 100° C. for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (12 mL × 3). The combined organic layers were washed with brine (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 22%-52%) and lyophilized to give compound 17 (11.21 mg, 22.90 μmol, 12.29% yield) as a gray solid. LCMS (ESI) m / z [M+H] + = 485.0; 1 H NMR (400 MHz, methanol-d₄) δ 8.22–8.21 (m, 1H), 8.01–7.99 (m, 1H), 7.83–7.82 (m, 1H), 7.78 (s, 1H), 7.63–7.60 (m, 1H), 7.56–7.51 (m, 2H), 7.28–7.26 (m, 1H), 6.81–6.79 (m, 1H), 4.25 (s, 2H), 3.37 (s, 3H), 2.70 (s, 3H).

[0228] Example 17. Preparation of N-(2-((4-(3-(1-methyl-1H-imidazol-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 18) [ka] 4-Bromo-1-methyl-imidazole (36.42 mg, 226.23 μmol), 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (Example 1) in dioxane (2 mL) and HO (0.5 mL). A mixture of [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (100 mg, 188.53 μmol), KPO (120.05 mg, 565.59 μmol), and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (24.57 mg, 37.71 μmol) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 80 °C for 12 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.075% TFA)-acetonitrile]; B%: 12%-42%) and lyophilized to give compound 18 (18.25 mg, 30.49 μmol, 16.17% yield, TFA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 485.1; 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 9.05 (s, 1H), 8.69-8.68 (m, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.85-7.84 (m, 1H), 7.71-7.68 (m, 2H), 7.60-7.56 (m, 1H), 7.32-7.31 (m, 1H), 6.78-6.76 (m, 1H), 4.15 (d, J=5.6 Hz, 2H), 3.90 (s, 3H), 3.57 (s, 3H).

[0229] Example 18. Preparation of N-(2-((4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 19) [ka] Step 1: Preparation of 1-(4-bromopyridin-2-yl)-4-methylpiperazine (Intermediate C) [ka] To a solution of 4-bromo-2-fluoropyridine (500 mg, 2.84 mmol) and 1-methylpiperazine (313.03 mg, 3.13 mmol, 346.66 μL) in DMSO (5 mL) was added DIPEA (1.10 g, 8.52 mmol, 1.48 mL), and the mixture was stirred at 130° C. for 2 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and the filtrate was evaporated to dryness to give Intermediate C (720 mg, crude) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ 7.93 (d, J=5.6 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 6.83-6.81 (m, 1H), 3.56-3.54 (m, 4H), 2.56-2.49 (m, 4H), 2.33 (s, 3H). LCMS (ESI) m / z [M+H] + = 258.0.

[0230] Step 2: Preparation of N-(2-((4-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 19) [ka] 1-(Methylsulfonyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (prepared according to the method in Example 1) (60 mg, 113.12 μmol), Intermediate C (86.92 mg, 339.35 μmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14.74 mg, 22.62 μmol) and KPO (96.05 mg, 452.47 μmol) were added to dioxane (1.5 mL) and HO (0.3 mL), and the mixture was purged with N three times, then stirred at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 8%-38%) and lyophilized to give compound 19 (33.80 mg, 48.72 μmol, 43.07% yield, TFA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 580.2; 1H NMR (400 MHz, methanol-d4) δ 8.25-8.24 (m, 2H), 8.01 (d, J=8.0 Hz, 1H), 7.84-7.83 (m, 1H), 7.68-7.66 (m, 1H), 7.56-7.52 (m, 2H), 7.29-7.28 (m, 2H), 7.20-7.18 (m, 1H), 6.82-6.80 (m, 1H), 4.26 (s, 2H), 3.86-3.34 (m, 11H), 2.98 (s, 3H).

[0231] Example 19. Preparation of N-(2-((4-(3-(2-((2-(dimethylamino)ethyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 20) [ka] Step 1: Preparation of N1-(4-bromopyridin-2-yl)-N2,N2-dimethylethane-1,2-diamine (Intermediate C) [ka] A solution of 4-bromo-2-fluoro-pyridine (1 g, 5.68 mmol) and N',N'-dimethylethane-1,2-diamine (525.94 mg, 5.97 mmol, 651.72 μL) in NMP (5 mL) was stirred at 80 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water (5 mL × 3) and brine (5 mL × 2), then dried over Na2SO4, filtered, and concentrated in vacuo to give Intermediate C (1.2 g, 4.92 mmol, 86.50% yield) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z [M+H] + = 246.2.

[0232] Step 2: Preparation of N-(2-((4-(3-(2-((2-(dimethylamino)ethyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 20) [ka] To a solution of Intermediate C (60 mg, 245.77 μmol), 1-methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (108.64 mg, 204.81 μmol), and KPO (130.42 mg, 614.43 μmol) in dioxane (3 mL) and water (0.5 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (26.70 mg, 40.96 μmol). The mixture was stirred at 90° C. for 2 hours. The reaction mixture was passed through a silica pad, and the pad was washed with EtOAc (30 mL), MeOH (30 mL), and DMF (2 mL). The combined organic layers were washed with water (5 mL × 3) and brine (5 mL × 2), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions) and lyophilized to give compound 20 (40 mg, 64.98 μmol, 31.73% yield, FA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 568.2; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 1H), 8.70-8.67 (m, 1H), 8.21-8.17 (m, 2H), 8.07 (d, J = 5.4 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.86-7.85 (m, 1H), 7.78 (s, 1H), 7.64-7.52 (m, 2H), 7.32-7.30 (m, 1H), 6.86-6.80 (m, 2H), 6.79-6.77 (m, 1H), 6.53-6.42 (m, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.58 (s, 3H), 3.43 (br d, J = 5.8 Hz, 2H), 2.58-2.54 (m, 2H), 2.29 (s, 6H).

[0233] Example 20. Preparation of N-(2-((4-(3-(2-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 21) [ka] Step 1: Preparation of N-(2-((4-(3-(2-((2-(dimethylamino)ethyl)(methyl)amino)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 21) [ka] 1-Methylsulfonyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (100 mg, 188.53 μmol) and N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 1) (100 mg, 188.53 μmol) in dioxane (2 mL) and HO (0.5 mL). To a mixture of '-(4-bromo-2-pyridyl)-N,N,N'-trimethyl-ethane-1,2-diamine (40.56 mg, 157.11 μmol), KPO (100.05 mg, 471.33 μmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (10.24 mg, 15.71 μmol) was added at 30 °C. The reaction mixture was heated to 75 °C and stirred at 75 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 25%-55%) and lyophilized to give compound 21 (47.01 mg, 73.26 μmol, 46.63% yield, FA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 582.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (br s, 1H), 8.70-8.67 (m, 1H), 8.21 (s, 2H), 8.17 (d, J=5.2 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.86-7.85 (m, 1H), 7.79 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.61-7.52 (m, 1H), 7.33-7.31 (m, 1H), 6.89-6.87 (m, 1H), 6.83 (s, 1H), 6.79-6.77 (m, 1H), 4.16 (d, J=5.6 Hz, 2H), 3.75-3.71 (m, 2H), 3.57 (s, 3H), 3.09 (s, 3H), 2.54 (s, 2H), 2.27 (s, 6H).

[0234] Example 21. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(6-methylpyrimidin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 22) [ka] Step 1: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(6-methylpyrimidin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 22) [ka] 1-tert-butyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 8) (100 mg, 196.68 μmol), 4-bromo A mixture of 2-methyl-6-pyrimidine (51.04 mg, 295.02 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.82 mg, 19.67 μmol), and KPO (125.25 mg, 590.04 μmol) was degassed and purged with N three times, then the mixture was stirred under N at 100 °C for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered through silica gel, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (5 mL) at 20 °C for 10 min. The mixture was then filtered and washed with MTBE (3 mL) to give a brown solid. The solid was then dissolved in HO / CHCN (4:1, 30 mL) and then lyophilized to give compound 22 (67.24 mg, 138.96 μmol, 70.65% yield) as a brown solid. LCMS (ESI) m / z [M+H] += 475.3; 1 H NMR (400 MHz, methanol-d4) δ 9.05 (d, J = 0.8 Hz, 1H), 8.69 (s, 1H), 8.08-8.06 (m, 2H), 7.95 (s, 1H), 7.58-7.54 (m, 3H), 6.96-6.94 (m, 1H), 6.58-6.57 (m, 1H), 4.24 (s, 2H), 2.61 (s, 3H), 1.56 (s, 9H) ppm.

[0235] Example 22. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(2-methylpyrimidin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 23) [ka] Step 1: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(2-methylpyrimidin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 23) [ka] A mixture of 1-tert-butyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 8) (50 mg, 98.34 μmol), 4-bromo-2-methyl-pyrimidine (25.52 mg, 147.51 μmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.41 mg, 9.83 μmol), KPO (62.62 mg, 295.02 μmol) in dioxane (1 mL) and HO (0.2 mL) was degassed and purged with N three times, then the mixture was stirred at 100 °C under N atmosphere for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were washed with brine (3 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (3 mL) at 20 °C for 10 min. The mixture was then filtered and washed with MTBE (3 mL) to give a yellow solid. The solid was dissolved in HO / CHCN (4:1, 30 mL) and then lyophilized to give compound 23 (20.96 mg, 44.17 μmol, 44.91% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 475.3; 1 H NMR (400 MHz, methanol-d4) δ 8.73-8.70 (m, 2H), 8.08 (d, J = 7.6 Hz, 2H), 7.84 (d, J = 5.2 Hz, 1H), 7.59-7.55 (m, 3H), 6.96-6.95 (m, 1H), 6.58-6.57 (m, 1H), 4.24 (s, 2H), 2.76 (s, 3H), 1.57 (s, 9H).

[0236] Example 23. Preparation of N-(2-((4-(3-(2-(aminomethyl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide (Compound 24) [ka] Step 1: Preparation of tert-butyl ((4-bromopyridin-2-yl)methyl)carbamate (Intermediate G) [ka] A mixture of (4-bromo-2-pyridyl)methanamine (200 mg, 894.86 μmol, HCl salt), BocO (234.36 mg, 1.07 mmol, 246.70 μL), and TEA (271.65 mg, 2.68 mmol, 373.66 μL) in DCM (3 mL) was stirred at 25 °C for 4 h. The reaction was diluted with water (5 mL), extracted with DCM (2 mL × 3), and the combined organic layers were concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% FA condition) and lyophilized to give intermediate G (150 mg, 475.36 μmol, 53.12% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 289.0.

[0237] Step 2: Preparation of tert-butyl ((4-(3-(2-(2-(1-(tert-butyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)phenyl)pyridin-2-yl)methyl)carbamate (Intermediate I) [ka] A mixture of 1-(tert-butyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide [prepared according to the method in 8] (50 mg, 98.34 μmol), Intermediate G (33.89 mg, 118.01 μmol), KPO (62.62 mg, 295.02 μmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.41 mg, 9.83 μmol) in dioxane (0.5 mL) and HO (0.25 mL) was degassed and purged with N three times, then the mixture was stirred at 80 °C under N atmosphere for 14 h. The reaction was diluted with water (5 mL) and filtered to give a solid. The solid was dissolved in DMSO (1 mL), purified by reverse-phase HPLC (0.1% FA condition), and lyophilized to give Intermediate I (15 mg, 22.17 μmol, 22.54% yield) as a yellow oil. LCMS (ESI) m / z [M+H] + =589.2.

[0238] Step 3: Preparation of N-(2-((4-(3-(2-(aminomethyl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(tert-butyl)-1H-pyrrole-3-carboxamide (compound 24) [ka] To a solution of intermediate I (15 mg, 22.17 μmol) in MeOH (0.1 mL) was added HCl / dioxane (0.2 mL). The mixture was stirred at 25° C. for 6 h. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse-phase HPLC (0.1% FA condition) and lyophilized to give compound 24 (1.65 mg, 2.90 μmol, 13.07% yield, FA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + =489.1. 1H NMR (400 MHz, methanol-d₄) δ 8.61–8.59 (m, 1H), 8.19 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H), 7.66–7.59 (m, 2H), 7.48–7.43 (m, 3H), 6.87–6.85 (m, 1H), 6.48–6.47 (m, 1H), 4.26 (s, 2H), 4.14 (s, 2H), 1.46 (s, 9H).

[0239] Example 24. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 25) [ka] Step 1: Preparation of 3-bromo-1-(2-methoxy-2-methylpropyl)-1H-pyrazole (Intermediate B) [ka] To a mixture of 1-(3-bromopyrazol-1-yl)-2-methyl-propan-2-ol (200 mg, 912.91 μmol) and MeI (259.15 mg, 1.83 mmol, 113.66 μL) in DMF (2 mL) was added NaH (43.82 mg, 1.10 mmol, 60% purity) in portions at 0 °C. The reaction mixture was warmed to 25 °C and stirred at 25 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (5 mL) and extracted with EtOAc (5 mL × 3). The organic phase was washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column chromatography (FA conditions) and lyophilized to give intermediate B (90 mg, 386.09 μmol, 42.29% yield) as a yellow oil. LCMS (ESI) m / z [M+H]+ = 233.9. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 2.4 Hz, 1H), 6.28 (d, J = 2.0 Hz, 1H), 4.10 (s, 2H), 3.25 (s, 3H), 1.16 (s, 6H).

[0240] Step 2: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-(2-methoxy-2-methylpropyl)-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 25) [ka] To a mixture of Intermediate B (22.92 mg, 98.34 μmol) and 1-(tert-butyl)-N-(2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide [prepared according to the method in 8] (50 mg, 98.34 μmol) in dioxane (0.8 mL) and HO (0.2 mL) was added KPO (62.62 mg, 295.02 μmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.41 mg, 9.83 μmol) under N at 25° C. The reaction mixture was heated to 75° C. and stirred at 75° C. for 2 h. The reaction mixture was poured into HO (2 mL) and extracted with EtOAc (2 mL × 5). The combined organic phase was dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE / EtOAc = 3 / 1 - EtOAc) (TLC: EtOAc, Rf = 0.7) to give a yellow solid. The yellow solid was purified by reverse-phase column (FA conditions) and lyophilized to give compound 25 (3.51 mg, 6.04 μmol, 6.15% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 535.2; 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.34 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.59-7.58 (m, 1H), 7.47-7.39 (m, 2H), 6.96-6.94 (m, 1H), 6.68 (d, J = 2.0 Hz, 1H), 6.58-6.57 (m, 1H), 4.24 (s, 2H), 4.21 (s, 2H), 3.30 (br s, 3H), 1.57 (s, 9H), 1.19 (s, 6H).

[0241] Example 25. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 26) [ka] Step 1: Preparation of methyl 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (Intermediate B) [ka] To a solution of methyl 3-bromo-1H-pyrazole-5-carboxylate (500 mg, 2.44 mmol) and MeI (1.73 g, 12.19 mmol, 759.16 μL) in DMF (5 mL) was added KCO (505.61 mg, 3.66 mmol), and the mixture was stirred at 60 °C for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 3 / 1 to 1:1) and concentrated to give intermediate B (330 mg, 1.51 mmol, 61.77% yield) as a white solid. LCMS (ESI) m / z [M+H] + =220.8; 1 H NMR (400 MHz, DMSO-d6) δ 6.99 (s, 1H), 4.06 (s, 3H), 3.84 (s, 3H).

[0242] Step 2: Preparation of (3-bromo-1-methyl-1H-pyrazol-5-yl)methanol (Intermediate C) [ka] A solution of Intermediate B (320 mg, 1.46 mmol) in THF (2 mL) was added to a solution of LiAlH (110.90 mg, 2.92 mmol) in THF (4 mL) at 0 °C, and the mixture was then warmed to 30 °C and stirred at 30 °C for 1 h. The reaction mixture was quenched at 0 °C with 10 mL of EtOAc and then diluted with water (0.11 mL), 15% NaOH solution (0.11 mL), water (0.4 mL), and 2 g of NaSO, followed by filtration. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 3:1 to 2:1) and concentrated under reduced pressure to give Intermediate C (110 mg, 575.84 μmol, 39.42% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 191.1; 1H NMR (400 MHz, DMSO-d6) δ 6.26 (s, 1H), 5.37-5.34 (m, 1H), 4.45 (d, J = 5.6 Hz, 2H), 3.74 (s, 3H).

[0243] Step 3: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 26) [ka] To a solution of 1-tert-butyl-N-[2-oxo-2-[[4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (prepared according to the method in Example 8) (100 mg, 196.68 μmol), Intermediate C (45.09 mg, 236.02 μmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.82 mg, 19.67 μmol) in dioxane (1 mL) and water (0.25 mL) was added KPO (125.25 mg, 590.04 μmol) under N and the mixture was stirred at 80° C. for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 0:1) (PE / EtOAc = 0:1, Rf = 0.6) and concentrated under reduced pressure to give compound 26 (23.60 mg, 47.29 μmol, 24.04% yield) as a white solid. LCMS (ESI) m / z [M+H] + =493.4; 1H NMR (400 MHz, methanol-d₄) δ 8.31–8.30 (m, 1H), 7.84–7.82 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.59–7.58 (m, 1H), 7.43–7.39 (m, 2H), 6.96–6.94 (m, 1H), 6.64 (s, 1H), 6.58–6.57 (m, 1H), 4.67 (s, 2H), 4.24 (s, 2H), 3.93 (s, 3H), 1.56 (s, 9H).

[0244] Example 26. Preparation of 1-(1-methoxy-2-methylpropan-2-yl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 27) [ka] Step 1: Preparation of tert-butyl 1-(1-methoxy-2-methyl-1-oxopropan-2-yl)-1H-pyrrole-3-carboxylate (Intermediate B) [ka] To a solution of tert-butyl 1-(2-methoxy-2-oxo-ethyl)pyrrole-3-carboxylate (500 mg, 2.09 mmol), MeI (1.19 g, 8.36 mmol, 520.38 μL) in THF (5 mL) was added NaHMDS (1 M, 10.45 mL) at 0 °C. After the addition, the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with NaCl (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give Intermediate B (440 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H-56] + = 212.1.

[0245] Step 2: Preparation of 2-(3-(tert-butoxycarbonyl)-1H-pyrrol-1-yl)-2-methylpropanoic acid (Intermediate C) [ka] To a solution of intermediate B (400 mg, 1.50 mmol) in HO (2 mL) and MeOH (6 mL) was added NaOH (119.71 mg, 2.99 mmol). The mixture was stirred at 25 °C for 12 h. The residue was purified by reverse phase (FA conditions) and lyophilized to give intermediate C (224 mg, 809.27 μmol, 54.08% yield) as a pale yellow oil. LCMS (ESI) m / z [M+H-56] + = 198.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.19-13.08 (m, 1H), 7.38-7.36 (m, 1H), 6.93-6.91 (m, 1H), 6.35-6.34 (m, 1H), 1.71 (s, 6H), 1.48 (s, 9H).

[0246] Step 3: Preparation of tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylate (Intermediate E) [ka] To a solution of intermediate C (200 mg, 789.60 μmol), EtN (119.85 mg, 1.18 mmol, 164.85 μL) in THF (2 mL) was added isobutyl chloroformate (129.41 mg, 947.52 μmol, 124.43 μL) at 0 °C. After the addition, the mixture was stirred at this temperature for 1 h, and then NaBH (268.83 mg, 7.11 mmol) in MeOH (0.4 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA conditions) and lyophilized to give Intermediate E (170 mg, 710.38 μmol, 89.97% yield) as a white solid. LCMS (ESI) m / z [M+H-56] + = 184.1. 1 H NMR (400 MHz, DMSO-d6) δ 7.37-7.35 (m, 1H), 6.96-6.90 (m, 1H), 6.31 (dd, J = 1.8, 3.0 Hz, 1H), 5.06-5.53 (m, 1H), 3.48 (d, J = 5.4 Hz, 2H), 1.48 (s, 9H), 1.42 (s, 6H).

[0247] Step 4: Preparation of tert-butyl 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylate (Intermediate F) [ka] To a solution of intermediate E (90 mg, 376.08 μmol) in THF (1 mL) was added MeI (106.76 mg, 752.16 μmol, 46.83 μL) at 25° C., followed by NaH (30.09 mg, 752.16 μmol, 60% purity) at 0° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched by the addition of water (3 mL) and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate F (130 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H-56] + = 198.1. 1 H NMR (400 MHz, CDCl3) δ 7.36-7.29 (m, 1H), 6.71-6.70 (m, 1H), 6.45 (dd, J = 1.8, 3.0 Hz, 1H), 3.35 (s, 2H), 3.21 (s, 3H), 1.49-1.43 (m, 15H).

[0248] Step 5: Preparation of 1-(1-methoxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylic acid (Intermediate G) [ka] A solution of intermediate F (130 mg, 513.15 μmol) in HCl / dioxane (4 M, 1.28 mL) was stirred at 25° C. for 2 h. The mixture was concentrated in vacuo to give intermediate G (50 mg, crude) as a yellow oil, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 198.1.

[0249] Step 6: Preparation of 1-(1-methoxy-2-methylpropan-2-yl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 27) [ka] A mixture of intermediate G (50 mg, 253.51 μmol), 2-amino-N-[4-[3-(1-methylpyrazol-3-yl)phenyl]thiazol-2-yl]acetamide (prepared according to the method in Example 2) (119.17 mg, 340.63 μmol, HCl salt), DIEA (163.82 mg, 1.27 mmol, 220.78 μL), EDCI (97.20 mg, 507.02 μmol), and HOBt (68.51 mg, 507.02 μmol) in DMF (2 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25° C. for 1 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (3 mL × 2). The combined organic layers were washed with brine (3 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (TFA conditions) and lyophilized to give compound 27 (11 mg, 21.88 μmol, 8.63% yield, TFA salt) as a brown oil. LCMS (ESI) m / z [M+H] + = 493.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.38 (s, 1H), 8.21-8.20 (m, 1H), 7.85-7.64 (m, 4H), 7.53-7.40 (m, 2H), 6.95-6.94 (m, 1H), 6.73 (d, J = 2.2 Hz, 1H), 6.51-6.44 (m, 1H), 4.10 (br d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.22-3.20 (m, 3H), 1.48-1.43 (m, 6H).

[0250] Example 27. Preparation of 1-(2-hydroxy-2-methylpropyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 28) [ka] Step 1: Preparation of 1-(2-hydroxy-2-methylpropyl)-1H-pyrrole-3-carboxylic acid (Intermediate C) [ka] To a solution of tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylate [prepared as described in Example 26] (50 mg, 208.93 μmol) in dioxane (0.5 mL) was added HCl / dioxane (4 M, 522.34 μL), and the mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give Intermediate C (23 mg, crude) as a brown solid. LCMS (ESI) m / z [M+H] + = 184.1.

[0251] Step 2: Preparation of 1-(2-hydroxy-2-methylpropyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 28) [ka] A mixture of intermediate C (20 mg, 109.17 μmol), 2-amino-N-[4-[3-(1-methylpyrazol-3-yl)phenyl]thiazol-2-yl]acetamide (prepared according to the method in Example 2) (51.32 mg, 146.69 μmol, HCl salt), DIEA (42.33 mg, 327.50 μmol, 57.05 μL), HOBt (29.50 mg, 218.34 μmol), and EDCI (41.86 mg, 218.34 μmol) in DMF (1 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified via preparative HPLC (FA conditions) and lyophilized to give compound 28 (8 mg, 15.74 μmol, 14.42% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 479.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.81-11.85 (m, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 8.20-8.18 (m, 1H), 7.84-7.67 (m, 4H), 7.46-7.44 (m, 1H), 7.32 (s, 1H), 6.76-6.71 (m, 2H), 6.48-6.44 (m, 1H), 4.66 (br s, 1H), 4.10 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 2H), 1.06 (s, 6H).

[0252] Example 28. Preparation of 1-(2-methoxy-2-methylpropyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 29) [ka] Step 1: Preparation of tert-butyl 1-(2-hydroxy-2-methylpropyl)-1H-pyrrole-3-carboxylate (Intermediate D) [ka] To a solution of tert-butyl 1-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate (500 mg, 2.09 mmol) [prepared according to the method described in Example 27] in THF (3 mL) was added MeMgBr (3 M, 2.79 mL) at 0 °C. After the addition, the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched with NH4Cl (3 mL) and then extracted with EtOAc (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient eluent at 40 mL / min) and concentrated to give intermediate D (202 mg, 774.62 μmol, 37.07% yield) as a pale yellow solid. LCMS (ESI) m / z [M+H-56] + = 184.1.

[0253] Step 2: Preparation of tert-butyl 1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxylate (Intermediate E) [ka] To a solution of intermediate D (50 mg, 208.93 μmol) in DMF (1 mL) was added NaH (16.71 mg, 417.87 μmol, 60% purity) at 0° C. After the addition, the mixture was stirred at this temperature for 1 h, and then MeI (44.48 mg, 313.40 μmol, 19.51 μL) was added at 0° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched by the addition of water (2 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give intermediate E (50 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+H-56] + =198.1.

[0254] Step 3: Preparation of 1-(2-methoxy-2-methylpropyl)-1H-pyrrole-3-carboxylic acid (Intermediate F) [ka] A mixture of intermediate E (50 mg, 132.24 μmol) in HCl / dioxane (4 M, 330.59 μL) was stirred at 25° C. for 12 h. The mixture was concentrated in vacuo to give intermediate F (40 mg, crude) as a yellow oil. LCMS (ESI) m / z [M+H] + =198.1.

[0255] Step 4: Preparation of 1-(2-methoxy-2-methylpropyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 29) [ka] A mixture of Intermediate F (40 mg, 202.81 μmol), 2-amino-N-[4-[3-(1-methylpyrazol-3-yl)phenyl]thiazol-2-yl]acetamide (prepared according to the method in Example 2) (127.11 mg, 363.34 μmol, HCl salt), EDCI (77.76 mg, 405.62 μmol), HOBt (54.81 mg, 405.62 μmol), and DIEA (131.06 mg, 1.01 mmol, 176.62 μL) in DMF (1 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 1 h. The reaction mixture was quenched by the addition of water (2 mL) and extracted with EtOAc (1 mL × 3). The combined organic layers were washed with brine (3 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give compound 29 (12 mg, 24.12 μmol, 11.89% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =493.4. 1H NMR (400 MHz, DMSO-d6) δ 12.53-12.25 (m, 1H), 8.39 (s, 1H), 8.22-8.20 (m, 1H), 7.83-7.68 (m, 4H), 7.46-7.44 (m, 1H), 7.29-7.27 (m, 1H), 6.79-6.70 (m, 2H), 6.51-6.39 (m, 1H), 4.10 (br d, J = 5.8 Hz, 2H), 3.91 (s, 5H), 3.17 (s, 3H), 1.06 (s, 6H).

[0256] Example 29. Preparation of 1-(1-hydroxy-2-methylpropan-2-yl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 30) [ka] Step 1: Preparation of 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylic acid (Intermediate H) [ka] A mixture of tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrrole-3-carboxylate [prepared according to the method described in Example 26] (70 mg, 292.51 μmol) and HCl / dioxane (4 M, 731.27 μL) was degassed, and then the mixture was stirred under a N atmosphere at 25° C. for 12 hours. The mixture was concentrated in vacuo to give Intermediate H (50 mg, crude) as a yellow oil. LCMS (ESI) m / z [M+H] + = 184.1.

[0257] Step 2: Preparation of 1-(1-hydroxy-2-methylpropan-2-yl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 30) [ka] A mixture of Intermediate H (50 mg, 272.92 μmol), 2-amino-N-[4-[3-(1-methylpyrazol-3-yl)phenyl]thiazol-2-yl]acetamide (prepared according to the method in Example 2) (128.29 mg, 409.38 μmol), DIEA (176.36 mg, 1.36 mmol, 237.68 μL), EDCI (104.64 mg, 545.84 μmol), and HOBt (73.75 mg, 545.84 μmol) in DMF (1 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 1 h. The reaction mixture was quenched by the addition of water (5 mL) and extracted with EtOAc (3 mL × 2). The combined organic layers were washed with brine (3 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA conditions) and lyophilized to give compound 30 (10 mg, 20.90 μmol, 7.66% yield) as a white solid. LCMS (ESI) m / z [M+H] + =479.3; 1 H NMR (400 MHz, DMSO-d6) δ 12.50-12.25 (m, 1H), 8.39 (s, 1H), 8.17-8.15 (m, 1H), 7.87-7.65 (m, 4H), 7.54-7.39 (m, 2H), 6.94-6.92 (m, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.51-6.42 (m, 1H), 5.08-5.06 (m, 1H), 4.10 (d, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.49 (d, J = 5.4 Hz, 2H), 1.44 (s, 6H).

[0258] Example 30. Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-methyl-1H-imidazole-5-carboxamide (Compound 31) [ka] Step 1: Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-methyl-1H-imidazole-5-carboxamide (compound 31) [ka] To a solution of 3-methylimidazole-4-carboxylic acid (24.41 mg, 193.56 μmol) in DCM (1 mL) were added HATU (88.32 mg, 232.28 μmol) and DIEA (125.09 mg, 967.87 μmol, 168.58 μL), and the mixture was stirred at 25° C. for 5 minutes. 2-Amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (50 mg, 169.63 μmol, HCl salt) was then added, and the mixture was stirred at 25° C. for 1 hour. A white solid formed, and the precipitate was collected by filtration. The solid was triturated with MeOH (2 mL), then filtered and dried in vacuo to give compound 31 (27.74 mg, 75.38 μmol, 44.44% yield) as a white solid. LCMS (ESI) m / z [M+H] + =367.0; 1 H NMR (400 MHz, DMSO-d6) δ 8.71-8.68 (m, 1H), 8.33-8.32 (m, 1H), 8.24-8.21 (m, 1H), 7.87 (s, 1H), 7.80-7.77 (m, 2H), 7.67-7.64 (m, 2H), 4.14 (d, J=6.0 Hz, 2H), 3.80 (s, 3H).

[0259] Example 31. Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (Compound 32) [ka] Step 1: Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide (compound 32) [ka] To a solution of 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (50 mg, 169.63 μmol, HCl salt) in DCM (3 mL) was added 2-methylpyrazole-3-carboxylic acid (21.39 mg, 169.63 μmol), HOBt (22.92 mg, 169.63 μmol), DIEA (65.77 mg, 508.89 μmol, 88.64 μL), and EDCI (39.02 mg, 203.56 μmol). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was concentrated to dryness to give a residue. The residue was triturated with MeOH (5 mL) at 25° C. for 30 minutes, filtered, and dried in vacuo to give compound 32 (22.07 mg, 59.42 μmol, 35.03% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 367.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (br s, 1H), 8.93-8.91 (m, 1H), 8.37-8.30 (m, 1H), 8.27-8.21 (m, 1H), 7.89 (s, 1H), 7.83-7.76 (m, 1H), 7.70-7.63 (m, 1H), 7.50 (d, J=2.0 Hz, 1H), 6.94 (d, J=2.0 Hz, 1H), 4.19-4.17 (m, 2H), 4.06 (s, 3H).

[0260] Example 32. Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 33) [ka] Step 1: Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 33) [ka] To a solution of 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid [prepared according to the method in Example 4] (21.97 mg, 116.14 μmol), EDCI (33.40 mg, 174.22 μmol), HOBt (23.54 mg, 174.22 μmol), and DIPEA (45.03 mg, 348.43 μmol, 60.69 μL) in DMF (0.5 mL) was added 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (30 mg, 116.14 μmol) at 25° C. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was poured into water (2 mL) and filtered to give the crude desired compound as a white solid. The residue was dissolved in DMSO (2 mL), purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 40%-70%), and lyophilized to give compound 33 (21.25 mg, 44.29 μmol, 38.14% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 430.0; 1H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 1H), 8.67 - 8.65 (m, 1H), 8.32 (s, 1H), 8.23 ​​(d, J=8.0 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.31 - 7.30 (m, 1H), 6.77 -6.76 (m, 1H), 4.14 (d, J=5.6 Hz, 2H), 3.57 (s, 3H).

[0261] Example 33. Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(2-cyanopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 34) [ka] Step 1: Preparation of tert-butyl 1-(cyanomethyl)-1H-pyrrole-3-carboxylate (Intermediate C) [ka] A mixture of tert-butyl 1H-pyrrole-3-carboxylate (500 mg, 2.99 mmol), 2-bromoacetonitrile (430.42 mg, 3.59 mmol, 239.12 μL), and benzyltributylammonium chloride (93.28 mg, 299.03 μmol) in THF (10 mL) was stirred at 0 °C under a N atmosphere, then NaH (179.42 mg, 4.49 mmol, 60% purity) was added, and the reaction mixture was warmed to 25 °C and stirred for an additional 2 h. The reaction mixture was poured into NH Cl (15 mL), extracted with EtOAc (15 mL × 2), and the combined organic layers were washed with brine (10 mL × mL × 2), then concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA), and the solution was extracted with EtOAc (15 mL x 2) and concentrated in vacuo to give Intermediate C (304 mg, 1.36 mmol, 45.35% yield) as a dark brown oil. LCMS (ESI) m / z [M+H-56] + =150.9; 1 H NMR (400 MHz, CDCl3) δ 7.29-7.28 (m, 1H), 6.68-6.67 (m, 1H), 6.63-6.62 (m, 1H), 4.82(s, 2H), 1.55 (s, 9H).

[0262] Step 2: Preparation of tert-butyl 1-(2-cyanopropan-2-yl)-1H-pyrrole-3-carboxylate (Intermediate D) [ka] To a solution of intermediate C (304 mg, 1.36 mmol) and MeI (769.93 mg, 5.42 mmol, 337.69 μL) in THF (8 mL) was added NaHMDS (1 M, 6.78 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched at 25 °C by the addition of NH Cl (25 mL) and then diluted with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with brine (15 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (0.1% FA), and the solution was then extracted with EtOAc (10 mL × 2). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give intermediate D (285 mg, 1.12 mmol, 82.52% yield) as a brown oil. LCMS (ESI) m / z [M+H-56] + = 178.9.

[0263] Step 3: Preparation of 1-(2-cyanopropan-2-yl)-1H-pyrrole-3-carboxylic acid (Intermediate E) [ka] Intermediate D (100 mg, 426.82 μmol) was dissolved in HCl / dioxane (4 M, 1 mL) and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give Intermediate E (76 mg, crude) as a brown oil, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 178.9.

[0264] Step 4: Preparation of N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(2-cyanopropan-2-yl)-1H-pyrrole-3-carboxamide (compound 34) [ka] To a solution of intermediate E (72.54 mg, 407.11 μmol), HATU (154.80 mg, 407.11 μmol), and DIEA (175.39 mg, 1.36 mmol, 236.37 μL) in DCM (2 mL) was added 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (80 mg, 271.41 μmol, HCl salt), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 46%-58%) and lyophilized to give compound 34 (12.28 mg, 29.05 μmol, 10.70% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 419.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.39-8.32 (m, 2H), 8.23-8.21 (m, 1H), 7.86 (s, 1H), 7.80-7.78 (m, 1H), 7.68-7.64 (m, 2H), 7.15-7.14 (m, 1H), 6.61-6.60 (m, 1H), 4.12 (d, J=6.0 Hz, 2H), 1.95 (s, 6H).

[0265] Example 34. Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 35) [ka] Step 1: Preparation of 1-(tert-butyl)-1H-pyrrole-3-carbaldehyde (Intermediate C) [ka] A solution of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (800 mg, 4.99 mmol, 707.96 μL) and 2-methylpropan-2-amine (365.30 mg, 4.99 mmol, 524.86 μL) in CHCOOH (25 mL) was stirred at 120 °C for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (10 mL × mL × 3). The combined organic layers were washed with water (5 mL × mL × 3) and brine (5 mL × mL × 2), then dried over NaSO, filtered, and concentrated in vacuo to give Intermediate C (800 mg, crude) as a yellow solid. LCMS (ESI) m / z [M+H] + = 152.0; 1 H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.39-7.38 (m, 1H), 6.80-6.79 (m, 1H), 6.57-6.56 (m, 1H), 1.49 (s, 9H).

[0266] Step 2: Preparation of 1-(tert-butyl)-1H-pyrrole-3-carboxylic acid (Intermediate D) [ka] KMnO4 (1.25 g, 7.94 mmol) was added dropwise to a cooled (0 °C) suspension of Intermediate C (800 mg, 5.29 mmol) in acetone (40 mL) and water (8 mL). Each small addition was performed after the purple color of the oxidant had disappeared. After the addition was complete, the mixture was stirred at 30 °C for 2 h. Excess potassium permanganate was quenched with 38% sodium bisulfite solution, and the solution was acidified with HCl (6 N) to pH = 4-5. The mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water (10 mL × 3) and brine (10 mL × 2), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash (FA conditions) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with water (10 mL x 3) and brine (10 mL x 2), then dried over Na2SO4, filtered and concentrated in vacuo to give Intermediate D (400 mg, crude) as a white solid. LCMS (ESI) m / z [M+H] + = 168.0; 1 H NMR (400 MHz, CDCl3) δ 7.53-7.42 (m, 1H), 6.77-6.71 (m, 1H), 6.56-6.55 (m, 1H), 1.48 (s, 9H).

[0267] Step 3: Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 35) [ka] To a solution of Intermediate D (34.04 mg, 203.56 μmol) in DCM (3 mL) was added HATU (96.75 mg, 254.44 μmol) and DIEA (65.77 mg, 508.89 μmol, 88.64 μL). Then, 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (50 mg, 169.63 μmol, HCl salt) was added. The mixture was stirred at 30° C. for 2 hours. The mixture was diluted with DCM (30 mL), washed with water (5 mL×3) and brine (5 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 25%-55%) and lyophilized to give compound 35 (6 mg, 14.72 μmol, 8.68% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 408.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (br s, 1H), 8.33 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.70-7.63 (m, 1H), 7.52-7.51 (m, 1H), 6.98-6.96 (m, 1H), 6.48-6.47 (m, 1H), 4.10 (d, J = 5.6 Hz, 2H), 3.29 (s, 2H), 1.50 (s, 9H).

[0268] Example 35. Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrazole-3-carboxamide (Compound 36) [ka] Step 1: Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrazole-3-carboxamide (compound 36) [ka] To a solution of 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (50 mg, 169.63 μmol, HCl salt) and 1-tert-butylpyrazole-3-carboxylic acid (34.24 mg, 203.56 μmol) in DCM (2 mL) was added HATU (77.40 mg, 203.56 μmol) and DIEA (109.62 mg, 848.15 μmol, 147.73 μL), and the mixture was stirred at 30° C. for 16 h. The reaction mixture was poured into MeOH (2 mL), the solution was filtered to obtain a solid, and the solid was dried under vacuum to give compound 36 (15.63 mg, 37.81 μmol, 22.29% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 409.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.33-8.22 (m, 3H), 7.94 (d, J=2.4 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.68-7.65 (m, 1H), 6.65 (d, J=2.4 Hz, 1H), 4.19 (d, J=6.0 Hz, 2H), 1.58 (s, 9H).

[0269] Example 36. Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxamide (Compound 37) [ka] Step 1: Preparation of 1-(tert-butyl)-N-(2-((4-(3-cyanophenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxamide (compound 37) [ka] To a solution of 2-amino-N-[4-(3-cyanophenyl)thiazol-2-yl]acetamide (prepared according to the method in Example 3) (50 mg, 193.57 μmol) and 1-tert-butylpyrazole-4-carboxylic acid (39.07 mg, 232.29 μmol) in DCM (2 mL) was added HATU (88.32 mg, 232.29 μmol) and DIEA (125.09 mg, 967.87 μmol, 168.59 μL), and the mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 29%-59%) and lyophilized to give compound 37 (22.12 mg, 54.15 μmol, 27.98% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 409.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.50-8.48 (m, 1H), 8.32-8.31 (m, 2H), 8.23-8.21 (m, 1H), 7.88 (d, J=10.0 Hz, 2H), 7.79 (d, J=7.6 Hz, 1H), 7.67-7.64 (m, 1H), 4.14 (d, J=6.0 Hz, 2H), 1.53 (s, 9H).

[0270] Example 37. Preparation of 1-(2-aminoethyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 38) [ka] Step 1: Preparation of methyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylate (Intermediate C) [ka] To a solution of methyl 1H-pyrrole-3-carboxylate (300 mg, 2.40 mmol) in DMF (5 mL) was added CsCO (2.34 g, 7.19 mmol) under N at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. tert-Butyl (2-bromoethyl)carbamate (805.94 mg, 3.60 mmol) was then added, and the mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (FA conditions) and lyophilized to give intermediate C (420 mg, 1.55 mmol, 64.64% yield) as a yellow solid. 1 H NMR (400 MHz, methanol-d4) δ 7.34 (s, 1H), 6.70-6.69 (m, 1H), 6.49 (br s, 1H), 4.01-3.98 (m, 2H), 3.76 (s, 3H), 3.36-3.33 (m, 2H), 1.40 (s, 9H).

[0271] Step 2: Preparation of 1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-pyrrole-3-carboxylic acid (Intermediate D) [ka] To a solution of intermediate C (250 mg, 931.76 μmol) in MeOH (1 mL) was added aqueous NaOH (2 M, 559.06 μL), and the mixture was stirred at 30° C. for 1 h. 1.5 mL of aqueous HCl (1 M) and water (30.0 mL) were added, and the mixture was extracted with EtOAc (30.0 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and the filtrate was evaporated to dryness to give intermediate D (200 mg, 786.53 μmol, 84.41% yield) as a yellow oil, which was used directly for the next step. 1 H NMR (400 MHz, methanol-d4) δ 7.33 (s, 1H), 6.70-6.69 (m, 1H), 6.49 (br s, 1H), 4.01-3.98 (m, 2H), 3.36-3.33 (m, 2H), 1.41 (s, 9H).

[0272] Step 3: Preparation of tert-butyl (2-(3-((2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamoyl)-1H-pyrrol-1-yl)ethyl)carbamate (Intermediate F) [ka] To a mixture of Intermediate D (50 mg, 196.63 μmol) and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide (prepared according to the method in Example 4) (68.20 mg, 196.63 μmol, HCl salt) in DMF (2 mL) was added DIPEA (101.65 mg, 786.53 μmol, 137.00 μL). The mixture was stirred at 30° C. for 15 minutes, then EDCI (56.54 mg, 294.95 μmol) and HOBt (39.85 mg, 294.95 μmol) were added and stirred at 30° C. for 6 hours. The reaction solution was poured into HO (3 mL) and stirred for 5 minutes. The precipitate was collected by filtration, washed with MeOH (3 mL), and dried in vacuo to give Intermediate F (90 mg, 163.00 μmol, 82.89% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 547.2.

[0273] Step 4: Preparation of 1-(2-aminoethyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 38) [ka] To a mixture of intermediate F (40 mg, 73.17 μmol) in DCM (0.5 mL) was added TFA (166.87 mg, 1.46 mmol, 108.36 μL). The mixture was stirred at 30° C. for 0.5 h. The reaction mixture was evaporated to dryness. The residue was triturated with MTBE (5 mL) and stirred for 5 min. The precipitate was collected by filtration, washed with MTBE (5 mL), and dried in vacuo to give compound 38 (18.52 mg, 33.04 μmol, 45.15% yield, TFA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + =447.1; 1H NMR (400 MHz, methanol-d4) δ 8.85 (d, J=6.8 Hz, 2H), 8.48-8.47 (m, 1H), 8.36-8.34 (m, 2H), 8.18 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.69-7.65 (m, 1H), 7.62 (s, 1H), 7.43-7.42 (m, 1H), 6.86-6.85 (m, 1H), 6.67-6.66 (m, 1H), 4.29-4.26 (m, 4H), 3.39-3.35 (m, 2H).

[0274] Example 38. Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1-(piperidin-4-yl)-1H-pyrrole-3-carboxamide (Compound 39) [ka] Step 1: Preparation of tert-butyl 4-(3-(methoxycarbonyl)-1H-pyrrol-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate C) [ka] A mixture of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.47 g, 7.99 mmol), copper(II) acetate (870.95 mg, 4.80 mmol), 2-(2-pyridyl)pyridine (624.10 mg, 4.00 mmol), and Na2CO3 (847.07 mg, 7.99 mmol) in DMF (30 mL) was stirred at 80 °C for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with water (15 mL × 3) and brine (15 mL × 2), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, PE: EtOAc = 20:1 to 1:1) to give intermediate C (360 mg, 1.18 mmol, 29.41% yield) as a yellow oil. LCMS (ESI) m / z [M+H-56] + =251.1; 1 H NMR (400 MHz, CDCl3) δ 7.54-7.47 (m, 1H), 6.89-6.85 (m, 1H), 6.67-6.62 (m, 1H), 5.77 (br s, 1H), 4.09 (br d, J = 2.8 Hz, 2H), 3.83(s, 3H), 3.71-3.68 (m, 2H), 2.64-2.50 (m, 2H), 1.51 (s, 9H).

[0275] Step 2: Preparation of tert-butyl 4-(3-(methoxycarbonyl)-1H-pyrrol-1-yl)piperidine-1-carboxylate (Intermediate D) [ka] To a solution of intermediate C (300 mg, 979.25 μmol) in MeOH (30 mL) was added ammonium formate (617.48 mg, 9.79 mmol) and Pd / C (200 mg, 10% purity). The mixture was stirred at 70° C. for 16 hours. The mixture was diluted with MeOH (30 mL) and filtered to remove Pd / C. The filtrate was concentrated in vacuo to give intermediate D (300 mg, crude) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI) m / z [M+Na] + =331.2; 1 H NMR (400 MHz, chloroform-d) δ 7.29-7.28 (m, 1H), 6.59-6.58 (m, 1H), 6.54-6.48 (m, 1H), 4.19 (br d, J = 6.0 Hz, 2H), 3.92-3.84 (m, 1H), 3.72 (s, 3H), 2.78-2.76 (m, 2H), 1.98 (br d, J = 12.0 Hz, 2H), 1.78-1.68 (m, 2H), 1.41 (s, 9H).

[0276] Step 3: Preparation of 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrrole-3-carboxylic acid (Intermediate E) [ka] To a solution of intermediate D (300 mg, 972.85 μmol) in MeOH (10 mL) was added water (10 mL) and NaOH (38.91 mg, 972.85 μmol). The mixture was stirred at 30 °C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (10 mL × 3). The organic layer was discarded, and the aqueous layer was treated with HCl (2 M) to adjust the pH to 6-7, then extracted with EtOAc (10 mL × 5). The combined organic layers were washed with water (5 mL × 3) and brine (5 mL × 2), then dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate E (140 mg, 475.63 μmol, 48.89% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.36 (br s, 1H), 6.58 (br d, J = 17.2 Hz, 2H), 4.21 (br s, 2H), 3.92-3.86 (m, 1H), 2.78-2.73 (m, 2H), 1.98 (br d, J = 11.4 Hz, 2H), 1.81-1.65 (m, 2H), 1.41 (s, 9H).

[0277] Step 4: Preparation of tert-butyl 4-(3-((2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamoyl)-1H-pyrrol-1-yl)piperidine-1-carboxylate (Intermediate G) [ka] To a solution of intermediate E (20 mg, 67.95 μmol) in DMF (2 mL) was added HATU (32.29 mg, 84.93 μmol) and DIEA (21.95 mg, 169.87 μmol). 2-Amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide (prepared according to the method in Example 4) (19.64 mg, 56.62 μmol, HCl salt) was then added. The mixture was stirred at 30° C. for 2 hours. The mixture was poured into water (30 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with water (5 mL×3) and brine (5 mL×2), then dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate G (30 mg, crude) as a yellow oil, which was used directly in the next step. LCMS (ESI) m / z [M+H] + = 587.2.

[0278] Step 5: Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1-(piperidin-4-yl)-1H-pyrrole-3-carboxamide (compound 39) [ka] A mixture of intermediate G (25 mg, 42.61 μmol) in DCM (3 mL) and TFA (0.5 mL) was stirred at 30° C. for 2 hours. The mixture was diluted with DCM (30 mL) and concentrated under reduced pressure. This procedure was repeated three times. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 5% to 35%, 9 min) and lyophilized to give compound 39 (15.28 mg, 25.44 μmol, 59.70% yield, TFA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 487.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.82 (d, J = 6.4 Hz, 2H), 8.73 (br d, J = 10.0 Hz, 1H), 8.46 (br d, J = 10.0 Hz, 1H), 8.38 (s, 1H), 8.28-8.25 (m, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.03 (d, J = 6.2 Hz, 2H), 7.88-7.83 (m, 2H), 7.66-7.63 (m, 1H), 7.42-7.41 (m, 1H), 6.87-6.86 (m, 1H), 6.55-6.54 (m, 1H), 4.35-4.23 (m, 1H), 4.12 (br d, J = 5.6 Hz, 2H), 3.43 (br d, J = 12.8 Hz, 2H), 3.13-2.99 (m, 2H), 2.18 (br d, J = 12.2 Hz, 2H), 2.07-1.91 (m, 2H).

[0279] Example 39. Preparation of 1-((2-aminoethyl)sulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 40) [ka] Step 1: Preparation of tetrabutylammonium 2-((tert-butoxycarbonyl)amino)ethanesulfonate (Intermediate B) [ka] 2-Aminoethanesulfonic acid (1.25 g, 9.99 mmol, 1.25 mL) was dissolved in HO (10 mL), followed by the addition of tetrabutylammonium hydroxide (6.48 g, 9.99 mmol, 8.10 mL, 40% purity). BocO (2.18 g, 9.99 mmol, 2.29 mL) in acetone (30 mL) was then added dropwise. The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove acetone. The aqueous layer was extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give Intermediate B (4 g, crude) as a colorless oil.

[0280] Step 2: Preparation of tert-butyl (2-(chlorosulfonyl)ethyl)carbamate (Intermediate C) [ka] To a solution of intermediate B (1.8 g, 3.86 mmol) in DCM (13 mL) was added triphosgene (457.79 mg, 1.54 mmol) and DMF (28.19 mg, 385.67 μmol, 29.67 μL) in one portion under N at 20 °C. The mixture was stirred at 20 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in PE / EtOAc (2:1, v / v, 5 mL) and then purified by column chromatography (SiO, petroleum, petroleum ether / EtOAc = 2:1) and concentrated under reduced pressure to give intermediate C (500 mg, crude) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.11 (br s, 1H), 3.92-3.90 (m, 2H), 3.80-3.76 (m, 2H), 1.46 (s, 9H).

[0281] Step 3: Preparation of methyl 1-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)-1H-pyrrole-3-carboxylate (Intermediate E) [ka] To methyl 1H-pyrrole-3-carboxylate (100 mg, 799.20 μmol) in THF (2 mL) was added NaH (95.89 mg, 2.40 mmol, 60% purity) in one portion at 0 °C under N. The mixture was stirred at 0 °C for 30 min, then Intermediate C (233.73 mg, 959.04 μmol) was added to the solution, heated to 20 °C, and stirred for 0.5 h. The reaction mixture was quenched by adding 20 mL of NH.sub.4Cl at 20 °C and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The reaction was purified by reverse phase (NH.sub.3·H.sub.2O), concentrated under reduced pressure to remove MeCN, and extracted with 30 mL of EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give Intermediate E (100 mg, 288.83 .mu.mol, 36.14% yield) as a pale yellow solid. 1 H NMR (400MHz, CDCl3) δ 7.72-7.71 (m, 1H), 7.10-7.09 (m, 1H), 6.78-6.77 (m, 1H), 4.86 (br s, 1H), 3.85 (s, 3H), 3.52 (br s, 4H), 1.41 (s, 9H).

[0282] Step 4: Preparation of 1-((2-((tert-butoxycarbonyl)amino)ethyl)sulfonyl)-1H-pyrrole-3-carboxylic acid (Intermediate F) [ka] To a solution of intermediate E (50 mg, 150.43 μmol) in MeOH (0.2 mL) and THF (0.1 mL) was added aqueous NaOH (2 M, 225.65 μL). The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was acidified with 2 N HCl to pH = 6-7, and then the mixture was concentrated in vacuo to give intermediate F (50 mg, crude) as a yellow solid. LCMS (ESI) m / z [M+H-100] + = 218.2.

[0283] Step 5: Preparation of tert-butyl (2-((3-((2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamoyl)-1H-pyrrol-1-yl)sulfonyl)ethyl)carbamate (Intermediate H) [ka] To a solution of intermediate F (49.23 mg, 154.65 μmol), HATU (58.80 mg, 154.65 μmol), and DIEA (99.94 mg, 773.26 μmol, 134.69 μL) in DCM (0.6 mL) was added 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide (prepared according to the method in Example 4) (40 mg, 115.33 μmol, HCl salt). The mixture was stirred at 25 °C for 2 h. The mixture was then concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.1% NH H O). The solution was concentrated in vacuo to remove MeCN, and the aqueous layer was then extracted with EtOAc (50 mL × 3). The combined organic phases were concentrated in vacuo to give Intermediate H. (20 mg, 28.29 μmol, 21.95% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 611.2.

[0284] Step 6: Preparation of 1-((2-aminoethyl)sulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 40) [ka] A mixture of intermediate H (20 mg, 32.75 μmol) in TFA (0.05 mL) and DCM (0.5 mL) was stirred at 25° C. under a N atmosphere for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 5%-35%) and lyophilized to give compound 40 (6.76 mg, 13.24 μmol, 40.43% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 511.1; 1 H NMR (400 MHz, methanol-d4) δ 8.86-8.84 (m, 2H), 8.47 (s, 1H), 8.37-8.35 (m, 2H), 8.18 (d, J=8.30 Hz, 1H), 7.91-7.87 (m, 2H), 7.69-7.65 (m, 1H), 7.63 (s, 1H), 7.36-7.35 (m, 1H), 6.90-6.89 (m, 1H), 4.28 (s, 2H), 3.92-3.88 (m, 2H), 3.33-3.30 (m, 2H).

[0285] Example 40. Preparation of 1-(tert-butyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 41) [ka] Step 1: Preparation of 1-(tert-butyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 41) [ka] To a solution of 1-(tert-butyl)-1H-pyrrole-3-carboxylic acid [prepared according to the method in Example 34] (36.16 mg, 216.24 μmol) in DCM (3 mL) was added HATU (82.22 mg, 216.24 μmol) and DIEA (55.89 mg, 432.48 μmol, 75.33 μL). Then, 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (50 mg, 144.16 μmol, HCl salt) was added. The mixture was stirred at 30° C. for 2 hours. The mixture was diluted with DCM (30 mL), washed with water (5 mL×3) and brine (5 mL×2), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 25%-55%) and lyophilized to give compound 41 (23.32 mg, 40.66 μmol, 28.20% yield, TFA salt) as a white solid. LCMS (ESI) m / z [M+H] + =460.3; 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.85 (br d, J = 6.6 Hz, 2H), 8.40 (s, 1H), 8.21 - 8.16 (m, 1H), 8.15-8.06 (m, 3H), 7.90-7.83 (m, 2H), 7.68-7.62 (m, 1H), 7.53 (s, 1H), 6.98-6.97 (m, 1H), 6.50-6.46 (m, 1H), 4.11 (d, J = 6.0 Hz, 2H), 1.50 (s, 9H).

[0286] Example 41. Preparation of 1-(1-amino-2-methylpropan-2-yl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 42) [ka] Step 1: Preparation of methyl 1-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]pyrrole-3-carboxylate (Intermediate F) [ka] To a solution of methyl 1-(2-cyanopropan-2-yl)-1H-pyrrole-3-carboxylate [prepared according to the method in Example 33] (2 g, 9.47 mmol, 1 equiv.) and NiCl.6HO (5.63 g, 23.67 mmol) in MeOH (50 mL) was added NaBH (3.58 g, 94.69 mmol) at 0 °C and stirred for 1 h. Then TEA (2.87 g, 28.41 mmol, 3.95 mL) and BocO (4.13 g, 18.94 mmol, 4.35 mL) were added to the reaction mixture and stirred for an additional 2 h at 25 °C. The reaction mixture was acidified with aqueous HCl (2 M) to pH = 5 and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 50 / 1 to 5:1) and concentrated in vacuo to give intermediate F (1.93 g, 6.19 mmol, 65.34% yield) as a yellow oil. LCMS (ESI) m / z [M+H-100] + =197.3. 1 H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 6.76 (s, 1H), 6.62 (s, 1H), 4.30 (s, 1H), 3.80 (s, 3H), 3.41 (s, 2H), 1.53 (s, 6H), 1.40 (s, 9H).

[0287] Step 2: Preparation of 1-[2-(tert-butoxycarbonylamino)-1,1-dimethyl-ethyl]pyrrole-3-carboxylic acid (Intermediate G) [ka] A solution of intermediate F (1.87 g, 6.31 mmol) and NaOH (2 M, 6.31 mL) in MeOH (20 mL) was stirred at 25 °C for 2 h, and then another batch of NaOH (504.75 mg, 12.62 mmol) was added to the reaction mixture. The reaction mixture was stirred at 55 °C for another 2 h. The reaction mixture was adjusted to pH = 6 with aqueous HCl (2 M) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (15 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase HPLC (FA conditions), and the combined fractions were extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (255 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give intermediate G (1.47 g, 5.21 mmol, 82.51% yield) as a yellow oil. LCMS (ESI) m / z [M+23] + =305.0. 1 H NMR (400 MHz, methanol-d₄) δ 7.49 (s, 1H), 6.89 (d, J = 5.6 Hz, 1H), 6.51 (d, J = 5.2 Hz, 1H), 3.32 (s, 2H), 1.52 (s, 6H), 1.39 (s, 9H).

[0288] Step 3: Preparation of tert-butyl (2-methyl-2-(3-((2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamoyl)-1H-pyrrol-1-yl)propyl)carbamate (Intermediate I) [ka] To a solution of intermediate G (97.68 mg, 345.99 μmol), EDCI (66.33 mg, 345.99 μmol), HOBt (46.75 mg, 345.99 μmol), and DIEA (186.32 mg, 1.44 mmol, 251.10 μL) in DCM (2 mL) was added 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (100 mg, 288.32 μmol, HCl salt), and the mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was triturated with MeOH (10 mL) at 25° C. for 15 minutes, then filtered and dried in vacuo to give intermediate I (70 mg, 110.84 μmol, 38.44% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 575.5.

[0289] Step 4: Preparation of 1-(1-amino-2-methylpropan-2-yl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 42) [ka] A solution of intermediate I (68 mg, 118.32 μmol) in HCl / dioxane (1 mL) was stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse-phase HPLC (0.1% FA), and the fractions were lyophilized to give compound 42 (26.23 mg, 48.87 μmol, 41.30% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 475.0; 1H NMR (400 MHz, DMSO-d6) δ 8.69-8.68 (m, 2H), 8.31-8.30 (m, 1H), 8.23-8.20 (m, 2H), 8.03-8.00 (m, 1H), 7.83-7.76 (m, 4H), 7.62-7.58 (m, 1H), 7.50 (s, 1H), 6.94 (s, 1H), 6.51 (s, 1H), 4.10 (d, J=6.0 Hz, 2H), 2.83 (s, 2H), 1.46 (s, 6H).

[0290] Example 42. Preparation of 1-isopropylsulfonyl-N-[2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (Compound 43) [ka] Step 1: Preparation of methyl 1-isopropylsulfonylpyrrole-3-carboxylate (intermediate C) [ka] To a solution of methyl 1H-pyrrole-3-carboxylate (500 mg, 4.00 mmol) in THF (20 mL) was added KHMDS (1 M, 7.99 mL) slowly at 0 °C under N. The reaction mixture was stirred at 0 °C under N for 30 min. To the reaction mixture was then added propane-2-sulfonyl chloride (683.82 mg, 4.80 mmol, 534.23 μL) slowly at 0 °C under N. The reaction mixture was warmed to 30 °C and stirred at 30 °C under N for 16 h. The reaction mixture was poured slowly into HO (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (FA conditions) and lyophilized to give intermediate C (490 mg, 2.12 mmol, 53% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 232.0; 1H NMR (400 MHz, CDCl3) δ 7.70-7.69 (m, 1H), 7.07-7.06 (m, 1H), 6.75-6.74 (m, 1H), 3.85 (s, 3H), 3.49-3.39 (m, 1H), 1.36 (d, J=6.8 Hz, 6H).

[0291] Step 2: Preparation of 1-isopropylsulfonylpyrrole-3-carboxylic acid (intermediate D) [ka] To a mixture of intermediate C (490 mg, 2.12 mmol) in THF (10 mL) and MeOH (5 mL) was added a solution of LiOH.HO (266.73 mg, 6.36 mmol) in HO (5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding aqueous HCl (1 M) until pH = 4 and extracted with EtOAc (20 mL × 4). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse-phase column (FA conditions) to give intermediate D (360 mg, 1.66 mmol, 78% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 218.0; 1 H NMR (400 MHz, CDCl3) δ 7.80-7.79 (m, 1H), 7.12-7.11 (m, 1H), 6.80-6.79 (m, 1H), 3.53-3.42 (m, 1H), 1.39 (d, J=7.2 Hz, 6H).

[0292] Step 3: Preparation of 1-isopropylsulfonyl-N-[2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]pyrrole-3-carboxamide (compound 43) [ka] To a mixture of intermediate D (17.00 mg, 78.27 μmol) in DCM (1 mL) was added DIPEA (50.58 mg, 391.34 μmol, 68.16 μL), HATU (44.64 mg, 117.40 μmol), and 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (30 mg, 78.27 μmol, diHCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 16 h. The reaction mixture was filtered, and the filter cake was washed with DCM (5 mL) and MeOH (2 mL) to give compound 43 (8.59 mg, 15.85 μmol, 20% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 510.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (br s, 1H), 8.72-8.69 (m, 3H), 8.31 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.83-7.82 (m, 2H), 7.77-7.76 (m, 3H), 7.62-7.58 (m, 1H), 7.30-7.27 (m, 1H), 6.80-6.79 (m, 1H), 4.16 (d, J=5.6 Hz, 2H), 3.91-3.85 (m, 1H), 1.24 (d, J=6.8 Hz, 6H).

[0293] Example 43. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrazole-4-carboxamide (Compound 44) [ka] Step 1: Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrazole-4-carboxamide (Intermediate C) [ka] To a mixture of 1H-pyrazole-4-carboxylic acid (60 mg, 535.30 μmol), 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (166.14 mg, 479.03 μmol, HCl salt) and DIEA (345.92 mg, 2.68 mmol, 466.20 μL) in DMF (3 mL) was added HOBt (86.80 mg, 642.36 μmol) and EDCI (123.14 mg, 642.36 μmol), and the mixture was stirred under a N atmosphere at 25° C. for 2 hours. The reaction mixture was poured into water (5 mL), filtered, and the filter cake was dried in air to obtain the crude product. The crude product was triturated with MeOH (3 mL) at 25° C. for 30 min, filtered, and dried in vacuo to give Intermediate C (140 mg, 318.46 μmol, 59.49% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 405.0.

[0294] Step 2: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrazole-4-carboxamide (compound 44) [ka] To a solution of intermediate C (50 mg, 123.63 μmol) in THF (2 mL) was added TEA (100.08 mg, 989.01 μmol, 137.66 μL), and MsCl (42.48 mg, 370.88 μmol, 28.71 μL) was added dropwise. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was diluted with 3 mL of water, and some precipitate formed. The mixture was filtered to obtain a filter cake, which was then dried in air to obtain the crude product. The crude product was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile; B%: 13%-37%) and lyophilized to obtain compound 44 (35.18 mg, 57.20 μmol, 46.27% yield, TFA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 482.9;1 H NMR (400 MHz, DMSO-d6) δ 12.47 (s, 1H), 8.95-8.92 (m, 1H), 8.82-8.81 (m, 3H), 8.37 (s, 1H), 8.29 (s, 1H), 8.08-8.05 (m, 3H), 7.86-7.84(d, J=8.8 Hz, 2H), 7.66-7.62 (m, 1H), 4.19-4.18 (d, J=6 Hz, 2H), 3.64(s, 3H).

[0295] Example 44. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrazole-3-carboxamide (Compound 45) [ka] Step 1: Preparation of tert-butyl 1H-pyrazole-3-carboxylate (Intermediate C) [ka] To a solution of 1H-pyrazole-3-carboxylic acid (600 mg, 5.35 mmol) in toluene (10 mL) was added 1,1-di-tert-butoxy-N,N-dimethylmethanamine (4.35 g, 21.41 mmol, 5.13 mL) at 80° C., and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organics were washed with water and brine, dried over NaSO, filtered, and the filtrate was evaporated to dryness. MTBE (10 mL) was added to the residue, stirred for 10 minutes, then filtered and dried in vacuo to give intermediate C (600 mg, 3.46 mmol, 64.64% yield) as a yellow solid. LCMS (ESI) m / z [M+Na] + =191.3; 1H NMR (400 MHz, DMSO-d6) δ 13.77-13.34 (m, 1H), 7.80-7.57 (m, 1H), 6.72-6.64 (m, 1H), 1.51 (s, 9H).

[0296] Step 2: Preparation of tert-butyl 1-(methylsulfonyl)-1H-pyrazole-3-carboxylate (Intermediate D) [ka] To a solution of intermediate C (150 mg, 891.83 μmol) in THF (3 mL) was added TEA (270.73 mg, 2.68 mmol, 372.40 μL) under N at 0° C., and the mixture was stirred at 0° C. for 10 min. MsCl (132.81 mg, 1.16 mmol, 89.74 μL) was then added, and the mixture was stirred at 30° C. for 1 h. The reaction mixture was poured into cold NH4Cl solution (50.0 mL) and extracted with EtOAc (30 mL × 3). The combined organics were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give intermediate D (210 mg, crude) as a yellow solid, which was used directly for the next step. LCMS (ESI) m / z [M+H-56] + =190.8. 1 H NMR (400 MHz, methanol-d₄) δ 8.24 (d, J = 2.8 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 3.49 (s, 3H), 1.60 (s, 9H).

[0297] Step 3: Preparation of 1-(methylsulfonyl)-1H-pyrazole-3-carboxylic acid (intermediate E) [ka] To a mixture of intermediate D (100 mg, 406.04 μmol) in DCM (3 mL) was added TFA (462.98 mg, 4.06 mmol, 300.63 μL). The mixture was stirred at 30° C. for 1 h. The reaction mixture was evaporated to dryness to give intermediate E (75 mg, crude) as a yellow solid. 1 H NMR (400 MHz, methanol-d₄) δ 8.27 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 3.51 (s, 3H).

[0298] Step 4: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrazole-3-carboxamide (compound 45) [ka] To a mixture of Intermediate E (70 mg, 368.08 μmol) and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide [prepared according to the method in Example 4] (140.43 mg, 404.89 μmol, HCl salt) in DMF (1 mL) was added DIPEA (190.29 mg, 1.47 mmol, 256.45 μL). The mixture was stirred at 30° C. for 15 min, then EDCI (105.84 mg, 552.12 μmol) and HOBt (74.60 mg, 552.12 μmol) were added and stirred at 30° C. for 1 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organics were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 10%-40%) and lyophilized to give compound 45 (45 mg, 85.14 μmol, 23.13% yield, FA salt) as a yellow solid. LCMS (ESI) m / z [M+H] + =483.1; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (br s, 1H), 8.85-8.82 (m, 1H), 8.68-8.67 (m, 2H), 8.41 (d, J=2.8 Hz, 1H), 8.30 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.75 (m, 3H), 7.61-7.57 (m, 1H), 6.96 (d, J=2.8 Hz, 1H), 4.20 (d, J=6.0 Hz, 2H), 3.68 (s, 3H).

[0299] Example 45. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-imidazole-4-carboxamide (Compound 46) [ka] Step 1: Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-imidazole-4-carboxamide (Intermediate C) [ka] To a mixture of 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (250 mg, 720.81 μmol, HCl salt) and 1H-imidazole-4-carboxylic acid (105.03 mg, 937.05 μmol) in DMF (4 mL) was added DIEA (372.63 mg, 2.88 mmol, 502.19 μL), EDCI (207.27 mg, 1.08 mmol), and HOBt (146.09 mg, 1.08 mmol). The resulting mixture was stirred at 25° C. for 4 hours. The mixture was poured into water (30 mL), and the precipitate was collected by filtration. The precipitate was triturated with MeOH (10 mL) and stirred for 5 minutes. The precipitate was then collected by filtration, washed with MTBE (2 mL), and dried in vacuo to give Intermediate C (180 mg, 417.86 μmol, 57.97% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 405.2.

[0300] Step 2: Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-imidazole-4-carboxamide (compound 46) [ka] To a mixture of intermediate C (100 mg, 247.25 μmol) in pyridine (2 mL) was added MsCl (1.42 g, 12.36 mmol, 956.86 μL) slowly at 25° C., and the mixture was then stirred at 25° C. for 0.5 h. The mixture was poured into water (50 mL), and the precipitate was collected by filtration. The precipitate was triturated in MeOH (10 mL) and stirred for 5 min. The precipitate was then collected by filtration, washed with MTBE (3 mL), and dried in vacuo to give compound 46 (56.32 mg, 115.20 μmol, 46.59% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 482.8; 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.70-8.68 (m, 2H), 8.59-8.56 (m, 1H), 8.32-8.30 (m, 2H), 8.15 (d, J=1.2 Hz, 1H), 8.02-8.00 (m, 1H), 7.83 (s, 1H), 7.80-7.76 (m, 3H), 7.62-7.58 (m, 1H), 4.15 (d, J=6.0 Hz, 2H), 3.77 (s, 3H).

[0301] Example 46. Preparation of 1-(N,N-dimethylsulfamoyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 47) [ka] Step 1: Preparation of methyl 1-(N,N-dimethylsulfamoyl)-1H-pyrrole-3-carboxylate (Intermediate B) [ka] To a solution of methyl 1H-pyrrole-3-carboxylate (100 mg, 799.20 μmol) in THF (3 mL) was added KHMDS (1 M, 1.60 mL) at 0 °C. The mixture was stirred under N at 0 °C for 30 min. N,N-Dimethylsulfamoyl chloride (137.71 mg, 959.04 μmol, 102.77 μL) was added at 0 °C, and the mixture was stirred under N at 20 °C for 16 h. The reaction was quenched by adding water (10 mL), and the resulting mixture was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with water (10 mL), dried over NaSO, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 2 / 1) to give intermediate B (60 mg, 258.34 μmol, 32.32% yield) as a colorless oil. LCMS (ESI) m / z [M+H] + = 233.2;1 H NMR (400 MHz, CDCl3) δ 7.70 (dd, J=2.0 Hz, 1.6 Hz, 1H) 7.07 (dd, J=3.2 Hz, 2.0 Hz, 1H), 6.73 (dd, J=3.2 Hz, 1.6 Hz, 1H), 3.86 (s, 3H), 2.86 (s, 6H).

[0302] Step 2: Preparation of 1-(N,N-dimethylsulfamoyl)-1H-pyrrole-3-carboxylic acid (Intermediate C) [ka] To a solution of intermediate B (50 mg, 215.28 μmol) in MeOH (2 mL) and HO (2 mL) was added LiOH.HO (18.07 mg, 430.56 μmol). The mixture was stirred at 20 °C for 16 h. The pH of the reaction mixture was adjusted to 4 with 1 N HCl solution, and the resulting mixture was extracted with EtOAc (15 mL × 2). The combined organic phases were washed with water (5 mL), dried over NaSO, and concentrated to give intermediate C (35 mg, 160.38 μmol, 74.50% yield) as a yellow solid. The product was used for the next step without further purification. LCMS (ESI) m / z [M+H] + = 219.2; 1 H NMR (400 MHz, CDCl3) δ 7.69 (m, 1H) 7.00 (dd, J=3.2 Hz, 1.6 Hz, 1H), 6.68 (dd, J=3.2 Hz, 1.6 Hz, 1H), 2.79 (s, 6H).

[0303] Step 3: Preparation of 1-(N,N-dimethylsulfamoyl)-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 47) [ka] To a solution of intermediate C (30 mg, 137.47 μmol) in DCM (3 mL) were added DIPEA (53.30 mg, 412.41 μmol, 71.83 μL) and HATU (62.72 mg, 164.96 μmol). The mixture was stirred at 20° C. for 10 minutes. 2-Amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (47.68 mg, 137.47 μmol, HCl salt) was added, and the mixture was stirred at 20° C. for 16 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (10 mL) and dried in vacuo to give compound 47 (44.55 mg, 85.84 μmol, 62.44% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 511.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (br s, 1H), 8.72-8.64 (m, 3H), 8.31 (s, 1H), 8.02 (d, J= 8.0. Hz, 1H), 7.86-7.80 (m, 2H), 7.79-7.74 (m, 3H), 7.65-7.56 (m, 1H), 7.29 (d, J= 3.2 Hz, 2.0 Hz, 1H), 6.76 (d, J= 3.2 Hz, 2.0 Hz, 1H), 4.16 (m, 2H), 2.81 (s, 6H).

[0304] Example 47. Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 48) [ka] To a mixture of 1H-pyrrole-3-carboxylic acid (20 mg, 180.02 μmol) in DCM (2 mL) was added DIPEA (116.33 mg, 900.10 μmol, 156.78 μL), HATU (102.67 mg, 270.03 μmol), and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide [prepared according to the method in Example 4] (69.00 mg, 180.02 μmol, diHCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 16 h. The reaction mixture was filtered, and the filter cake was washed with DCM (10 mL) and MeOH (3 mL) to give a brown solid, which was further purified by preparative HPLC (mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 23%-53%) to give compound 48 (2.03 mg, 4.89 μmol, 2.72% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 404.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (br s, 1H), 11.18 (br s, 1H), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 8.18-8.17 (m, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.77-7.75 (m, 3H), 7.62-7.58 (m, 1H), 7.36-7.35 (m, 1H), 6.79-6.77 (m, 1H), 6.51-6.50 (m, 1H), 4.11 (d, J=6.0 Hz, 2H).

[0305] Example 48. Preparation of 1-methyl-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 49) [ka] To a mixture of 1-methyl-1H-pyrrole-3-carboxylic acid (10.82 mg, 86.50 μmol) in DCM (1 mL) was added DIPEA (55.89 mg, 432.48 μmol, 75.33 μL), HATU (49.33 mg, 129.75 μmol), and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide [prepared according to the method in Example 4] (30 mg, 86.50 μmol, HCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 16 h. The reaction mixture was filtered, and the filter cake was washed with DCM (5 mL) and MeOH (2 mL) to give a yellow solid. The yellow solid was purified by preparative HPLC (mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; B%: 23%-56%, 11 min) to give a yellow solid. The yellow solid was further purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 20%-50%) to give compound 49 (9.2 mg, 19.44 μmol, 22.47% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 418.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.33 (br s, 1H), 8.68 (d, J=6.0 Hz, 2H), 8.30 (s, 1H), 8.18-8.16 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.81 (s, 1H), 7.76-7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.28 (s, 1H), 6.73-6.71 (m, 1H), 6.47-6.46 (m, 1H), 4.09 (d, J=5.6 Hz, 2H), 3.64 (s, 3H).

[0306] Example 49. Preparation of 1-acetyl-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 50) [ka] Step 1: Preparation of 1-acetyl-1H-pyrrole-3-carboxylic acid (intermediate B) [ka] To a solution of 1H-pyrrole-3-carboxylic acid (50 mg, 450.05 μmol) in DMF (2 mL) was added NaH under N at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture was added AcO (50.54 mg, 495.05 μmol, 46.37 μL) dropwise at 0 °C. The reaction mixture was warmed to 30 °C and stirred at 30 °C for 16 h. The reaction mixture was slowly poured into HO (2 mL). HCl (2 M) was added to the mixture to adjust the pH to 2, giving a red solution. The red solution was purified by reverse-phase column (FA conditions) and lyophilized to give intermediate B (25 mg, 135.69 μmol, 30.15% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 154.0; 1 H NMR (400 MHz, DMSO-d6) δ 7.91-7.90 (m, 1H), 7.50-7.43 (m, 1H), 6.56-6.55 (m, 1H), 2.60 (s, 3H).

[0307] Step 2: Preparation of 1-acetyl-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (compound 50) [ka] To a mixture of Intermediate B (15 mg, 97.95 μmol) in DCM (1 mL) was added DIPEA (63.30 mg, 489.76 μmol, 85.31 μL), HATU (55.87 mg, 146.93 μmol), and 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide [prepared according to the method in Example 4] (33.97 mg, 97.95 μmol, HCl salt) at 30° C. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was filtered, and the filter cake was washed with DCM (5 mL) and MeOH (2 mL) to give a yellow solid. The yellow solid was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 12%-36%) and lyophilized to give compound 50 (7.59 mg, 15.44 μmol, 15.76% yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + = 446.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (br s, 1H), 8.69-8.67 (m, 2H), 8.64-8.61 (m, 1H), 8.44 (br s, 1H), 8.31 (s, 1H), 8.03-8.00 (m, 2H), 7.82 (s, 1H), 7.77-7.76 (m, 3H), 7.62-7.58 (m, 1H), 7.48-7.46 (m, 1H), 6.71-6.70 (m, 1H), 4.16 (d, J=5.6 Hz, 2H), 2.61 (s, 3H).

[0308] Example 50. Preparation of N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-imidazole-4-carboxamide (Compound 51) [ka] To a mixture of 1H-imidazole-4-carboxylic acid (15 mg, 133.82 μmol) and 2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]acetamide [prepared according to the method in Example 4] (46.41 mg, 133.82 μmol, HCl salt) in DCM (1 mL) was added DIEA (51.89 mg, 401.47 μmol, 69.93 μL) and HATU (61.06 mg, 160.59 μmol). The resulting mixture was stirred at 30° C. for 1 hour. The precipitate was collected by filtration. The solid was slurried in MeOH (2 mL) and stirred for 5 minutes. The precipitate was collected by filtration. The solid was then purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 1%-30%) and lyophilized to give compound 51 (5.44 mg, 13.45 μmol, 10.05% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 405.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 8.87-8.82 (m, 3H), 8.55 (s, 1H), 8.40-8.38 (m, 1H), 8.10-7.85 (m, 7H), 7.67-7.63 (m, 1H), 4.23 (d, J=5.6 Hz, 2H).

[0309] Example 51. Preparation of 1-methyl-N-(2-oxo-2-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-imidazole-4-carboxamide (Compound 52) [ka] To a solution of 1-methyl-1H-imidazole-4-carboxylic acid (21.82 mg, 172.99 μmol), HATU (65.78 mg, 172.99 μmol), and DIEA (93.16 mg, 720.81 μmol, 125.55 μL) in DCM (0.5 mL) was added 2-amino-N-(4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)acetamide [prepared according to the method in Example 4] (50 mg, 144.16 μmol, HCl salt), and the mixture was stirred at 30° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (5.0 mL), filtered, and dried in vacuo to give compound 52 (32.73 mg, 77.90 μmol, 54.04% yield) as a gray solid. LCMS (ESI) m / z [M+H] + = 419.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (br s, 1H), 8.68-8.66 (m, 2H), 8.30-8.29 (m, 1H), 8.21-8.18 (m, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.76-7.74 (m, 3H), 7.69-7.66 (m, 2H), 7.61-7.57 (m, 1H), 4.16 (d, J=6.0 Hz, 2H), 3.70 (s, 3H).

[0310] Example 52. Preparation of N-(2-((4-(3'-(aminomethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 53) [ka] Step 1: Preparation of tert-butyl 3-bromobenzylcarbamate (Intermediate B) [ka] To a solution of (3-bromophenyl)methanamine (3.7 g, 19.89 mmol) in THF (20 mL) was added NaHCO (3.34 g, 39.77 mmol, 1.55 mL) and BocO (4.77 g, 21.88 mmol, 5.03 mL), and the mixture was stirred at 30 °C for 16 h. The reaction mixture was filtered to obtain the filtrate. The filtrate was concentrated to obtain Intermediate B (5.6 g, 16.67 mmol, 83.85% yield) as a white solid, which was used directly for the next step. LCMS (ESI) m / z [M+H-56] + = 231.9.

[0311] Step 2: Preparation of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (Intermediate D) [ka] To a solution of Intermediate B (5.6 g, 16.67 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.08 g, 20.01 mmol) in dioxane (60 mL), dichloro1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (1.36 g, 1.67 mmol) and KOAc (4.91 g, 50.02 mmol) were added, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was poured into water (100 mL), and the solution was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over NaSO, and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=1:0 to 10:1) and concentrated in vacuo to give intermediate D (5.5 g, 16.51 mmol, 98.98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 1H), 7.53 (d, J = 6.8 Hz, 1H), 7.35-7.32 (m, 3H), 4.13 (d, J = 6.0 Hz, 2H), 1.39 (s, 9H), 1.29 (s, 12H).

[0312] Step 3: Preparation of tert-butyl ((3'-(2-(2-(1-(methylsulfonyl)-1H-pyrrole-3-carboxamido)acetamido)thiazol-4-yl)-[1,1'-biphenyl]-3-yl)methyl)carbamate (Intermediate F) [ka] To a solution of N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (prepared according to the method in Example 1) (500 mg, 1.03 mmol) and Intermediate D (413.64 mg, 1.24 mmol) in dioxane (5 mL) and HO (0.5 mL) was added Pd(dppf)Cl (75.69 mg, 103.44 μmol) and KCO (428.89 mg, 3.10 mmol), and the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated to give a residue. The crude product was purified by reverse-phase HPLC (0.1% FA condition) and lyophilized to give Intermediate F (600 mg, crude) as a yellow solid. LCMS (ESI) m / z [M+H] + = 610.2.

[0313] Step 4: Preparation of N-(2-((4-(3'-(aminomethyl)-[1,1'-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 53) [ka] A mixture of intermediate F (400 mg, 656.04 μmol) in HCl / dioxane (5 mL) was stirred at 30° C. for 2 hours. The reaction mixture was concentrated to give a residue. The residue was triturated with MTBE (2 mL) and then filtered to give a yellow solid. The yellow solid was purified by two preparative HPLC runs (mobile phase: [water (0.05% HCl)-acetonitrile]; B%: 18%-38% and then (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 10%-40%), and the solution was lyophilized to give compound 53 (68.49 mg, 134.40 μmol, 56.45% yield) as a white solid. LCMS (ESI) m / z [M+H] + =510.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.69-8.67 (m, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.85-7.83 (m, 1H), 7.75 (s, 2H), 7.64-7.60 (m, 2H), 7.55-7.52 (m, 1H), 7.49-7.45 (m, 1H), 7.40-7.38 (m, 1H), 7.32-7.30 (m, 1H), 6.78 (dd, J = 1.6, 3.2 Hz, 1H), 4.15 (d, J = 5.6 Hz, 2H), 3.92 (s, 2H), 3.57 (s, 3H).

[0314] Example 53. Preparation of 1-(methylsulfonyl)-N-(2-oxo-2-((4-(3-(2-(piperazin-1-yl)pyridin-4-yl)phenyl)thiazol-2-yl)amino)ethyl)-1H-pyrrole-3-carboxamide (Compound 54) [ka] To a solution of N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (prepared according to the method in Example 1) (50 mg, 96.26 μmol) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (41.76 mg, 144.40 μmol) in dioxane (0.5 mL) and HO (0.05 mL) was added KPO (61.30 mg, 288.79 μmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (12.55 mg, 19.25 μmol) under N. The reaction mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into water (5 mL), and the solution was extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.225% FA)-acetonitrile]; B%: 10%-34%) to give compound 54 (18.81 mg, 33.25 μmol, 34.54% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 566.2; 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (br t, J=5.6 Hz, 1H), 8.67-8.26 (m, 3H), 8.22-8.20 (m,1H), 7.85 (s,1H), 7.81 (s, 1H), 7.71 (br d, J=7.6 Hz, 1H), 7.62-7.52 (m, 1H), 7.32 (dd, J=2.4, 3.2 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J=5.2 Hz, 1H), 6.78-6.77 (m, 1H), 4.15 (d, J=5.6 Hz, 2H), 3.58 (s, 7H), 2.88 (br s, 4H).

[0315] Example 54. Preparation of N-(2-((4-(3',5'-dimethyl-[1,1'-biphenyl]-3-yl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 55) [ka] To a solution of N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (prepared according to the method in Example 1) (100 mg, 206.89 μmol), (3,5-dimethylphenyl)boronic acid (62.06 mg, 413.77 μmol), and KPO (131.74 mg, 620.66 μmol) in dioxane (0.8 mL) and HO (0.2 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (13.48 mg, 20.69 μmol) under N at 25° C. The reaction mixture was stirred at 80° C. under N for 16 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were dried over anhydrous NaSO and then concentrated to give a brown solid. The brown solid was dissolved in DMSO (2 mL) and purified by reverse-phase HPLC (FA), then concentrated and lyophilized to give compound 55 (57.31 mg, 110.37 μmol, 53.35% yield) as an off-white solid. LCMS (ESI) m / z [M+H] + = 509.1; 1H NMR (400 MHz, DMSO-d6) δ 12.40 (br s, 1H), 8.67-8.66 (m, 1H), 8.16 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.84-7.83 (m, 1H), 7.75 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.53-7.46 (m, 1H), 7.31 (s, 3H), 7.02 (s, 1H), 6.77-6.76 (m, 1H), 4.14 (d, J = 5.6 Hz, 2H), 3.57 (s, 3H), 2.35 (s, 6H).

[0316] Example 55. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(3-methylisoxazol-5-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 56) [ka] To a solution of N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]-1-tert-butyl-pyrrole-3-carboxamide (prepared according to the method in Example 8) (70 mg, 151.72 μmol) in dioxane (1 mL) and water (0.2 mL), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (38.06 mg, 182.06 μmol), KPO (96.62 mg, 455.16 μmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.89 mg, 15.17 μmol) were added under a N atmosphere. The mixture was stirred at 100° C. for 2 hours. The mixture was diluted with water (3 mL) and extracted with EtOAc (10 mL × 3). The organic layer was dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by reverse-phase HPLC (0.1% NH3·H2O) and lyophilized to give compound 56 (2.53 mg, 5.46 μmol, 3.60% yield) as a white solid. LCMS (ESI) m / z [M+H]+ = 464.3; 1 H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.57-7.55 (m, 1H), 7.49-7.47 (m, 1H), 7.23 (s, 1H), 6.86-6.84 (m, 1H), 6.47-6.45 (m, 3H), 4.37 (d, J = 6.0 Hz, 2H), 2.38 (s, 3H), 1.56 (s, 9H).

[0317] Example 56. Preparation of N-(2-((4-(3-(2-(N-methylacetamido)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 57) [ka] Step 1: Preparation of N-(4-bromopyridin-2-yl)-N-methylacetamide (Intermediate B) [ka] A mixture of 4-bromo-N-methylpyridin-2-amine (200 mg, 1.07 mmol) in acetic anhydride (3.27 g, 32.03 mmol, 3 mL) was stirred at 120° C. for 4 hours. The mixture was concentrated in vacuo at 50° C. to give Intermediate B (180 mg, 785.77 μmol, 73.48% yield) as a yellow oil. The oil was used in the next step without purification. LCMS (ESI) m / z [M+H] + = 229.1; 1 H NMR (400 MHz, methanol-d4) δ 8.33 (d, J = 5.4 Hz, 1H), 7.99 (s, 1H), 7.54 (d, J = 5.4 Hz, 1H), 3.35 (s, 3H), 2.10 (s, 3H).

[0318] Step 2: Preparation of tert-butyl (2-((4-(3-(2-(N-methylacetamido)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate D) [ka] To a mixture of tert-butyl (2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamate [prepared according to the method in Example 57] (200 mg, 435.38 μmol) and Intermediate B (129.66 mg, 566.00 μmol) in dioxane (10 mL) and HO (2 mL) was added [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (28.38 mg, 43.54 μmol) and KPO (184.84 mg, 870.77 μmol) in one portion at 25° C. under N. The mixture was stirred at 75° C. under N for 12 h. The mixture was poured into water (40 mL) and stirred for 5 min. The aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give intermediate D (180 mg, 373.78 μmol, 85.85% yield) as a yellow oil. The oil was used directly for the next step without purification. LCMS (ESI) m / z [M+H] + = 482.0.

[0319] Step 3: Preparation of 2-amino-N-(4-(3-(2-(N-methylacetamido)pyridin-4-yl)phenyl)thiazol-2-yl)acetamide (Intermediate E) [ka] To a mixture of intermediate D (180 mg, 373.78 μmol) in EA (5 mL) was added HCl / EtOAc (4 M, 93.45 μL) in one portion at 25° C. The mixture was stirred at 25° C. for 1 h. The mixture was filtered and the solid was dried in vacuo to give intermediate E (100 mg, 239.28 μmol, 64.02% yield, HCl salt) as a black solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J=5.2 Hz, 1H), 8.39-8.28 (m, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.95 (d, J=3.2 Hz, 2H), 7.82 (d, J=7.0 Hz, 1H), 7.75 (d, J=4.4 Hz, 1H), 7.66-7.57 (m, 1H), 3.92 (d, J=4.8 Hz, 2H), 3.35 (s, 3H), 2.09 (s, 3H).

[0320] Step 4: Preparation of N-(2-((4-(3-(2-(N-methylacetamido)pyridin-4-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 57) [ka] To a mixture of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (16.30 mg, 86.14 μmol) and DIEA (46.39 mg, 358.93 μmol, 62.52 μL) in DCM (1 mL) was added HATU (40.94 mg, 107.68 μmol) in one portion under N at 25° C. The mixture was stirred at 25° C. for 5 minutes, and then intermediate E (30 mg, 71.79 μmol, HCl) was added to the mixture and stirred at 25° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse-phase column (FA) and then lyophilized to give compound 57 (11.70 mg, 19.22 μmol, 26.78% yield, FA salt) as an off-white solid. LCMS (ESI) m / z [M+H] + = 553.3;1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J=5.2 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.86 (s, 1H), 7.84-7.83 (m, 1H), 7.81 (s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.61-7.60 (m, 1H), 7.32-7.31 (m, 1H), 6.78-6.77 (m, 1H), 4.14 (s, 2H), 3.55 (s, 3H), 3.33 (s, 3H), 2.06 (m, 3H).

[0321] Example 57. Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (Compound 58) [ka] Step 1: Preparation of tert-butyl (2-oxo-2-((4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-yl)amino)ethyl)carbamate (Intermediate C) [ka] tert-Butyl N-[2-[[4-(3-bromophenyl)thiazol-2-yl]amino]-2-oxo-ethyl]carbamate (6 g, 14.55 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.06 g, 16.01 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (948.45 mg, 1.46 mmol), and KOAc (2.86 g, 29.10 mmol) were taken up in dioxane (60 mL), and the mixture was purged with N three times. The resulting mixture was then stirred at 100 °C for 2 h. The reaction mixture was filtered and the filtrate was evaporated to dryness to give Intermediate C (6.68 g, crude) as a black oil. LCMS (ESI) m / z [M+H] + =460.3.

[0322] Step 2: Preparation of tert-butyl (2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)carbamate (Intermediate E) [ka] Intermediate C (6.68 g, 14.54 mmol), 3-bromo-1-methyl-pyrazole (2.34 g, 14.54 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (947.76 mg, 1.45 mmol), and KPO (6.17 g, 29.08 mmol) were taken in dioxane (50 mL) and HO (10 mL), and the mixture was purged with N three times. The resulting mixture was then stirred at 80 °C for 4 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 5 / 1 to 1:1) and concentrated in vacuo to give intermediate E (3 g, 7.26 mmol, 49.89% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =414.1.

[0323] Step 3: Preparation of 2-amino-N-(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)acetamide (Intermediate F) [ka] Intermediate E (3 g, 7.26 mmol) was dissolved in HCl / dioxane (20 mL). The mixture was stirred at 30° C. for 1 h. The reaction mixture was evaporated to dryness to give Intermediate F (4.2 g, crude, HCl salt) as a yellow solid, which was used directly for the next step. LCMS (ESI) m / z [M+H] + = 314.2.

[0324] Step 4: Preparation of 1-(tert-butyl)-N-(2-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-2-oxoethyl)-1H-pyrrole-3-carboxamide (compound 58) [ka] To a mixture of 1-tert-butylpyrrole-3-carboxylic acid [prepared according to the method in Example 34] (1.43 g, 8.58 mmol) in DCM (20 mL) was added HATU (2.61 g, 6.86 mmol) and DIPEA (3.69 g, 28.58 mmol, 4.98 mL). The mixture was stirred at 30 °C for 15 min, and then Intermediate F (2 g, 5.72 mmol, HCl salt) was added and stirred for 1 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organics were washed with water and brine, dried over Na SO , filtered, and the filtrate was evaporated to dryness. The residue was purified by column chromatography (SiO, DCM / MeOH = 100 / 1 to 80:1) and concentrated in vacuo to give compound 58 (1.5 g, 3.18 mmol, 55.64% yield) as a white solid. LCMS (ESI) m / z [M+H] + =463.3;1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.38 (s, 1H), 8.19-8.16 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.68 (s, 1H), 7.53-7.52 (m, 1H), 7.46-7.42 (m, 1H), 6.98-6.96 (m, 1H), 6.73 (d, J = 2.0 Hz, 1H), 6.48-6.47 (m, 1H), 4.10 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 1.49 (s, 9H).

[0325] Example 58. Preparation of (S)—N-(1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-4-(methylthio)-1-oxobutan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 59) [ka] Step 1: Preparation of 4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-amine (Intermediate C) [ka] A mixture of 4-(3-bromophenyl)thiazol-2-amine (1 g, 3.92 mmol), (2-methyl-4-pyridyl)boronic acid (590.43 mg, 4.31 mmol), KCO (1.63 g, 11.76 mmol), and Pd(dppf)Cl (286.79 mg, 391.95 μmol) in dioxane (10 mL) and HO (3 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 3 / 1) and concentrated to give intermediate C (1 g, 3.74 mmol, 95.43% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =268.2; 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J=5.2 Hz, 1H), 8.10-8.08 (m, 1H), 7.85-7.83 (m, 1H), 7.59-7.54 (m, 1H), 7.53-7.47 (m, 1H), 7.45 (s, 1H), 7.40-7.38 (m, 1H), 6.84 (s, 1H), 5.04 (br s, 2H), 2.66 (s, 3H).

[0326] Step 2: Preparation of (S)-tert-butyl (1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (Intermediate E) [ka] To a solution of intermediate C (0.5 g, 1.87 mmol) and 2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (699.45 mg, 2.81 mmol) in DCM (8 mL) was added EEDQ (924.97 mg, 3.74 mmol). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 1 / 1) and concentrated to give intermediate E (0.74 g, 1.48 mmol, 79.35% yield) as a yellow oil. LCMS (ESI) m / z [M+H] + =499.1;100% ee value.

[0327] Step 3: Preparation of (S)-2-amino-N-(4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)-4-(methylthio)butanamide (Intermediate F) [ka] To a solution of intermediate E (0.7 g, 1.40 mmol) in MeOH (5 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated to dryness to give intermediate F (0.6 g, crude, HCl salt) as a yellow solid, which was used for the next step without further purification. LCMS (ESI) m / z [M+H] + = 399.0.

[0328] Step 4: Preparation of (S)—N-(1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-4-(methylthio)-1-oxobutan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 59) [ka] To a solution of intermediate F (200 mg, 459.76 μmol, HCl salt) in DCM (3 mL) was added 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (95.68 mg, 505.74 μmol), HOBt (62.12 mg, 459.76 μmol), DIEA (237.68 mg, 1.84 mmol, 320.32 μL), and EDCI (105.76 mg, 551.72 μmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated to dryness to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.1% TFA)-acetonitrile]; B%: 18%-48%) and lyophilized to give compound 59 (95.37 mg, 167.40 μmol, 36.41% yield) as a white solid. LCMS (ESI) m / z [M+H] + =570.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.84 (br s, 1H), 8.53-8.41 (m, 2H), 8.33-8.07 (m, 3H), 7.99-7.86 (m, 3H), 7.70-7.68 (m, 1H), 7.37-7.26 (m, 1H), 6.79 (dd, J=3.2 Hz, 1.60 Hz, 1H), 4.78-4.65 (m, 1H), 3.58 (s, 3H), 2.76 (br d, J=2.4 Hz, 3H), 2.16-1.96 (m, 6H);ee%=100%.

[0329] Example 59. Preparation of (S)—N-(3-methoxy-1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 60) [ka] Step 1: Preparation of (S)-tert-butyl (3-methoxy-1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)carbamate (Intermediate E) [ka] A mixture of 4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-amine [prepared according to the method in Example 58] (950 mg, 3.55 mmol), 2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (934.84 mg, 4.26 mmol), EEDQ (1.76 g, 7.11 mmol) in DCM (10 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25 °C for 12 h. The reaction mixture was quenched by the addition of water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (NHOH) and lyophilized to give Intermediate E (1.3 g, 2.77 mmol, 78.08% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =469.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.54 (d, J = 5.2 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.67-7.48 (m, 3H), 7.17 (br d, J = 7.6 Hz, 1H), 4.52 (br d, J = 6.6 Hz, 1H), 3.58 (br d, J = 5.6 Hz, 2H), 3.27 (s, 3H), 2.56 (s, 3H), 1.44-1.25 (m, 9H).

[0330] Step 2: Preparation of (S)-2-amino-3-methoxy-N-(4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)propanamide (Intermediate F) [ka] A mixture of Intermediate E (300 mg, 640.25 μmol) in HCl / dioxane (4 M, 1.60 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25° C. for 2 h. The mixture was concentrated to remove the solvent to give Intermediate F (350 mg, crude, HCl salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 369.2.

[0331] Step 3: Preparation of (S)—N-(3-methoxy-1-((4-(3-(2-methylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 60) [ka] A mixture of Intermediate F (250 mg, 617.42 μmol, HCl salt), 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (140.17 mg, 740.90 μmol), DIEA (398.97 mg, 3.09 mmol, 537.70 μL), HOBt (166.85 mg, 1.23 mmol), and EDCI (236.72 mg, 1.23 mmol) in DMF (3 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 25 °C for 12 h. Water (10 mL) was added to the reaction mixture, and it was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 3), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give compound 60 (160 mg, 296.50 μmol, 48.02% yield, FA salt) as a yellow solid. LCMS (ESI) m / z [M+H]+ =540.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.4 Hz, 1H), 8.27-8.21 (m, 1H), 8.13 (s, 1H), 8.01-7.90 (m, 2H), 7.76-7.68 (m, 2H), 7.66-7.52 (m, 3H), 7.28 (dd, J = 2.2, 3.4 Hz, 1H), 6.79 (dd, J = 1.8 Hz, 3.2 Hz, 1H), 4.86-4.84 (m, 1H), 3.79-3.63 (m, 2H), 3.47 (s, 3H), 3.29 (s, 3H), 2.53 (br s, 3H);ee%=95.212%.

[0332] Example 60. Preparation of (S)—N-(1-((4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 61) [ka] Step 1: Preparation of 4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-amine (Intermediate C) [ka] To a solution of 4-(3-bromophenyl)thiazol-2-amine (600 mg, 2.35 mmol) and (2,6-dimethyl-4-pyridyl)boronic acid (532.56 mg, 3.53 mmol) in dioxane / HO (10 mL) (4 / 1) was added KPO (1.50 g, 7.06 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (229.91 mg, 352.76 μmol). The mixture was stirred at 75 °C under N for 4 h. The reaction mixture was diluted with HO (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 1:0 to 1:1) and concentrated in vacuo to give intermediate C (400 mg, 1.42 mmol, 60.45% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + =282.0; 1 H NMR (400 MHz, methanol-d4) δ 8.11 (m, 1H), 7.83-7.81 (m, 1H), 7.61 (m, 1H), 7.50-7.48 (m, 1H), 7.42 (s, 2H), 6.96 (s, 1H), 2.56 (s, 6H).

[0333] Step 2: Preparation of (S)-tert-butyl (1-((4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (Intermediate E) [ka] To a solution of (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (397.37 mg, 1.81 mmol) in DCM (5 mL) was added EEDQ (597.63 mg, 2.42 mmol), and the mixture was stirred at 30° C. for 0.5 h. Intermediate C (340 mg, 1.21 mmol) was then added to the mixture. The mixture was stirred at 30° C. for 16 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (0.1% FA condition), concentrated to remove acetonitrile, and then extracted with EtOAc (20 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to give Intermediate E (300 mg, 621.64 μmol, 51.45% yield) as a white solid. LCMS (ESI) m / z [M+H] + =483.1;1H NMR (400 MHz, CDCl3) δ 9.88-9.80 (m, 1H), 8.09 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.58-7.49 (m, 2H), 7.25 (d, J = 4.0 Hz, 3H), 5.47-5.46 (m, 1H), 4.55 (br d, J = 2.0 Hz, 1H), 3.98-3.95 (m, 1H), 3.63-3.61 (m, 1H), 3.44 (s, 3H), 1.62 (br s, 6H), 1.50 (s, 9H).

[0334] Step 3: Preparation of (S)-2-amino-N-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)-3-methoxypropanamide (Intermediate F) [ka] A solution of intermediate E (300 mg, 621.64 μmol) in HCl / dioxane (4 M, 5 mL) was stirred at 30° C. for 0.5 h. The reaction mixture was directly concentrated to give intermediate F (260 mg, 620.61 μmol, 99.83% yield, HCl salt) as a white solid, which was used directly in the next step. LCMS (ESI) m / z [M+H] + =383.2; 1 H NMR (400 MHz, DMSO-d6) δ 13.02-12.95 (m, 1H), 8.65-8.62 (m, 3H), 8.46 (s, 1H), 8.20 (s, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.96-7.94 (m, 1H), 7.73-7.69 (m, 1H), 4.37 (br d, J = 4.4 Hz, 1H), 3.92-3.79 (m, 2H), 3.32 (s, 3H), 2.79 (s, 6H).

[0335] Step 4: Preparation of (S)—N-(1-((4-(3-(2,6-dimethylpyridin-4-yl)phenyl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 61) [ka] To a solution of intermediate F (150 mg, 358.05 μmol, HCl salt) in DMF (2 mL) was added 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (74.51 mg, 393.85 μmol) and DIEA (231.37 mg, 1.79 mmol, 311.82 μL), and then EDCI (102.96 mg, 537.07 μmol) and HOBt (58.06 mg, 429.66 μmol) were added to the mixture. The mixture was stirred at 30° C. for 16 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by reverse phase (0.1% FA condition) and lyophilized to give compound 61 (109.15 mg, 182.01 μmol, 50.84% ​​yield, FA salt) as a white solid. LCMS (ESI) m / z [M+H] + =554.2; 1 H NMR (400 MHz, methanol-d4) δ 8.26 (br d, J = 2.4 Hz, 1H), 8.02-7.95 (m, 1H), 7.91-7.90 (m, 1H), 7.70-7.63 (m, 1H), 7.54-7.47 (m, 4H), 7.26-7.25 (m, 1H), 6.83 (m, 1H), 4.97-4.95 (m, 1H), 3.88-3.82 (m, 2H), 3.81-3.79 (m, 3H), 3.44-3.42 (m, 3H), 2.58 (d, J = 1.6 Hz, 6H);ee% =100%.

[0336] Example 61 Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 62) [ka] Step 1: Preparation of (S)-tert-butyl (3-methoxy-1-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)carbamate (Intermediate G) [ka] To a solution of 4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-amine (prepared according to the method in Example 2) (500 mg, 1.95 mmol) and (2S)-2-(tertbutoxycarbonylamino)-3-methoxy-propanoic acid (513.18 mg, 2.34 mmol) in DCM (5 mL) was added EEDQ (723.56 mg, 2.93 mmol), and the mixture was stirred at 30 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 3 / 1 to 2:1) and concentrated to give intermediate G (800 mg, 1.71 mmol, 87.84% yield) as a white solid. LCMS (ESI) m / z [M+H] + =458.4;ee%=100%.

[0337] Step 2: Preparation of (S)-2-amino-3-methoxy-N-(4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)propanamide (Intermediate H) [ka] A solution of intermediate G (0.8 g, 1.75 mmol) in 4 M HCl / dioxane (10 mL) was stirred at 30° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was triturated with MTBE (10 mL), filtered, and dried in vacuo to give intermediate H (600 mg, 1.52 mmol, 87.12% yield, HCl salt) as a white solid. LCMS (ESI) m / z [M+H] + = 358.4; 1H NMR (400MHz, DMSO-d6) δ 12.99 (br s, 1H), 8.70-8.69 (m, 3H), 8.39-8.38 (m, 1H), 7.82-7.77 (m, 4H), 7.46-7.43 (m, 1H), 6.74-6.73 (m, 1H), 4.34-4.32 (m, 1H), 3.93-3.81 (m, 5H), 3.31 (m, 3H);ee%=100%.

[0338] Step 3: Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 62) [ka] To a solution of 1-tert-butylpyrrole-3-carboxylic acid [prepared according to the method in Example 34] (63.67 mg, 380.82 μmol), EDCI (97.34 mg, 507.76 μmol), HOBt (68.61 mg, 507.76 μmol), and DIEA (164.06 mg, 1.27 mmol, 221.10 μL) in DCM (1 mL) was added intermediate H (100 mg, 253.88 μmol, HCl salt), and the mixture was stirred at 30° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give compound 62 (31.20 mg, 60.69 μmol, 23.90% yield) as a white solid. LCMS (ESI) m / z [M+H] + =507.4; 1H NMR (400 MHz, methanol-d4) δ 8.33-8.32 (m, 1H), 7.84-7.82 (m, 1H), 7.71-7.69 (m, 1H), 7.64-7.61 (m, 2H), 7.45-7.40 (m, 2H), 6.95-6.94 (m, 1H), 6.67-6.66 (m, 1H), 6.61-6.59 (m, 1H), 4.97-4.94 (m, 1H), 3.95 (s, 3H), 3.86-3.82 (m, 2H), 3.43 (s, 3H), 1.56 (s, 9H);ee%=100%.

[0339] Example 62 Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 63) [ka] Step 1: Preparation of 7-(2-aminothiazol-4-yl)-2-methylisoquinolin-1(2H)-one (Intermediate E) [ka] A mixture of 4-bromothiazol-2-amine (500 mg, 2.79 mmol), 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one [prepared according to the method in Example 7] (955.59 mg, 3.35 mmol), KPO (1.78 g, 8.38 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (182.01 mg, 279.27 μmol) in dioxane (8 mL) and HO (2 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 100° C. for 2 h. Water (50 mL) was added, and the reaction mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by reverse-phase HPLC (0.1% NH H O) and lyophilized to give Intermediate E (400 mg, 1.37 mmol, 48.98% yield) as a yellow solid. LCMS (ESI) m / z [M+H] + = 258.3.

[0340] Step 2: Preparation of (S)-tert-butyl (3-methoxy-1-((4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)carbamate (Intermediate G) [ka] To a solution of intermediate E (330 mg, 1.28 mmol) and (2S)-2-(tertbutoxycarbonylamino)-3-methoxy-propanoic acid (337.40 mg, 1.54 mmol) in DCM (20 mL) was added EEDQ (475.72 mg, 1.92 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The crude product was triturated with MeOH (20 mL) at 25 °C for 10 min, then filtered and dried in vacuo to give intermediate G (400 mg, 817.74 μmol, 63.76% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 459.0.

[0341] Step 3: Preparation of (S)-2-amino-3-methoxy-N-(4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thiazol-2-yl)propanamide (Intermediate H) [ka] To a solution of intermediate G (200 mg, 436.18 μmol) in dioxane (2 mL) was added HCl / dioxane (2 mL). The mixture was stirred at 25° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give intermediate H (180 mg, crude, HCl salt) as a brown solid. LCMS (ESI) m / z [M+H] + = 359.1.

[0342] Step 4: Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 63) [ka] To a solution of [prepared according to the method in Example 34] (50.81 mg, 303.89 μmol) in DCM (2 mL) was added EDCI (58.26 mg, 303.89 μmol), HOBt (41.06 mg, 303.89 μmol), and DIEA (104.74 mg, 810.38 μmol, 141.15 μL), followed by the addition of Intermediate H (80 mg, 202.60 μmol, HCl salt). The mixture was stirred at 25° C. for 12 hours. Water (30 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.075% TFA)-acetonitrile]; B%: 35%-65%) and then re-purified by preparative TLC (SiO, DCM: EtOAc = 2:1) to give compound 63 (17 mg, 33.49 μmol, 16.53% yield) as a white solid. LCMS (ESI) m / z [M+H] + =508.4. 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.22-8.20 (m, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.63-7.61 (m, 1H), 7.48 (d, J=7.2 Hz, 1H), 6.96-6.95 (m, 1H), 6.63 (d, J=6.8 Hz, 1H), 6.51-6.50 (m, 1H), 4.94-4.89 (m, 1H), 3.75-3.67 (m, 2H), 3.52 (s, 3H), 3.32-3.31 (m, 3H), 1.49 (s, 9H);ee%=89.392%.

[0343] Example 63 Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 64) [ka] Step 1: Preparation of 7-(2-aminothiazol-4-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (Intermediate D) [ka] A mixture of 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [prepared according to the method in Example 7] (200 mg, 696.47 μmol), 4-bromothiazol-2-amine (124.70 mg, 696.47 μmol), KPO (591.35 mg, 2.79 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (45.39 mg, 69.65 μmol) in dioxane (2 mL) and HO (0.5 mL) was degassed and purged with N three times, and then the mixture was stirred under N atmosphere at 100° C. for 2 h. Water (20 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was triturated with MeOH (10 mL) at 25 °C for 10 min, then filtered and dried in vacuo to give Intermediate D (180 mg, 691.75 μmol, 99.32% yield) as a white solid. LCMS (ESI) m / z [M+H] + = 260.1.

[0344] Step 2: Preparation of (S)-tert-butyl (3-methoxy-1-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)carbamate (Intermediate F) [ka] To a solution of intermediate D (110.86 mg, 427.50 μmol) and (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (103.09 mg, 470.25 μmol) in DCM (2 mL) was added EEDQ (158.57 mg, 641.25 μmol). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The crude product was triturated with MeOH (5 mL) at 25° C. for 10 min, then filtered and dried in vacuo to give intermediate F (150 mg, 325.70 μmol, 76.19% yield) as a brown solid. LCMS (ESI) m / z [M+H] + = 461.4.

[0345] Step 3: Preparation of (S)-2-amino-3-methoxy-N-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)propanamide (Intermediate G) [ka] To a solution of intermediate F (100 mg, 217.13 μmol) in MeOH (2 mL) was added HCl / dioxane (2 mL). The mixture was stirred at 30° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give intermediate G (80 mg, crude, HCl salt) as a yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 361.2.

[0346] Step 4: Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-((4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)thiazol-2-yl)amino)-1-oxopropan-2-yl)-1H-pyrrole-3-carboxamide (Compound 64) [ka] To a solution of [prepared according to the method in Example 34] (50.55 mg, 302.35 μmol) in DMF (2 mL) was added EDCI (57.96 mg, 302.35 μmol), HOBt (40.85 mg, 302.35 μmol), and DIEA (104.20 mg, 806.27 μmol, 140.43 μL), followed by the addition of Intermediate G (80 mg, 201.57 μmol, HCl salt). The mixture was stirred at 25° C. for 12 hours. Water (30 mL) was added, and the reaction mixture was extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (mobile phase: [water (0.075% TFA)-acetonitrile]; B%: 35%-65%), then repurified by preparative TLC (SiO, DCM: EtOAc = 2:1) and concentrated to give compound 64 (17 mg, 33.36 μmol, 16.55% yield) as a white solid. LCMS (ESI) m / z [M+H] + =510.3; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 7.98-7.91 (m, 2H), 7.68 (s, 1H), 7.62-7.61 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.96-6.95 (m, 1H), 6.50-6.49 (m, 1H), 4.93-4.88 (m, 1H), 3.74-3.66 (m, 2H), 3.58-3.55 (m, 2H), 3.31 (s, 3H), 3.05 (s, 3H), 3.01-2.98 (m, 2H), 1.49 (s, 9H);ee%=100%.

[0347] Example 64 (S)—N-(3-methoxy-1-oxo-1-((4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)amino)propan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (Compound 65) [ka] Step 1: Preparation of (S)-tert-butyl (1-((4-(3-bromophenyl)thiazol-2-yl)amino)-3-methoxy-1-oxopropan-2-yl)carbamate (Intermediate C) [ka] A mixture of (2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (300 mg, 1.37 mmol), 4-(3-bromophenyl)thiazol-2-amine (418.95 mg, 1.64 mmol), and EEDQ (676.78 mg, 2.74 mmol) in DCM (5 mL) was degassed and purged with N three times, then the mixture was stirred under N atmosphere at 25 °C for 12 h. The reaction mixture was poured into HO (10 mL) and then extracted with EtOAc (3 mL × 4). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (FA) and lyophilized to give intermediate C (410 mg, 843.62 μmol, 61.65% yield) as a white gum. LCMS (ESI) m / z [M+H] + = 458.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.53-12.30 (m, 1H), 8.11 (s, 1H), 7.95-7.88 (m, 1H), 7.79 (s, 1H), 7.54-7.50 (m, 1H), 7.41 (s, 1H), 7.17 (d, J = 6.8 Hz, 1H), 4.50 (d, J = 5.6 Hz, 1H), 3.57 (d, J = 5.2 Hz, 2H), 3.27 (s, 4H), 1.39 (s, 9H).

[0348] Step 2: Preparation of (S)-tert-butyl (3-methoxy-1-oxo-1-((4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)amino)propan-2-yl)carbamate (Intermediate E) [ka] A mixture of intermediate C (300 mg, 657.39 μmol), tributyl(pyrimidin-4-yl)stannane (363.99 mg, 986.08 μmol), and Pd(PPh3)2Cl2 (46.14 mg, 65.74 μmol) in dioxane (3 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 100 °C for 2 h. The reaction mixture was poured into aqueous KF solution (5 mL), stirred for 30 min, and then extracted with EtOAc (2 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0–80% ethyl acetate / petroleum ether gradient) and concentrated under reduced pressure to give intermediate E (265 mg, 431.88 μmol, 65.70% yield) as a pale yellow solid. LCMS (ESI) m / z [M+H] + = 456.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 9.30 (d, J = 1.2 Hz, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.83-8.82 (m, 1H), 8.19-8.15 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.65-7.61 (m, 2H), 7.22-7.17 (m, 1H), 4.58-4.47 (m, 1H), 3.58 (d, J = 5.6 Hz, 2H), 3.28 (s, 3H), 1.40 (s, 9H).

[0349] Step 3: Preparation of (S)-2-amino-3-methoxy-N-(4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)propanamide (Intermediate F) [ka] To a solution of intermediate E (100 mg, 219.52 μmol) in dioxane (1 mL) was added HCl / dioxane (4 M, 548.81 μL), and the mixture was then stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was washed with MTBE (6 mL) and concentrated in vacuo to give intermediate F (78 mg, crude) as a pale yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z [M+H] + = 356.2.

[0350] Step 4: Preparation of (S)—N-(3-methoxy-1-oxo-1-((4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)amino)propan-2-yl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxamide (compound 65) [ka] To a solution of 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (26.62 mg, 140.68 μmol) and Intermediate F (50 mg, 140.68 μmol) in DMF (0.3 mL) was added HOBT (38.02 mg, 281.36 μmol), EDCI (53.94 mg, 281.36 μmol), and DIEA (54.55 mg, 422.04 μmol). The resulting mixture was stirred at 25° C. for 6 hours. The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layer was washed with brine (5 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent: 0-100% ethyl acetate / petroleum ether gradient), then repurified via preparative HPLC (TFA conditions) and lyophilized to give compound 65 (18 mg, 27.22 μmol, 19.35% yield, TFA salt) as an off-white solid. LCMS (ESI) m / z [M+H] + = 527.2; 1H NMR (400 MHz, DMSO+D2O) δ 9.27 (d, J = 1.2 Hz, 1H), 8.89 (d, J = 5.2 Hz, 1H), 8.79 (s, 1H), 8.15-8.12 (m, 2H), 8.09 (d, J = 7.6 Hz, 1H), 7.98-7.97 (m, 1H), 7.79 (s, 1H), 7.66-7.61 (m, 1H), 7.31-7.28 (m, 1H), 6.80-6.79 (m, 1H), 4.94-4.89 (m, 1H), 3.74-3.71 (m, 2H), 3.54 (s, 3H), 3.32 (s, 3H);ee%=100%.

[0351] Example 65. Preparation of (S)-1-(tert-butyl)-N-(3-methoxy-1-oxo-1-((4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)amino)propan-2-yl)-1H-pyrrole-3-carboxamide (Compound 66) [ka] To a solution of (S)-2-amino-3-methoxy-N-(4-(3-(pyrimidin-4-yl)phenyl)thiazol-2-yl)propanamide [prepared according to the method in Example 64] (50 mg, 140.68 μmol, HCl salt) and 1-tert-butylpyrrole-3-carboxylic acid [prepared according to the method in Example 34] (23.52 mg, 140.68 μmol) in DMF (0.3 mL) was added HOBt (38.02 mg, 281.36 μmol), EDCI (53.94 mg, 281.36 μmol), and DIEA (54.54 mg, 422.04 μmol). The resulting mixture was stirred at 25° C. for 6 hours. The reaction mixture was poured into HO (5 mL) and extracted with EtOAc (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient eluent at 30 mL / min) and concentrated to give compound 66 (20 mg, 39.64 μmol, 28.17% yield) as an off-white solid. LCMS (ESI) m / z [M+H] + =505.4; 1 H NMR (400 MHz, DMSO-d6) δ 12.63-12.43 (m, 1H), 9.30 (s, 1H), 8.96-8.89 (m, 1H), 8.83 (s, 1H), 8.20-8.07 (m, 3H), 7.97-7.91 (m, 1H), 7.82 (s, 1H), 7.69-7.59 (m, 2H), 6.97 (br s, 1H), 6.58-6.48 (m, 1H), 4.96-4.91 (m, 1H), 3.73-3.71 (m, 2H), 2.70 (d, J = 1.0 Hz, 3H), 1.50 (s, 9H);ee%=94.616%.

[0352] Example 66. Preparation of (S)-1-(methylsulfonyl)-N-(4-(methylthio)-1-oxo-1-((4-(3-(pyridin-4-yl)phenyl)thiazol-2-yl)amino)butan-2-yl)-1H-pyrrole-3-carboxamide (Compound 67) [ka] To a mixture of (2S)-2-amino-4-methylsulfanyl-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]butanamide (2 g, 4.75 mmol, HCl salt) and 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (898.81 mg, 4.75 mmol) in DMF (20 mL) was added EDCI (1.37 g, 7.13 mmol), HOBt (962.92 mg, 7.13 mmol), and DIEA (2.46 g, 19.00 mmol, 3.31 mL), and the mixture was stirred at 25 °C for 3 h. The mixture was poured into HO (100 mL), and the precipitate was collected by filtration. The solid was triturated with MeOH (20 mL), and the precipitate was collected by filtration. The solid was dissolved in DMSO (10 mL), then the mixture was poured into MeOH (50 mL), and the precipitate that formed was collected by filtration and lyophilized to give compound 67 (2.05 g, 3.66 mmol, 77.01% yield) as a white solid. LCMS (ESI) m / z [M+H] + =555.9; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.68-8.66 (m, 2H), 8.46 (d, J=7.2 Hz, 1H), 8.31-8.30 (m, 1H), 8.02-8.00 (m, 1H), 7.94-7.96 (m, 1H), 7.83 (s, 1H), 7.73-7.74 (m, 3H), 7.61-7.57 (m, 1H), 7.31-7.29 (m, 1H), 6.79-6.77 (m, 1H), 4.74-4.69 (m, 1H), 3.57 (s, 3H), 2.67-2.53 (m, 2H), 2.13-2.01 (m, 5H);ee%=100%.

[0353] Example 67. Preparation of N-[(1S)-1-methyl-2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (Compound 68) [ka] Step 1: Preparation of tert-butyl N-[(1S)-1-methyl-2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]carbamate (Intermediate E) [ka] To a mixture of -[3-(4-pyridyl)phenyl]thiazol-2-amine [prepared according to the method in Example 4] (205 mg, 809.25 μmol) and (2S)-2-(tert-butoxycarbonylamino)propanoic acid (153.12 mg, 809.25 μmol) in DCM (7 mL) was added EEDQ (400.24 mg, 1.62 mmol) at 30° C. The reaction mixture was stirred at 30° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column (NH 3 .HO condition) to give intermediate E (80 mg, 188.45 μmol) as a yellow solid. LCMS (ESI) m / z [M+H] + = 425.3; 1 H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.84 (s, 1H), 7.77-7.75 (m, 3H), 7.62-7.58 (m, 1H), 7.26 (d, J=6.8 Hz, 1H), 4.29-4.25 (m, 1H), 1.39 (s, 9H), 1.30-1.28 (m, 3H). Chiral HPLC: OJ-3-MeOH (DEA)-5-40-3mL-35T, t=1.744 min, ee%=100%.

[0354] Step 2: Preparation of (2S)-2-amino-N-[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]propanamide (Intermediate F) [ka] To a mixture of intermediate E (80 mg, 188.45 μmol) in dioxane (2 mL) was added HCl / dioxane (4 M, 2 mL) at 30° C. The reaction mixture was stirred at 30° C. for 2 hours. The reaction mixture was filtered and dried in vacuo to give intermediate F (75 mg, 172.20 μmol, 91% yield, HCl salt) as a yellow solid. LCMS (ESI) m / z [M+H] + = 325.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.89 (br s, 1H), 9.00 (d, J=6.8 Hz, 2H), 8.53 (br s, 2H), 8.48 (s, 1H), 8.43 (d, J=6.8 Hz, 2H), 8.16 (d, J=7.6 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.73-7.69 (m, 1H), 4.23-4.15 (m, 1H), 1.51 (d, J=7.2 Hz, 3H).

[0355] Step 3: Preparation of N-[(1S)-1-methyl-2-oxo-2-[[4-[3-(4-pyridyl)phenyl]thiazol-2-yl]amino]ethyl]-1-methylsulfonyl-pyrrole-3-carboxamide (compound 68) [ka] To a mixture of intermediate F (30 mg, 83.13 μmol, HCl salt) and 1-methylsulfonylpyrrole-3-carboxylic acid [prepared according to the method in Example 4] (15.73 mg, 83.13 μmol) in DMF (1 mL) was added DIPEA (53.72 mg, 415.67 μmol, 72.40 μL), EDCI (23.91 mg, 124.70 μmol), and HOBt (16.85 mg, 124.70 μmol) at 30° C. The reaction mixture was stirred at 30° C. for 16 hours. ...

Claims

1. structure: 【Chemistry 1】 (In the formula, Each of X, Y, and Z is independently N or CH; R １ is H, optionally substituted C １ -C ６ Acyl, optionally substituted C １ -C ６ Alkyl, optionally substituted C １ -C ６ Heteroalkyl, optionally substituted C ２ -C ９ Heterocyclyl, or -SO ２ R ６ and R ２ and R ５ Each of is independently H or optionally substituted C １ -C ６ is alkyl, R ３ is H, R ４ is H, R ６ is an optionally substituted C １ -C ６ Alkyl or -NR ７ R ８ and R ７ and R ８ independently represents an optionally substituted C １ -C ６ is alkyl, Het is 【Chemistry 2】 and A is an optionally substituted C ６ -C １０ Arylene, optionally substituted C ２ -C ９ Heterocyclylene, or optionally substituted C ２ -C ９ Heteroarylene, L is absent, optionally substituted C １ -C ６ Alkylene, optionally substituted C １ -C ６ Heteroalkylene, or optionally substituted C ２ -C ６ alkenylene, B is H, cyano, optionally substituted C ６ -C １０ Aryl, optionally substituted C ３ -C １０ Cycloalkyl, optionally substituted C ２ -C ９ heterocyclyl, or optionally substituted C ２ -C ９ Heteroaryl) or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein each of X, Y, and Z is CH.

3. 2. The compound of claim 1, wherein X is N and each of Y and Z is CH.

4. 2. The compound of claim 1, wherein Z is N and each of X and Y is CH.

5. 2. The compound of claim 1, wherein Y is N and each of X and Z is CH.

6. R ２ The compound according to any one of claims 1 to 5, wherein is H.

7. R ５ The compound according to any one of claims 1 to 6, wherein is H.

8. R ５ is an optionally substituted C １ -C ６ The compound according to any one of claims 1 to 6, which is alkyl.

9. R ５ The compound of claim 8 , wherein is methyl.

10. R ３ The compound according to any one of claims 1 to 9, wherein is H.

11. R ４ The compound according to any one of claims 1 to 10, wherein is H.

12. The compound of any one of claims 1 to 11, wherein L is absent.

13. L is an optionally substituted C １ -C ６ The compound according to any one of claims 1 to 11, which is an alkylene.

14. L is, 【Chemistry 3】 14. The compound of claim 13,

15. L is an optionally substituted C １ -C ６ The compound according to any one of claims 1 to 11, which is a heteroalkylene.

16. L is, 【Chemistry 4】 16. The compound of claim 15,

17. L is an optionally substituted C ２ -C ６ The compound according to any one of claims 1 to 11, which is an alkenylene.

18. L is, 【Chemistry 5】 18. The compound of claim 17,

19. A is an optionally substituted C ６ -C １０ The compound according to any one of claims 1 to 18, which is an arylene.

20. A is, 【Chemistry 6】 20. The compound of claim 19,

21. A is an optionally substituted C ２ -C ９ The compound according to any one of claims 1 to 18, which is a heteroarylene.

22. A is, 【Chemistry 7】 22. The compound of claim 21 ,

23. A is, 【Chemistry 8】 23. The compound of claim 22, wherein

24. A is an optionally substituted C ２ -C ９ The compound according to any one of claims 1 to 18, which is a heterocyclylene.

25. A is, 【Chemistry 9】 25. The compound of claim 24, wherein

26. The compound according to any one of claims 1 to 25, wherein B is H.

27. The compound of any one of claims 1 to 25, wherein B is cyano.

28. B is an optionally substituted C ６ -C １０ The compound according to any one of claims 1 to 25, which is aryl.

29. B is, 【Chemistry 10】 29. The compound of claim 28,

30. B is an optionally substituted C ３ -C １０ The compound of any one of claims 1 to 25, which is cycloalkyl.

31. B is an optionally substituted C ２ -C ９ The compound of any one of claims 1 to 25 which is heterocyclyl.

32. B is, 【Chemistry 11】 32. The compound of claim 31 ,

33. B is, 【Chemistry 12】 32. The compound of claim 31 ,

34. B is, 【Chemistry 13】 32. The compound of claim 31 ,

35. B is, 【Chemistry 14】 32. The compound of claim 31 ,

36. B is, 【Chemistry 15】 36. The compound of claim 35,

37. B is an optionally substituted C ２ -C ９ The compound of any one of claims 1 to 25, which is heteroaryl.

38. B is, 【Chemistry 16-1】 【Chemistry 16-2】 38. The compound of claim 37, wherein:

39. B is an optionally substituted C ３ -C ８ The compound of any one of claims 1 to 25, which is cycloalkyl.

40. B is, 【Chemistry 17】 40. The compound of claim 39, wherein:

41. R １ The compound according to any one of claims 1 to 40, wherein is H.

42. R １ is an optionally substituted C １ -C ６ The compound according to any one of claims 1 to 40, which is acyl.

43. R １ is acetyl.

44. R １ is an optionally substituted C １ -C ６ The compound according to any one of claims 1 to 40, which is alkyl.

45. R １ is methyl, tert-butyl, isopropyl, or 【Chemistry 18】 45. The compound of claim 44, wherein:

46. R １ is an optionally substituted C １ -C ６ The compound of any one of claims 1 to 40, which is heteroalkyl.

47. R １ teeth, 【Chemistry 19】 47. The compound of claim 46,

48. R １ is an optionally substituted C ２ -C ９ The compound of any one of claims 1 to 40 which is heterocyclyl.

49. R １ teeth, 【Chemistry 20】 49. The compound of claim 48, wherein:

50. R １ is -SO ２ R ６ The compound according to any one of claims 1 to 40,

51. R ６ is an optionally substituted C １ -C ６ 51. The compound of claim 50, which is alkyl.

52. R ６ is methyl, isopropyl, or 【Chemistry 21】 52. The compound of claim 51, wherein:

53. R ６ is -NR ７ R ８ 51. The compound of claim 50,

54. R ７ is methyl.

55. R ８ is methyl.

56. The compound is the following compound: 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 【Chemistry 22-4】 【Chemistry 22-5】 【Chemistry 22-6】 【Chemistry 22-7】 【Chemistry 22-8】 【Chemistry 22-9】 56. The compound of any one of claims 1 to 55, having the structure:

57. 57. A pharmaceutical composition comprising a compound according to any one of claims 1 to 56 and a pharma- ceutically acceptable excipient.

58. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for reducing the activity of a BAF complex in a cell.

59. 59. The pharmaceutical composition of claim 58, wherein the BAF complex is in a cancer cell.

60. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for treating a BAF complex-associated disorder in a subject in need of said treatment.

61. 61. The pharmaceutical composition of claim 60, wherein the BAF complex-associated disorder is cancer or a viral infection.

62. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for a method of inhibiting BRM, said method comprising contacting a cell with said compound.

63. 63. The pharmaceutical composition of claim 62, wherein the cell is a cancer cell.

64. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for treating a disorder associated with a BRG1 loss-of-function mutation in a subject in need of said treatment.

65. 65. The pharmaceutical composition of claim 64, wherein the disorder associated with a BRG1 loss-of-function mutation is cancer.

66. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for inducing apoptosis in a cell.

67. 67. The pharmaceutical composition of claim 66, wherein the cell is a cancer cell.

68. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for treating cancer in a subject in need of said treatment.

69. 68. The pharmaceutical composition of any one of claims 59, 61, 63, 65, and 67, wherein the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumors, germ cell tumors, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumors, uterine sarcoma, gastrointestinal stromal tumors, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, or penile cancer.

70. 68. The pharmaceutical composition of any one of claims 59, 61, 63, 65, and 67, wherein the cancer is non-small cell lung cancer, colon cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, or penile cancer.

71. 68. The pharmaceutical composition of any one of claims 59, 61, 63, 65, and 67, wherein the cancer is non-small cell lung cancer.

72. 68. The pharmaceutical composition of any one of claims 59, 61, 63, 65, and 67, wherein the cancer is a soft tissue sarcoma.

73. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for treating a viral infection in a subject in need of said treatment.

74. 74. The pharmaceutical composition of claim 73, wherein the viral infection is an infection with a virus of the family Retroviridae, Hepadnaviridae, Flaviviridae, Adenoviridae, Herpesviridae, Papillomaviridae, Parvoviridae, Polyomaviridae, Paramyxoviridae, or Togaviridae.

75. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for treating melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer in a subject in need of said treatment.

76. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for reducing melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer tumor growth in a subject in need thereof.

77. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for inhibiting metastatic progression of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject.

78. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or the pharmaceutical composition according to claim 57, for inhibiting metastatic colonization of melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer in a subject.

79. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 56, or a pharmaceutical composition according to claim 57, for reducing the level and / or activity of BRG1 and / or BRM in melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer cells.

80. 80. The pharmaceutical composition of claim 79, wherein the cell is in a subject.

81. The pharmaceutical composition of any one of claims 75 to 80, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer is metastatic.

82. The pharmaceutical composition of any one of claims 75 to 78 and 80 to 81, wherein the subject is further administered an anti-cancer therapy.

83. 83. The pharmaceutical composition of claim 82, wherein the anti-cancer therapy is administration of a chemotherapeutic or cytotoxic agent, immunotherapy, surgery, radiation therapy, hyperthermia, or photocoagulation.

84. 83. The pharmaceutical composition of claim 82, wherein the anti-cancer therapy is surgery.

85. 83. The pharmaceutical composition of claim 82, wherein the anti-cancer therapy is the administration of a chemotherapeutic or cytotoxic agent.

86. 86. The pharmaceutical composition of claim 85, wherein the chemotherapeutic or cytotoxic agent is an antimetabolite, a mitotic inhibitor, an antitumor antibiotic, an asparagine-specific enzyme, a bisphosphonate, an anti-neoplastic agent, an alkylating agent, a DNA repair enzyme inhibitor, a histone deacetylase inhibitor, a corticosteroid, a demethylating agent, an immunomodulatory agent, a Janus-related kinase inhibitor, a phosphinositide 3-kinase inhibitor, a proteasome inhibitor, or a tyrosine kinase inhibitor.

87. 87. The pharmaceutical composition of claim 85 or 86, wherein the chemotherapeutic or cytotoxic agent is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp150, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

88. 88. The pharmaceutical composition of any one of claims 82-87, wherein said anti-cancer therapy and said pharmaceutical composition are administered or administered within 28 days of each other, each together in an amount effective to treat the subject.

89. The pharmaceutical composition of any one of claims 75 to 88, wherein the subject or cancer has and / or has been identified as having a BRG1 loss-of-function mutation.

90. 89. The pharmaceutical composition of any one of claims 75 to 88, wherein the subject or cancer has and / or has been identified as having a BRM loss-of-function mutation.

91. 91. The pharmaceutical composition of any one of claims 75-90, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer has failed to respond to or progressed following administration of one or more chemotherapeutic or cytotoxic agents.

92. 92. The pharmaceutical composition of any one of claims 75-91, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or hematological cancer is resistant or predicted to be resistant to one or more chemotherapeutic agents.

93. 93. The pharmaceutical composition of claim 91 or 92, wherein the chemotherapeutic or cytotoxic agent is dacarbazine, temozolomide, cisplatin, treosulfan, fotemustine, IMCgp150, a CTLA-4 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a mitogen-activated protein kinase inhibitor, and / or a protein kinase C inhibitor.

94. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is melanoma.

95. 95. The pharmaceutical composition of claim 94, wherein the melanoma is uveal melanoma.

96. 95. The pharmaceutical composition of claim 94, wherein the melanoma is a mucosal melanoma.

97. 95. The pharmaceutical composition of claim 94, wherein the melanoma is cutaneous melanoma.

98. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is a blood cancer.

99. 99. The pharmaceutical composition of claim 98, wherein the hematological cancer is multiple myeloma, large cell lymphoma, acute T-cell leukemia, acute myeloid leukemia, myelodysplastic syndrome, immunoglobulin A lambda myeloma, diffuse mixed histiocytic and lymphocytic lymphoma, B-cell lymphoma, acute lymphoblastic leukemia, diffuse large cell lymphoma, or non-Hodgkin's lymphoma.

100. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is prostate cancer.

101. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is breast cancer.

102. The pharmaceutical composition of claim 101, wherein the breast cancer is ER-positive breast cancer, ER-negative breast cancer, triple-positive breast cancer, or triple-negative breast cancer.

103. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is bone cancer.

104. 104. The pharmaceutical composition of claim 103, wherein the bone cancer is Ewing's sarcoma.

105. 94. The pharmaceutical composition of any one of claims 75 to 93, wherein the melanoma, prostate cancer, breast cancer, bone cancer, renal cell carcinoma, or blood cancer is renal cell carcinoma.

106. The pharmaceutical composition of claim 105, wherein the renal cell carcinoma is microphthalmia transcription factor (MITF) family translocation renal cell carcinoma.

Images