Pyrazolo-triazine and / or pyrazolo-pyrimidine derivatives as selective inhibitors of cyclin-dependent kinases

Abstract

The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof, and the use of these derivatives as pharmaceutically active agents, particularly for the prevention and / or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases, and infectious diseases. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one of the pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof.

Description

[Technical Field]

[0001] The present invention relates to pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof, and the use of these derivatives as pharmaceutically active agents, particularly for the prevention and / or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases, and infectious diseases. Furthermore, the present invention relates to pharmaceutical compositions comprising at least one of the pyrazolo[1,5-a][1,3,5]triazine derivatives and pyrazolo[1,5-a]pyrimidine derivatives and / or pharmaceutically acceptable salts thereof. [Background technology]

[0002] Cyclin-dependent kinase (CDK) family members induce cell cycle progression and are therefore considered attractive therapeutic targets, particularly in cancer. CDK family members that regulate other processes, such as transcription and RNA processing, have received less attention but are increasingly being experimentally demonstrated to be involved in different pathological processes. In addition to regulating the cell cycle, CDK / cyclin complexes have also been identified as conserved components of the RNA polymerase II (Pol II) transcription apparatus (Bregman et al., 2000, Front Biosci. 5:244-257). Currently, 20 mammalian CDKs are known. While CDKs 7-13 are involved in transcription, only CDKs 1, 2, 4, and 6 have demonstrable association with the cell cycle. CDK7, unique among mammalian CDKs, combines kinase activity and controls both cell cycle progression and transcription (Desai et al., 1995, Mol. Cell Biol. 15:345-350).

[0003] The general transcription factor TFIIH, purified from mammalian cells, consists of 10 subunits, seven of which (p62, p52, p44, p34, XPD, XPB, and TTDA) form a core complex. Three subunits (cyclin H, MAT1, and CDK7) form the CDK-activating kinase (CAK), which is linked to the TFIIH core via the XPD (ATP-dependent helicase) subunit of the complex. During transcription initiation, the helicase activity of TFIIH cleaves the core promoter DNA, while CDK7 phosphorylates serines 5 and 7 in the C-terminal domain (CTD) of Pol II (Akhtar et al., 2009, Mol. Cell 34, 387-393) and other transcription factors that regulate the transition from initiation to elongation (Larochelle et al., 2012, Nat. Strut. Mol. Biol. 19, 1108-1115). Therefore, CDK7 is an essential factor in the transcription process, suggesting that CDK7 is a target for cancer therapy, particularly in transcription-dependent cancers.

[0004] CDK7 has long been postulated to have a critical role in cell metabolism and viability. Transcriptional CDK inhibitors inhibit a number of short-lived anti-apoptotic proteins (myeloid cell leukemia-1 (Mcl-1), B-cell lymphoma extra-long (Bcl-xL) and XIAP (X-linked IAP), D-cyclin, c-Myc, Mdm-2 (which stabilizes p53), p21 waf1 CDK7 downregulates anti-apoptotic proteins such as nuclear factor-κB (NF-κB) and hypoxia-induced VEGF (Shapiro GI. 2006, J Clin Oncol; 24(11): 1770-83). Flavopiridol, a transcriptionally nonselective cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma cells by transcriptional repression and downregulation of Mcl-1. These findings supported the previous hypothesis that CDK7 may be a valuable target for drugs aimed at treating malignant diseases and cell cycle-related disorders (Lolli G and Johnson LN. 2005. Cell Cycle 4: 572-577).

[0005] CDK7 functions as a regulator of basal transcription, making it a therapeutic target for the treatment of numerous diseases and syndromes associated with mutations in regulatory regions and transcription factors, cofactors, chromatin regulators, and non-coding RNAs. These mutations may contribute to cancer, autoimmunity, neurological disorders, developmental syndromes, diabetes, cardiovascular disease, and obesity, among others. Several transcription factors regulate the release and extension of RNA polymerase II pauses, and altered expression or function can produce invasive tumor cells (c-Myc) or several autoimmune forms (AIRE) (Tong Ihn Lee and Richard A. Young, Cell, 2013, 152:1237-1251). Therefore, inhibiting human CDK7 kinase activity, whether associated with oncogenes through inhibition of basal transcription processes, is likely to confer antiproliferative activity through its functions in cell cycle progression and transcriptional regulation. More importantly, CDK7 has been shown to more dramatically regulate the exponential expression of oncogenic transcription factors than other housekeeping genes in cancer cells. Therefore, inhibiting CDK7 can affect the transcription of certain oncogenes and housekeeping genes in various ways, thus ensuring a therapeutic window.Therefore, transcriptional regulation and pharmacological inhibition by appropriate basal transcription inhibition by CDK7 can be applied to treat proliferative disorders (including cancer).CDK7, as a general regulator of transcription, is a therapeutic target for treating diseases such as inflammation, viral replication (such as HIV, EBV), cancer, and cardiac hypertrophy.

[0006] HIV-1 gene expression is controlled by the viral transactivator protein (Tat), which induces transcriptional elongation of HIV-1 long tandem repeats. This induction requires hyperphosphorylation of the C-terminal domain repeats of RNA polymerase II. To achieve this hyperphosphorylation, Tat stimulates the CTD kinase associated with the promoter complex, specifically the TFIIH-related CDK7 general transcription factor (Nekhai et al.; Biochem J. (2002) 364, 649-657). The inventors of U.S. Patent No. 615968 also report that Tat binds to CDK7 and that this interaction increases the ability of CDK7 to phosphorylate the CTD. The authors of U.S. Patent No. 615968 further disclose that transcriptional activation by Tat depends on the kinase activity of CDK7. Furthermore, Young Kyeung Kim et al. concluded that the recruitment and activation of TFIIH is the rate-limiting step in the emergence of HIV from latency (Young Kyeung Kim, EMBO (2006) 25, 3596-3604).

[0007] The levels of CDK7 and CDK9, as well as other components of the kinase complex (MAT-1 / cyclin H), are upregulated during human cytomegalovirus infection. Furthermore, the kinase activity of CDK7 and CDK9 increases (Tamrakar et al., Journal of Virology, 2005, 79; 15477-15493). Many antiviral drugs target viral proteins. These drugs have the drawback that viruses often develop resistance to these drugs. Antiviral drugs that target cellular proteins essential for viral processes, such as CDK7, can circumvent this drawback. These drugs may be even more effective in treating some unrelated viruses, and their effectiveness should exceed that of conventional antivirals. Inhibitors of CDK7, which has the dual functions of CDK-activating kinase and transcriptional regulation, are highly effective in treating some viruses. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 615968 [Non-patent literature]

[0009] [Non-Patent Document 1] Bregman et al.,2000,Front Biosci.5:244-257 [Non-patent document 2] Desai et al.,1995,Mol.Cell Biol.15,345-350 [Non-patent document 3] Akhtar et al.,2009,Mol.Cell 34,387-393 [Non-patent document 4] Larochelle et al.,2012,Nat.Strut.Mol.Biol.19,1108-1115 [Non-patent document 5] Shapiro GI.2006,J Clin Oncol;24(11):1770-83 [Non-patent document 6] Lolli G and Johnson LN.2005.Cell Cycle 4:572-577 Summary of the Invention [Means for solving the problem]

[0010] One object of the present invention is to provide compounds and / or pharmaceutically acceptable salts thereof that can be used as pharmaceutically active agents for the prevention and / or treatment of, inter alia, cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases, and infectious diseases, as well as compositions comprising at least one of these compounds and / or pharmaceutically acceptable salts thereof as a pharmaceutically active ingredient. In one aspect, the present invention provides a compound of general formula I [ka] 1. A pyrazolo-triazine or pyrazolo-pyrimidine compound defined by the formula: X is independently selected in each occurrence from CH and N; L 1 is absent or independently, at each occurrence, selected from the group consisting of -NH-, -NH(CH2)-, -NH(C=O)-, -NHSO2-, -O-, -O(CH2)-, -(C=O)-, -(C=O)NH-, and -(C=O)(CH2)-; Q, in each occurrence, is independently selected from the group consisting of C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl, where C1-C6 alkyl is selected from the group consisting of -OR 5 , -N(R 5 )R 5 , aryl, heteroaryl, and heterocyclyl; C3-C8 cycloalkyl is R 3 and R 4 and -(C=O)R 5 may be substituted with one or two of Heterocyclyl is R 3 and R 4 and -(C=O)R 5 may be substituted with one or two of C1-C6 alkyl, -OR 5 , -N(R 5 )R 5 , -(C=O)R 5 aryl or heteroaryl substituted with one or two of halogen, heteroaryl, and heterocyclyl; R 1 is, at each occurrence, independently selected from the group consisting of hydrogen and methyl; R 2 is, at each occurrence, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH3, -NR 9 R 12and C1-C3 haloalkyl, any of which is optionally substituted; R 3 is independently, at each occurrence, hydrogen, -OR 5 , halogen, -N(R 5 )R 5 , -NR 9 R 12 , -NH(C=O)R 5 , —(C═O)NH2, aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with —OH or —NH2; R 4 is independently, at each occurrence, hydrogen, halogen, -OR 5 , -N(R 5 )R 5 , (=O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with -OH or -NH2; R 5 is, at each occurrence, hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl; halogen, -OR 11 , -N(R 11 )R 11 , C1-C6 alkyl, and heteroaryl substituted with one or two of C1-C6 alkyl substituted with -OH or -NH2; halogen, -OR 11 , -N(R 11 )R 11 , C1-C6 alkyl, and heterocyclyl substituted with one or two of -OH or -NH2-substituted C1-C6 alkyl; Z is Group A below: [ka] is any structure of; During the ceremony, X 1 is independently in each occurrence, 24 and N; X2 is independently in each occurrence, 25 and N; R 6 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with -OH, C3-C10 cycloalkyl, C3-C10 heterocyclyl, -(C=O)NHR 11 , -NHR 9 , -NH(C=O)NHR 11 , -N(CH3)(C=O)CH3, -NH(C=O)R 12 , -NR 9 R 12 , -OR 12 , and the following Group B: [ka] independently selected from the group consisting of any structure of R 7 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, -NH(C=O)R 12 , -NR 9 R 12 , -OR 12 , and the following C groups: [ka] independently selected from the group consisting of any structure of R 8 and R 10 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OH, -OR 5 , -CN, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, -S(=O)2NHR 21 , and -OH, -OR 5 , or -NHR 9independently selected from the group consisting of C1-C6 alkyl substituted with R 9 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 5 , -CN, C3-C10 cycloalkyl, C3-C10 heterocyclyl, and -OH or OR 5 independently selected from the group consisting of C1-C6 alkyl substituted with R 11 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C10 cycloalkyl; R 12 is absent or independently selected from C1-C6 alkyl, -OR 5 or -N(R 5 )R 5 C1-C6 alkyl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C9 heteroaryl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C6 heterocyclyl substituted with 1 to 4 halogens and / or 1 to 4 -NH(C=O)R 13 C6-C10 aryl substituted with; R 13 is, in each occurrence, hydrogen, C1-C6 alkyl; -CN, -OH, -OR 5 , -NH2, -NHR 5 , or -N(R 5 )R 5 C1-C6 alkyl substituted with; and C3-C10 cycloalkyl; R 14 and R 15 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with -OH or NH2, C3-C10 cycloalkyl, -(C=O)R 5 , -(C=O)NHR 21 , -C(R 9 )(R11 ) OR 21 , -NH(C=O)R 21 , -NR 9 R 21 , -OR 21 , -OC(R 9 )(R 11 )(R 21 ), C3-C10 heterocyclyl, R 4 C3-C10 heterocyclyl substituted with 1-4 halogen or C1-C3 alkyl, C6-C10 aryl [e.g., -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, or -S(=O)2NHR 21 phenyl and aryl substituted with; R 16 is, at each occurrence, hydrogen, C1-C6 alkyl, -(C=O)R 13 , and -OR 5 independently selected from the group consisting of C1-C6 alkyl substituted with R 17 , R 18 , R 19 , and R 20 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, C6-C10 aryl [e.g., phenyl], -CN, -CHCF3NR 9 R 11 , -OH, -OR 21 , -NO2, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -NH(C=O)R 13 , -NHR 5 , -NHS(=O)2R 5 , -S(=O)2NH2, -S(=O)2NHR 21 , and -CN, -OH, -OR 5, -(C=O)NHR 5 , -NH2, -NH(C=O)R 5 , -NHR 5 , or -N(R 5 )R 5 independently selected from the group consisting of C1-C6 alkyl substituted with R 21 is, at each occurrence, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl, C1-C3 haloalkyl, aryl, phenyl, benzyl; -CN, -OH, -OR 5 , -NH2, -NHR 5 , or -N(R 5 )R 5 C1-C6 alkyl substituted with; aryl substituted with halogen or C1-C3 haloalkyl, C3-C10 heteroaryl substituted with 1-4 halogen or C1-C3 alkyl, and R 4 independently selected from the group consisting of C3-C10 heterocyclyl substituted with R 22 and R 23 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OH, -OR 5 , -CN, and -OH, -OR 5 , or -NHR 9 independently selected from the group consisting of C1-C6 alkyl substituted with R 24 and R 25 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OH, -OR 5 , -CN, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, or -S(=O)2NHR 21 , and -OH, -OR 5 , or -NHR 9independently selected from the group consisting of C1-C6 alkyl substituted with However, Z is [ka] If R 6 and R 7 One of them is not H; where R 1 is H and R 2 is CH(CH3)2 and L 1 does not exist and Q is R 3 and R 4 heterocyclyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not CH3, Cl, or 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R4 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not phenyl, CH(CH3)2, CH2CH3, or CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 6 is Cl and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 When is Cl, R 6 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R6 is Cl and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 When is Cl, R 6 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 6 is F and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not F; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If F, then R 6is not F; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q is R 3 and R 4 heterocyclyl substituted with R 4 is H, X is N, Z is phenyl, and R 6 is 1H-pyrazole and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 3 is not H; where R 1 is H and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q is R 3 and R 4 heterocyclyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6is not a 1H-pyrazole, where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH(CH3)2; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 C3-C8 cycloalkyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is NH and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is NH and Q is R 3 and R 4 C3-C8 cycloalkyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If F, then R 6 is not 1H-pyrazole; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is CH3 and R 2 is CH(CH3)2 and L1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 6 is H and R 8 is H and R 9 is H and R 10 If is H, then R 7 is not Cl; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R 3 and R 4 heterocyclyl substituted with R 3 is CH3 and R 4 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q is R3 and R 4 C3-C8 cycloalkyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is NH and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist and Q is R 3 and R 4 heterocyclyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist and Q is R 3 and R 4 heterocyclyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is NH and Q is R 3 and R 4 C3-C8 cycloalkyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q is R 3 and R 4 heterocyclyl substituted with R 3 is H and R 4 is H, X is N, Z is phenyl, and R6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q is R 3 and R 4 heterocyclyl substituted with R 3 is N(R 5 )R 5 and R 4 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3, or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

[0011] In one embodiment, R 1 is hydrogen and the compound has the general formula II [ka] wherein X, Q, L 1 , R 2 and Z are as defined above for general formula II.

[0012] In one embodiment, the present invention provides a compound of general formula III [ka] wherein X, L 1 , R 1 , R2 and Z are as defined above for general formula I; Q 1 is absent or independently, at each occurrence, aryl, heteroaryl, heterocyclyl; C1-C6 alkyl, -OR 5 , -N(R 5 )R 5 aryl substituted with one or two of the following: -C1-C6 alkyl, -OR 5 , -N(R 5 )R 5 heteroaryl substituted with one or two of the following: 29 and R 30 heterocyclyl substituted with one or two of: R 29 is absent or independently, at each occurrence, hydrogen, -OR 5 , halogen, -N(R 5 )R 5 , -NR 9 R 12 , -NH(C=O)R 5 , —(C═O)NH2, aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with —OH or —NH2; R 30 is independently, at each occurrence, hydrogen, halogen, -OR 5 , -N(R 5 )R 5 , (=O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with -OH or -NH2; where R 5 , R 9 , and R 12 is as defined in claim 1; L 2 is absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)—, and —(C═O)NH—; Y 1is independently selected at each occurrence from CH, C(OH), and N; Y 2 is independently in each occurrence CH, CR 30 , O, and N; m is independently selected in each occurrence from 0, 1, and 2; n is independently selected in each occurrence from 0 and 1; where R 1 is H and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not CH3, Cl, or 1H-pyrazole; where R 1 is H and R 2is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not phenyl, CH(CH3)2, CH2CH3, or CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 is Cl and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9is H and R 10 When is Cl, R 6 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 is Cl and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 When is Cl, R 6 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6is F and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not F; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If F, then R 6 is not F; where R 1 is H and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is N, m is 1, n is 1, and R 30 is H, X is N, Z is phenyl, and R 6 is 1H-pyrazole and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 29 is not H; where R 1 is H and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5)R 5 and R 30 is H and R 5 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH(CH3)2; where R 1 is H and R 2is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH(CH3)2; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is NH and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 0, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is NH and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 2, n is 0, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 2, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If F, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 2, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2is N, m is 1, n is 1, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 is H and R 8 is H and R 9 is H and R 10 If is H, then R 7 is not Cl; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 1, and R 29 is CH3 and R 30 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is O and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is NH and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, m is 1, n is 0, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 0, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is NH and Q 1 does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q 1 does not exist, and L 2 does not exist and Y1 is N and Y 2 is N, m is 1, n is 1, and R 29 is H and R 30 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 is -(C=O)- and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 1, n is 1, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2 and L 1 does not exist, and Q 1 does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, m is 2, n is 0, and R 29 is N(R 5 )R 5 and R 30 is H and R 5 is H, X is N, Z is phenyl, and R 6 is H and R7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3, or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

[0013] In one embodiment, the present invention provides compounds of general formula Ia [ka] A compound having the formula: X is independently selected in each occurrence from CH and N; Y 1 is independently, at each occurrence, selected from CH, C(OH) and N; Y 2 independently, in each occurrence, CH, CR 4 , O and N; m is independently, at each occurrence, selected from 0, 1, and 2; n is independently, at each occurrence, selected from 0 and 1; L 1 is absent or independently, at each occurrence, selected from the group consisting of -NH-, -NH(CH2)-, -NH(C=O)-, -NHSO2-, -O-, -O(CH2)-, -(C=O)-, -(C=O)NH-, and -(C=O)(CH2)-; Q is absent or independently at each occurrence selected from the group consisting of heterocyclyl, C-C heteroaryl, aryl (e.g., phenyl), and aryl substituted with halogen; L 2 is absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)—, and —(C═O)NH—; R 1 is, at each occurrence, independently selected from the group consisting of hydrogen and methyl; R 2 is, at each occurrence, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH3, -NR 9 R 12 and C1-C3 haloalkyl, any of which is optionally substituted; R 3 is, at each occurrence, absent or independently selected from hydrogen, -OH, halogen, -NH, -NR 9 R 12 , -NH(C=O)R 5 , —(C═O)NH2, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with —OH or —NH2; R 4 is absent or independently selected from hydrogen, halogen, -OH, -OR, at each occurrence; 5 , —NH2, (═O), C1-C6 alkyl, and C1-C6 alkyl substituted with —OH or —NH2; R 5 is selected at each occurrence from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C3-C10 heterocyclyl, C1-C3 haloalkyl, and C3-C10 heterocyclyl substituted with halogen, -OH, -NH2, C1-C6 alkyl, and C1-C6 alkyl substituted with -OH or -NH2; Z is Group A below: [ka] is any structure of; During the ceremony, X 1 is independently in each occurrence, 24 and N; X 2 is independently in each occurrence, 25 and N; R 6is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl, -(C=O)NHR 11 , -NHR 9 , -NH(C=O)NHR 11 , -N(CH3)(C=O)CH3, -NH(C=O)R 12 , -NR 9 R 12 , -OR 12 , and the following Group B: [ka] independently selected from the group consisting of any structure of R 7 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, -NH(C=O)R 12 , -NR 9 R 12 , -OR 12 , and the following C groups: [ka] independently selected from the group consisting of any structure of R 8 and R 10 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OH, -OR 5 , -CN, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, -S(=O)2NHR 21 , and -OH, -OR 5 , or -NHR 9 independently selected from the group consisting of C1-C6 alkyl substituted with R 9 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 5, -CN, C3-C10 cycloalkyl, C3-C10 heterocyclyl, and -OH or OR 5 independently selected from the group consisting of C1-C6 alkyl substituted with R 11 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C10 cycloalkyl; R 12 is absent or independently selected from C1-C6 alkyl, -OR 5 or -N(R 5 )R 5 C1-C6 alkyl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C9 heteroaryl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C6 heterocyclyl substituted with 1 to 4 halogens and / or 1 to 4 -NH(C=O)R 13 C6-C10 aryl substituted with; R 13 is, in each occurrence, hydrogen, C1-C6 alkyl; -CN, -OH, -OR 5 , -NH2, -NHR 5 , or -N(R 5 )R 5 C1-C6 alkyl substituted with; and C3-C10 cycloalkyl; R 14 and R 15 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with -OH or NH2, C3-C10 cycloalkyl, -(C=O)R 5 , -(C=O)NHR 21 , -C(R 9 )(R 11 ) OR 21 , -NH(C=O)R 21 , -NR 9 R 21 , -OR 21 , -OC(R 9 )(R11 )(R 21 ), C3-C10 heterocyclyl, R 4 C3-C10 heterocyclyl substituted with 1-4 halogen or C1-C3 alkyl, C6-C10 aryl [e.g., -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, or -S(=O)2NHR 21 phenyl and aryl substituted with; R 16 is, at each occurrence, hydrogen, C1-C6 alkyl, -(C=O)R 13 , and -OR 5 independently selected from the group consisting of C1-C6 alkyl substituted with R 17 , R 18 , R 19 , and R 20 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, C6-C10 aryl [e.g., phenyl], -CN, -CHCF3NR 9 R 11 , -OH, -OR 21 , -NO2, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -NH(C=O)R 13 , -NHR 5 , -NHS(=O)2R 5 , -S(=O)2NH2, -S(=O)2NHR 21 , and -CN, -OH, -OR 5 , -(C=O)NHR 5 , -NH2, -NH(C=O)R 5 , -NHR 5 , or -N(R 5 )R 5independently selected from the group consisting of C1-C6 alkyl substituted with R 21 is, at each occurrence, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl, C1-C3 haloalkyl, aryl, phenyl, benzyl; -CN, -OH, -OR 5 , -NH2, -NHR 5 , or -N(R 5 )R 5 C1-C6 alkyl substituted with; aryl substituted with halogen or C1-C3 haloalkyl, C3-C10 heteroaryl substituted with 1-4 halogen or C1-C3 alkyl, and R 4 independently selected from the group consisting of C3-C10 heterocyclyl substituted with R 22 and R 23 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OH, -OR 5 , -CN, and -OH, -OR 5 , or -NHR 9 independently selected from the group consisting of C1-C6 alkyl substituted with R 24 and R 25 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH2, -OH, -OR 5 , -CN, -(C=O)R 5 , -(C=O)OR 5 , -(C=O)NH2, -(C=O)NHR 21 , -CH2(C=O)NHR 21 , -NH(C=O)R 13 , -NHS(=O)2R 5 , -S(=O)2NH2, or -S(=O)2NHR 21 , and -OH, -OR 5 , or -NHR 9 independently selected from the group consisting of C1-C6 alkyl substituted with However, Z is [ka] If R 6 and R 7 One of them is not H; where R 1 is H and R 2 is CH(CH3)2 and R 3 is NH2 and R 4 is H and L 1 does not exist, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is N and Y 2 is CH, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not CH3, Cl or 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 6 OR 12 and R 7 is H and R8 is H and R 9 is H and R 10 If is H, then R 12 is not phenyl, CH(CH3)2, CH2CH3 or CH3; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 6 is Cl and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 When is Cl, R 6 is not Cl; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 6 is Cl and R7 is H and R 8 is H and R 9 If is H, then R 10 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 When is Cl, R 6 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 6 is F and R 7 is H and R 8 is H and R 9 If is H, then R 10 is not F; where R 1 is H and R 2 is CH(CH3)2 and R 3 is CH3 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 7 is H and R 8 is H and R 9is H and R 10 If F, then R 6 is not F; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is CH3 and R 4 is H, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is -(C=O)-, Q is absent, and L 2 does not exist and Y 1 is N and Y 2 is N, n is 1, and R 3 is H and R 4 is H, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is -(C=O)-, Q is absent, and L 2 does not exist and Y 1 is N and Y 2 is CH, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 7 is H and R 8is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is H and R 4 is H, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is H and R 4 is H, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH(CH3)2; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 0, and R 3 is H and R 4 is H, Z is phenyl, and R 7 is H and R8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 0, and R 3 is H and R 4 is H, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH(CH3)2; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 0, and R 3 is H and R 4 is H, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is H and R4 is H, Z is phenyl, and R 6 OR 12 and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is H and R 2 is CH(CH3)2 and R 3 is NH2 and R 4 is H and L 1 is O, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is CH, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is H and R 4 is H and L 1 is NH, Q is absent, and L 2 does not exist, X is N, n is 0, and Y 1 is CH and Y 2 is N, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is NH2 and R 4 is H and L 1 does not exist, Q does not exist, and L 2 does not exist, X is N, n is 0, and Y1 is N and Y 2 is CH, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is NH2 and R 4 is H and L 1 is NH, Q is absent, and L 2 does not exist, X is N, n is 1, and Y 1 is CH and Y 2 is CH, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is H and R 2 is CH(CH3)2 and R 3 is H and R 4 is NH2 and L 1 does not exist, Q does not exist, and L 2 does not exist, X is N, n is 1, and Y 1 is N and Y 2 is CH, Z is phenyl, and R 7 is H and R 8 is H and R 9 is H and R 10 If is H, then R 6 is not 1H-pyrazole; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3is H and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is CH3 and R 4 is H, Z is phenyl, and R 6 is H and R 8 is H and R 9 is H and R 10 If is H, then R 7 is not Cl; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 1, and R 3 is H and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y2 is N, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is O, Q does not exist, and L 2 does not exist and Y 1 is CH and Y 2 is CH, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 does not exist, Q does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2is CH(CH3)2, X is N, and L 1 is NH, Q is absent, and L 2 does not exist and Y 1 is CH and Y 2 is N, n is 0, and R 3 is H and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 does not exist, Q does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, n is 0, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is NH, Q is absent, and L 2 does not exist and Y 1 is CH and Y 2 is CH, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is -(C=O)-, Q is absent, and L 2 does not exist and Y 1 is N and Y 2 is N, n is 1, and R 3 is H and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 is -(C=O)-, Q is absent, and L 2 does not exist and Y 1 is N and Y 2 is CH, n is 1, and R 3 is NH2 and R 4 is H, Z is phenyl, and R 6 is H and R 7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3; where R 1 is CH3 and R 2 is CH(CH3)2, X is N, and L 1 does not exist, Q does not exist, and L 2 does not exist and Y 1 is N and Y 2 is CH, n is 1, and R 3 is NH and R 4 is NH2, Z is phenyl, and R 6 is H and R7 OR 12 and R 8 is H and R 9 is H and R 10 If is H, then R 12 is not CH3, or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

[0014] In one embodiment, the present invention provides a compound of general formula IV [ka] and In the formula, X, L 1 and R 2 is as defined above for general formula I; where m, n, Y 1 , Y 2 , L 2 , R 29 , R 30 , and Q 1 is as defined above for general formula III; where Z 1 is the following D group: [ka] is any structure of; In the formula, R 6 , R 7 , R 8 , R 9 , and R 10 relates to compounds as defined above for general formula I.

[0015] In one embodiment, the present invention provides a compound of general formula V [ka] and In the formula, X, 1 , X 2 , L 1 , R 2 , R 6 , R22 , and R 23 is as defined above for general formula I; where m, n, Y 1 , Y 2 , L 2 , R 29 , R 30 , and Q 1 relates to compounds as defined above for general formula III.

[0016] In one embodiment, the present invention provides a compound of general formula VI [ka] and In the formula, X, L 1 and R 2 is as defined above for general formula I; where m, n, Y 1 , Y 2 , L 2 , R 29 , R 30 , and Q 1 is as defined above for general formula III; X 3 is independently in each occurrence, 10 and N; R 26 , R 27 , and R 28 is, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR 5 , -CN, and -OH, -OR 5 , or -NHR 9 independently selected from the group consisting of C1-C6 alkyl substituted with R 5 , R 9 , and R 10 is as defined above for general formula I; R 7 is the following E group: [ka] is any structure of; In the formula, R 8 and R 14 ~R 20 relates to compounds as defined above for general formula I.

[0017] In one embodiment, the present invention provides a compound of general formula VII [ka] and In the formula, X, L 1 , R 2 , R 6 , R 22 , R 23 , R 24 , and R 25 is as defined above for general formula I; m, n, Y 1 , Y 2 , L 2 , R 29 , R 30 , and Q 1 relates to compounds as defined above for general formula III.

[0018] In one embodiment, the present invention provides a compound of general formula VIII [ka] and In the formula, X, L 1 , R 2 , R 6 , and R 10 relates to compounds as defined above for general formula I.

[0019] In one embodiment, the present invention provides a compound of general formula IX [ka] wherein L 1 , R 2 , R 6 , R 22 , R 23 , R 24 , and R 25 is as defined above for general formula I, and X3 is as defined above for general formula VI; Here, Q 2 is the following F group: [ka] is any structure of; R 31 and R 32 is absent or independently, at each occurrence, hydrogen, -OR 5 , halogen, -N(R 5 )R 5 , -NR 9 R 12 , -NH(C=O)R 5 , —(C═O)NH2, aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and C1-C6 alkyl substituted with —OH or —NH2; where R 5 , R 9 , and R 12 relates to compounds as defined above for general formula I.

[0020] In one embodiment, the present invention also relates to the pharmaceutically acceptable salts of the compounds according to the invention as defined herein.

[0021] In one embodiment, the compound according to the invention is a compound selected from structures 1-279, further listed in Table 11 below.

[0022] In a further aspect, the present invention also relates to a pharmaceutical composition comprising a compound according to the invention as defined herein as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0023] In one aspect, the present invention also relates to a compound according to the invention as defined herein for use as a medicine or pharmaceutically active agent, wherein said medicine or pharmaceutically active agent preferably has inhibitory activity against cyclin-dependent kinase 7 (CDK7).

[0024] In one aspect, the present invention also relates to a compound according to the invention as defined herein for use in a method for the prevention and / or treatment of a disease associated with inhibition of apoptosis, aberrant transcriptional activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7), wherein said disease is selected from proliferative diseases, infectious diseases including opportunistic diseases, immunological diseases, autoimmune diseases, and inflammatory diseases.

[0025] In one embodiment, diseases associated with apoptosis inhibition, abnormal transcription activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or more cyclin-dependent kinases (CDKs), particularly cyclin-dependent kinase 7 (CDK7), are diseases related to, accompanied by, caused by, and / or induced by CDK7 dysfunction and / or hyperactivity. In one embodiment, diseases associated with apoptosis inhibition, abnormal transcription activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or more cyclin-dependent kinases (CDKs), particularly cyclin-dependent kinase 7 (CDK7), are proliferative diseases. In one embodiment, the proliferative disease is cancer.

[0026] In one embodiment, the cancer is selected from the group consisting of adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and -independent breast cancer, Burkitt's lymphoma, corpus cancer, carcinoma of unknown primary site (CUP syndrome), colorectal cancer, small intestine cancer, small intestine tumor, ovarian cancer, endometrial cancer, ependymoma, epithelial carcinoma type, Ewing's tumor, gastrointestinal tumor, gastric cancer cancer), gallbladder cancer, uterine cancer, cervical cancer, cervix, glioblastoma, gynecological tumors, ear, nose and throat tumors, hematological tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal cancer, head and neck tumors (tumors of the ear, nose, and pharyngeal area), colon cancer, craniopharyngioma, oral cancer (cancer in the mouth and above the lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymphoma, stomach cancer cancer), malignant melanoma, malignant neoplasia, malignant tumors of the digestive tract, breast cancer, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin / non-Hodgkin lymphoma, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, kidney cancer, renal cell carcinoma, oligodendroglioma, esophageal cancer, osteolytic and osteoplastic carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, esophageal cancer, T-cell lymphoma, thymoma, ductal carcinoma, eye tumors, urethral cancer, urinary tract tumors, urothelial carcinoma, vulvar cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, nephroblastoma, cervical cancer, tongue Cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung cancer, non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brainstem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal region tumor, uterine sarcoma, salivary gland cancer, anal gland adenocarcinoma, mast cell tumor, pelvic tumor, ureteral tumor, hereditary papillary renal carcinoma, sporadic papillary renal carcinoma, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancercancer), squamous cell carcinoma, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma.

[0027] In one embodiment, the infectious disease comprising the opportunistic disease is AIDS, adenovirus infection, alveolar hydatid disease (AHD), amebiasis, angiostrongyliasis cantonensis, anisakiasis, anthrax, babesiosis, balantidiosis, Baylis ascaris infection, bilharzia (schistosomiasis), Blastocystis hominis infection, Lyme borreliosis, botulism, Brainerd diarrhea, brucellosis, bovine spongiform encephalopathy (BSE), candidiasis, capillary malaria, chronic fatigue syndrome (CFS), Chagas disease, chicken pox, Chlamydia pneumoniae pneumoniae infection, cholera, chronic fatigue syndrome, Creutzfeldt-Jakob disease (CJD), clonorchiasis, cutaneous larva migrans (CLM), coccidioidomycosis, conjunctivitis, Coxsackievirus A16 (CoxA16), cryptococcosis, cryptosporidiosis, West Nile fever, cyclosporosis, neurocysticercosis, cytomegalovirus infection, dengue fever, Dipylidium caninum infection, Ebola hemorrhagic fever (EHF), alveolar echinococcosis (AE), encephalitis, Entamoeba coli infection, Entamoeba dispar infection, Entamoeba hartmannii infection, Entamoeba poleckiipolecki infection, pinworm infection, enterovirus infection (polio / non-polio), Epstein-Barr virus infection, E. coli infection, foodborne infection, foot-and-mouth disease, fungal dermatitis, fungal infection, gastroenteritis, group A streptococcal disease, group B streptococcal disease, leprosy, hantavirus pulmonary syndrome, head lice infestation (pediculosis), Helicobacter pylori infection, blood disorders, Hendra virus infection, hepatitis (HCV, HBV), shingles (shingles), HIV infection, human ehrlichiosis, human parainfluenza virus infection, influenza, isosporosis, Lassa fever, leishmaniasis, visceral leishmaniasis (VL) ), malaria, Marburg hemorrhagic fever, measles, meningitis, Mycobacterium avium complex (MAC) infection, Naegleria infection, nosocomial infection, non-pathogenic intestinal ameba infection, onchocerciasis, opisthorchiasis, papillomavirus infection, parvovirus infection, plague, Pneumocystis jiroveci pneumonia (PCP), polyomavirus infection, Q fever, rabies, respiratory syncytial virus (RSV) infection, rheumatic fever, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, scabies, shigellosis, herpes zoster, sleeping sickness, smallpox, streptococcal infection, tapeworm infection, tetanus, toxic shock syndrome, tuberculosis, duodenal, Vibrio parahaemolyticus parahaemolyticus infection, Vibrio septicemia, viral hemorrhagic fever, warts, waterborne diseases, varicella-zoster virus infection, whooping cough, and yellow fever.

[0028] In one embodiment, the immunological and / or autoimmune disease is selected from the group consisting of asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary disease, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, allergic disease manifestations, primary immunodeficiency, antibody deficiency states, cell-mediated immunodeficiency, severe combined immunodeficiency, DiGeorge syndrome, hyper-IgE syndrome (HIES), Vulvovilli, and the like. The disease is selected from: Whitcott-Aldrich syndrome (WAS), ataxia-telangiectasia, immune-mediated cancer, white blood cell deficiency, autoimmune disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes mellitus, immune-mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, autoimmune thyroid disease, Hashimoto's disease, dermatomyositis, Goodpasture's syndrome (GPS), myasthenia gravis (MG), sympathetic ophthalmia, phacogene uveitis, chronic invasive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia, and Verhoef's disease.

[0029] In one embodiment, the inflammatory disease is caused by, induced by, initiated by, and / or enhanced by bacteria, viruses, prions, parasites, fungi, and / or is caused by irritating, traumatic, metabolic, allergic, autoimmune, or idiopathic factors.

[0030] In one embodiment, the inflammatory disease comprises or is selected from the group consisting of inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear, inflammatory bowel disease, inflammatory diseases of the skin, inflammatory uveitis, and inflammatory diseases of the larynx. In one embodiment, the inflammatory disease is selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear, inflammatory bowel disease, inflammatory diseases of the skin, inflammatory uveitis, and inflammatory diseases of the larynx, preferably, the inflammatory disease is selected from abscess formation, acanthamoeba infection, acne vulgaris, actinomycosis, acute inflammatory skin diseases, acute adult laryngeal infection, acute multifocal macular pigment epitheliopathy, acute (burn) injury, acute retinal necrosis, acute suppurative otitis media, algal viral disorders (algal viral disorders). disorder), allergic contact dermatitis, amyloidosis angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, pseudorabies, autoantibodies in vasculitis, bacterial disorders, bacterial laryngitis, bacterial meningitis, Behçet's disease (BD), birdshot choroidopathy, Gilchrist's disease, Borna's disease, brucellosis, bullous tympanocytosis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in young animals, canine hemorrhagic fever, canine herpesvirus encephalomyelitis, cholesteatoma, chronic granulomatous disease (CGD), chronic inflammatory skin diseases, chronic relapsing encephalomyelitis, chronic Suppurative otitis media, ocular cicatricial pemphigoid (OCP), common upper respiratory tract infections, granulomas, Crohn's disease, cryptococcal disease, dermatomyositis, diphtheria, discoid lupus erythematosus (DLE), drug-induced vasculitis, drug or hypersensitivity reactions, encephalitozoonosis, eosinophilic meningoencephalitis, erythema multiforme (EM), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalitis, feline spongiform encephalopathy, fibromyalgia, Fuchs heterochromia irido-uveitis, gastroesophageal (laryngopharyngeal) reflux disease, giant cell arteritis, glanders, glaucoma, cyclitis, gonococcal granulomatous myringitis granular myringitis), granulomatous meningoencephalitis (GME), herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune disorders and idiopathic disorders, infections in immunocompromised hosts, infectious canine hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki disease, La Crosse virus encephalitis, laryngeal abscess, laryngotracheobronchitis,Leishmaniasis, lens-induced uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lymphoma, meningitis, greyhound meningoencephalitis, various meningitis / meningoencephalitis, microscopic polyangiitis, multifocal choroiditis, multifocal distemper encephalomyelitis in adult animals, multiple sclerosis, myotonic dysphonia (MTD), mycoses (fungal diseases), mycoses of the CNS, necrotizing encephalitis, neosporosis, geriatric encephalitis, onchocerciasis, parasitic encephalomyelitis, parasitic infections, pars planitis, parvoviral encephalitis, pediatric laryngitis inflammation, pollution and inhalant allergies, polymyositis, post-vaccine canine distemper encephalitis, prion protein-induced diseases, protothecosis, protozoan encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug encephalitis, radiation injury, radiation laryngitis, radiation necrosis, relapsing polychondritis, Reiter's syndrome, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, rickettsial disorders, Rocky Mountain spotted fever, salmon toxic disease (SPD), sarcocystosiosis, sarcoidosis, schistosomiasis, scleroderma, rhinosclerosis, geographic choroiditis, shaker syndrome Sjogren's disease, Sjögren's syndrome, spastic croup, spirochetal (syphilitic) disease, spongiotic dermatitis, sporotrichosis, steroid-responsive meningitis-arteritis, Stevens-Johnson syndrome (SJS, severe form of erythema multiforme), epiglottitis, sympathetic ophthalmia, singamus, syphilis, systemic vasculitis in sarcoidosis, Takayasu's arteritis, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's disease), tick-borne encephalitis in dogs, toxic epidermal necrolysis (TEN), toxocariasis , toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, urticaria (hives), vasculitis, vasculitis and complications of malignant diseases, vasculitis and complications of rheumatoid arthritis, vasculitis in idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal, and parasitic infections, viral disorders, viral laryngitis, vitiligo, vocal cord abuse, vocal cord hemorrhage, Vogt-Koyanagi-Harada syndrome (VKH), Wegener's granulomatosis, and Whipple's disease.

[0031] The present invention also relates to a method for treating and / or preventing diseases associated with inhibition of apoptosis, aberrant transcriptional activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7), wherein said disease is selected from proliferative diseases, infectious diseases including opportunistic diseases, immunological diseases, autoimmune diseases, and inflammatory diseases, said method of treatment and / or prevention comprising the step of administering to a patient in need thereof a compound according to the invention as defined herein.

[0032] In one embodiment, the patient in need is a mammal. In one embodiment, the patient in need is a human. In another embodiment, the patient in need is a non-human animal.

[0033] In one embodiment, the disease prevented or treated by the aforementioned methods is as defined herein.

[0034] The present invention also relates to the use of a compound according to the invention as defined herein in the manufacture of a medicament for the prevention and / or treatment of a disease associated with inhibition of apoptosis, aberrant transcriptional activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or several cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7), wherein said disease is selected from proliferative diseases, infectious diseases including opportunistic diseases, immunological diseases, autoimmune diseases, and inflammatory diseases as defined herein.

[0035] Further advantageous features, aspects and details of the invention are apparent from the accompanying claims, description, examples and drawings.

[0036] The compounds of the present invention are highly effective inhibitors of CDK7 threonine / serine kinase and / or its complex (CDK7 / MAT1 / CycH).The compounds of the present invention are suitable for use as pharmaceutically active agents.The compounds of the present invention are suitable for treating disorders related to, accompanied by, caused by, and / or induced by CDK7 and its complex, particularly its hyperactivity or dysfunction.Therefore, the compounds of the present invention are suitable for treating diseases or disorders related to CDK7 and CDK7 complex-induced disorders.

[0037] The compounds of the present invention are also useful in the manufacture of medicaments or pharmaceutical compositions for the treatment of disorders related to, accompanied by, caused by, and / or induced by CDK7 and its complexes, particularly their hyperactivity or dysfunction. The compounds of the present invention are further used in the manufacture of medicaments or pharmaceutical compositions for the treatment and / or prevention of disorders induced by CDK7 and its complexes.

[0038] The term "optionally substituted," as used herein, is intended to indicate that one hydrogen atom or several such hydrogen atoms present in a group and bonded to member atoms within the group may be replaced with a suitable group (e.g., halogen (including fluorine), C1-C3 alkyl, C1-C3 haloalkyl, methylhydroxyl, COOMe, C(O)H, COOH, OMe, or OCF3, etc.).

[0039] The term "alkyl" refers to a monovalent straight-, branched-, or cyclic-chain saturated aliphatic hydrocarbon radical having a number of carbon atoms within the specified range. Thus, for example, "C1-C6 alkyl" refers to any of the hexyl and pentyl alkyl isomers, as well as n-, iso-, sec-, and t-butyl, n- and isopropyl, cyclic propyl, ethyl, and methyl.

[0040] The term "alkenyl" refers to a monovalent straight- or branched-chain aliphatic hydrocarbon radical containing one carbon-carbon double bond and having a number of carbon atoms within the specified range. Thus, for example, "C2-C6 alkenyl" refers to all of the hexenyl and pentenyl isomers, as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl, and ethenyl (or vinyl).

[0041] The term "cycloalkyl," unless otherwise defined, alone or in combination with any other term, refers to an optionally substituted or unsubstituted cyclic hydrocarbon, etc. group having 3 to 8 carbon atoms. Thus, for example, "C3-C8 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0042] The term "haloalkyl" refers to an alkyl group, as defined herein, substituted with at least one halogen. Examples of linear or branched "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl, each independently substituted with one or more halogens. The term "haloalkyl" should be interpreted to include substituents such as -CHF2, -CF3, -CH2-CH2-F, and -CH2-CF3.

[0043] The term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom such as O, N, or S. For example, when a carbon atom of an alkyl group that is attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkoxy group (e.g., -OCH), an amine (e.g., -NHCH, -N(CH), or a thioalkyl group (e.g., -SCH), respectively. When a non-terminal carbon atom of an alkyl group that is not attached to a parent molecule is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl group is an alkyl ether (e.g., -CHCH-O-CH), an alkylamine (e.g., -CHNHCH, -CHN(CH), or a thioalkyl ether (e.g., -CH-S-CH), respectively.

[0044] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0045] The term "phenyl," as used herein, is intended to denote an optionally substituted or unsubstituted phenyl group.

[0046] The term "benzyl," as used herein, is intended to denote an optionally substituted or unsubstituted benzyl group.

[0047] The term "heteroaryl" refers to (i) optionally substituted 5- and 6-membered aromatic heterocycles and (ii) optionally substituted 9- and 10-membered bicyclic fused ring systems in which at least one ring is aromatic, where the aromatic heterocycle or bicyclic fused ring system contains 1 to 4 heteroatoms independently selected from N, O, and S, each N optionally in the form of an oxide, and each S in a non-aromatic ring is optionally S(O) or S(O)2. Suitable 5- and 6-membered aromatic heterocycles include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. Suitable 9- and 10-membered heterobicyclic fused ring systems include, for example, benzofuranyl, indolyl, indazolyl, naphthyridinyl, isobenzofuranyl, benzopiperidinyl, benzisoxazolyl, benzoxazolyl, chromenyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuranyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl, and 2,3-dihydrobenzo-1,4-dioxinyl.

[0048] The term "heterocyclyl" refers to (i) optionally substituted 4-8 membered saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and 1-4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing 1-6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independent of fusion or bridging with other ring(s), each ring is saturated or unsaturated but non-aromatic, and each heteroatom in (i), (ii), and (iii) is independently selected from N, O, and S, wherein each N is optionally in the form of an oxide, and each S is optionally oxidized to S(O) or S(O). Suitable 4- to 8-membered saturated heterocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanyl, and azacyclooctyl. Suitable unsaturated heterocycles include unsaturated heterocycles corresponding to the saturated heterocycles listed above in which a single bond is replaced with a double bond. It is understood that the specific rings and ring systems suitable for use in the present invention are not limited to those listed in this and the preceding paragraphs. These rings and ring systems are merely representative.

[0049] Pharmaceutically acceptable salts Examples of pharmaceutically acceptable addition salts include non-toxic inorganic and organic acid addition salts (acetate from acetic acid, aconitate from aconitic acid, ascorbate from ascorbic acid, benzenesulfonate from benzenesulfonic acid, benzoate from benzoic acid, cinnamate from cinnamic acid, citrate from citric acid, embonate from embonic acid, enanthate from enanthic acid, formate from formic acid, fumarate from fumaric acid, glutamate from glutamic acid, glycolate from glycolic acid, hydrochloride from hydrochloric acid, hydrobromide from hydrobromic acid, lactate from lactic acid, maleic acid, Examples of suitable salts include, but are not limited to, maleates from malonic acid, malonates from malonic acid, mandelates from mandelic acid, methanesulfonates from methanesulfonic acid, naphthalene-2-sulfonates from naphthalene-2-sulfonic acid, nitrates from nitric acid, perchlorates from perchloric acid, phosphates from phosphoric acid, phthalates from phthalic acid, salicylates from salicylic acid, sorbates from sorbic acid, stearates from stearic acid, succinates from succinic acid, sulfates from sulfuric acid, tartrates from tartaric acid, and toluene-p-sulfonates from p-toluenesulfonic acid. Such salts can be formed by procedures well known and described in the art.

[0050] Other acids, such as oxalic acid, which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0051] In another embodiment, the compounds of the present invention are used in their respective free base form in accordance with the present invention.

[0052] Metal salts of compounds of the invention include alkali metal salts (such as sodium salts of compounds of the invention that contain a carboxy group).

[0053] The compounds of the present invention can be obtained in unsolvated form or in solvated form with pharmaceutically acceptable solvents (such as water and ethanol).Solvated forms can also include hydrated forms (such as monohydrate, dihydrate, hemihydrate, trihydrate, and tetrahydrate).Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

[0054] Further aspects of the present invention are illustrated and exemplified by the following schemes, examples, tables, and procedural descriptions, which are provided for illustrative purposes only and are not intended to limit the scope of the present invention, the scope of which is limited only by the appended claims.

[0055] Tables and Figures Here we refer to the table.

[0056] Table 1 shows activity data in CDK1, CDK2, CDK5, and CDK7 enzyme assays for selected compounds of the invention. Inhibition is measured as an IC 50 with the following notation: A = IC<100 nM 50 ; B = IC greater than 100 nM but less than 1,000 nM 50 ; C = IC > 1,000 nM 50 Table 1 also shows CDK1 / CDK7, CDK2 / CDK7, and CDK5 / CDK7 selectivity data for selected compounds of the invention. * , CDK2 / CDK7 ** , and CDK5 / CDK7 *** with the following symbolic explanation: A = more than 200-fold; B = less than 200-fold but more than 20-fold; C = less than 20-fold.

[0057] Table 2 shows activity data in the HCT116 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC50 .

[0058] Table 3 shows activity data in the H460 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0059] Table 4 shows activity data in the MM.1S cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0060] Table 5 shows activity data in the MV4-11 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0061] Table 6 shows activity data in the MOLT-4 cell viability assay for selected compounds of the invention. Inhibition is expressed as IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0062] Table 7 shows activity data in the RPMI-8226 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50;C=10uM or more IC 50 .

[0063] Table 8 shows activity data in the A2780 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0064] Table 9 shows activity data in the OVCAR-3 cell viability assay for selected compounds of the invention. Inhibition is expressed as an IC 50 with the following notation: A = IC less than 1uM 50 ;B=IC greater than 1uM but less than 10uM 50 ;C=10uM or more IC 50 .

[0065] Table 10 shows comparative data from a panel assay demonstrating the CDK7 selectivity profile in the CDK family for compound 210 of the present invention.

[0066] Table 11 summarizes compounds 1-279 with respect to their structures and corresponding characteristics. In an embodiment of the present invention, for example, the following items are provided: (Item 1) General formula I [ka] or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or a pharmaceutically acceptable salt thereof, wherein X is independently selected in each occurrence from CH and N; L 1 is absent or independently, at each occurrence, -NH-, -NH(CH 2 )-, -NH(C=O)-, -NHSO 2 -, -O-, -O(CH 2 )-, -(C=O)-, -(C=O)NH-, and -(C=O)(CH 2 )-selected from the group consisting of; Q, in each occurrence, is independently selected from the group consisting of C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl, where C1-C6 alkyl is selected from the group consisting of -OR 5 , -N(R 5 )R5 , aryl, heteroaryl, and heterocyclyl; C3-C8 cycloalkyl is R 3 and R 4 and -(C=O)R 5 may be substituted with one or two of Heterocyclyl is R 3 and R 4 and -(C=O)R 5 may be substituted with one or two of C1-C6 alkyl, -OR 5 , -N(R 5 )R 5 , -(C=O)R 5 aryl or heteroaryl substituted with one or two of halogen, heteroaryl, and heterocyclyl; R 1 is, at each occurrence, independently selected from the group consisting of hydrogen and methyl; R 2 is, at each occurrence, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH 3 , -NR 9 R 12 and C1-C3 haloalkyl, any of which is optionally substituted; R 3 is independently, at each occurrence, hydrogen, -OR 5 , halogen, -N(R 5 )R 5 , -NR 9 R 12 , -NH(C=O)R 5 , -(C=O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and -OH or -NH 2 C1-C6 alkyl substituted with; R 4 is independently, at each occurrence, hydrogen, halogen, -OR 5 , -N(R 5 )R 5 , (=O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and -OH or -NH 2 C1-C6 alkyl substituted with; R 5 is, at each occurrence, hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl; halogen, -OR 11 , -N(R 11)R 11 , C1-C6 alkyl, and -OH or -NH 2 heteroaryl substituted with one or two of C1-C6 alkyl substituted with -OR; halogen, -OR 11 , -N(R 11 )R 11 , C1-C6 alkyl, and -OH or -NH 2 C1-C6 alkyl substituted with , Z is Group A below:

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[0067] [Figure 1] FIG. 1 shows the in vivo antitumor activity of CDK7 inhibitors in the OVCAR-3 xenograft model. [Example]

[0068] The present invention will now be further described with reference to the following examples, which are intended to illustrate the invention and are not intended to limit the scope of the invention.

[0069] Example 1: Enzyme assays for CDK1, CDK2, CDK5, and CDK7 Protocols for CDK1, CDK2, CDK5, and CDK7 Enzyme-Binding Assays The inhibitory activity of each compound against CDK kinase at the Km value of ATP was tested in a FRET-based LANCE® Ultrakinase Assay (Perkin Elmer) using a ULight™-labeled peptide substrate and an appropriate europium-labeled anti-phospho antibody. Test compounds were prepared using DMSO solution, and then 8 doses of 4-fold serial dilutions were prepared using an automated liquid handler (POD™ 810, Labcyte). 80 nL / well of the diluted compound solution was added to a 384-well plate (Greiner, Cat. No. 784075). 68 nM ULight-MBP peptide (Perkin Elmer, Cat. No. TRF0109-M) and 5 ul / well of ATP (Sigma, Cat. No. A7699) were then added to the plate. After centrifugation at 1000 rpm for 1 minute, purified CDK / cyclin complexes were added at the following concentrations, respectively: 24 μM CDK1 / cyclin B (Invitrogen, Catalog No. PR4768C), 22 μM CDK2 / cyclin A (Invitrogen, Catalog No. PV6290), 10 μM CDK5 / p25 (Invitrogen, Catalog No. PR8543B), and 400 μM CDK7 / cyclin H / MNAT1 (Invitrogen, Catalog No. PR6749B) were added to corresponding plates for CDK1, CDK2, CDK5, and CDK7. After incubation at 23°C for 60 minutes, a mixture of Eu-labeled anti-phospho-myelin basic protein (PE, Catalog No. TRF0201-M) and EDTA (Invitrogen, Catalog No. 15575038) in Lance Detection Buffer (Perkin Elmer, Catalog No. CR97100) was added to each well. After a further incubation at 23°C for 60 minutes, the fluorescence of the test substances was measured using an Envision reader (Perkin Elmer, USA) using a laser as the excitation light; APC 615 nm and Europium 665 as the first and second emission filters. Data were analyzed using XL Fit software.

[0070] Example 2: Cell viability assays of HCT116, H460, MV4-11, MM.1S, MOLT-4, RPMI-8226, A2780, and OVCAR-3 cell culture The human T-cell acute lymphoblastic leukemia cell line MOLT-4 (ATCC, catalog number CRL-1582), the human multiple myeloma cell lines RPMI-8226 (Invitrogen, catalog number 22400-089) and MM.1S (ATCC, catalog number CRL-2974), the NSCLC (non-small cell lung cancer) cell line H460 (ATCC, catalog number HTB-177), the human colon colorectal carcinoma cell line HCT116 (ATCC, catalog number CCL-247), the human acute monoacute leukemia cell lines MV4-11 (ATCC, catalog number CRL-9591), OVCAR-3 (ATCC, catalog number HTB-161), and A2780 (ECACC, catalog number 93112519) were obtained from ATCC. Cells were grown in RPMI-1640 medium (Invitrogen, Catalog No. 22400-089) supplemented with 10% FBS (Invitrogen, Catalog No. 10099141) and 1% penicillin / streptomycin (Invitrogen, Catalog No. 15070063) and cultured in a humidified chamber at 37°C and 5% CO. All cell lines were routinely tested for mycoplasma.

[0071] Cell viability assay protocols for HCT116, H460, MV4-11, MM.1S, MOLT-4, RPMI-8226, A2780, and OVCAR-3 The inhibitory effect of CDK7 inhibitors on the growth of target cancer cells was evaluated by a 72-hour viability assay. Briefly, candidate cell lines were plated in 96-well plates at the following cell densities: 1 × 10 for MOLT-4, RPMI-8226, MV4-11, and MM.1S; 4 Cells / well, 5 x 10 for H460, HCT116, and OVCAR-3 3 , and 1 × 10 for A2780 3After 24 hours, cells were treated with various concentrations of compounds (ranging from 0.0015 μM to 10 μM). DMSO solvent without compound served as a control, and the final DMSO concentration was less than 0.1%. After 72 hours of incubation in a 37°C, 5% CO2 incubator, cells were analyzed for viability using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7570). All viability assays were performed in duplicate, and luminescence was read using Envision (Perkin Elmer, USA). Data were analyzed using XLfit software.

[0072] Example 3: In vitro IC for CDK family kinases 50 profile In vitro IC of CDK7 inhibitors among 28 CDK family kinases 50 profile Compound IC50 profiles were determined by ProQinase GmbH (Freiburg, Germany) using 28 CDK family protein kinases. All protocols and materials were provided by ProQinase GmbH. Briefly, in the process, 90 μl of HO was added to each well of the compound dilution plate. To minimize the possibility of precipitation, HO was added to the plate only a few minutes before transferring the compound solution to the assay plate. The plate was shaken thoroughly to obtain "compound dilution plate / 10% DMSO." The compound dilution plate(s) were discarded at the end of the working day. For the assay (see below), 5 μl of solution from each well of the compound dilution plate was transferred into the assay plate. The final volume of the assay was 50 μl. All compounds were diluted to 1×10 -05 M to 3 x 10 -10Ten final assay concentrations ranging from 0.1 to 10 M were tested. The final DMSO concentration in the reaction cocktail was 1% in all cases. All protein kinases provided by ProQinase were expressed in Sf9 insect cells or E. coli as recombinant GST-fusion proteins or His-tagged proteins, either full-length or enzymatically active fragments. All kinases were produced from human cDNA and purified by either GSH affinity chromatography or immobilized metal affinity chromatography. Protein kinase purity was tested by SDS-PAGE / Coomassie staining, and identity was checked by mass spectrometry. Kinases from external vendors (Carna Biosciences Inc.; Invitrogen Corp.; and Millipore Corp.) were expressed, purified, and quality-controlled according to the vendor's instructions. Radiometric protein kinase assays ( 33 The PanQinase® Activity Assay was used to measure the kinase activity of 28 protein kinases. All kinase assays were performed in 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA) in a reaction volume of 50 μl. The reaction cocktail was incubated at 30°C for 60 min. The reaction was stopped with 50 μl of 2% (v / v) H3PO4, and the plate was aspirated and washed twice with 200 μl of 0.9% (w / v) NaCl. 33 Pi incorporation was determined with a microplate scintillation counter (Microbeta, Wallac). All assays were performed on a BeckmanCoulter / SAGIAN™ Core System. As part of the data evaluation, the low control value for a particular plate was subtracted from the high control value and also from all 80 "compound values" for the corresponding plate. The residual activity (in %) for each well of a particular plate was calculated using the following formula: residual activity (%) = 100 x [(cpm of compound - low control) / (high control - low control)]. The results are shown in a table (in Table 10).

[0073] Example 4: In vivo efficacy study on the OVCAR-3 model In vivo efficacy of CDK7 inhibitors in the OVCAR-3 human epithelial ovarian cancer xenograft model. In vivo efficacy studies were conducted to evaluate the inhibitory activity against the growth of OVCAR-3 (ATCC, HTB-161) xenograft tumors. OVCAR-3 cells were grown in RPMI-1640 medium (Gibco, C2400500BT) supplemented with 20% fetal bovine serum (HyClone, SV30087.03), 0.01 mg / ml bovine insulin (Yuanyue, S12033), and 1% anti-antibody (Gibco, 15240-062) at 37°C in an atmosphere containing 5% CO2. To establish tumors, 10 × 10 6 OVCAR-3 cells were placed in 200 μl of PBS (Corning, 21-031-CVR) mixed with 50% Matrigel (Corning, 354234) and subcutaneously injected into the right upper flank of female Balb / c nude mice (Vital River Laboratory Animal Co., LTD., Beijing). Tumor volume was measured twice a week, and body weight was monitored daily. The tumor size of the mice was measured in two dimensions using calipers, and tumor volume (mm 3 ) into the equation "V = 0.5a × b 2 The tumor size was calculated using the formula: (where a and b are the long and short diameters of the tumor in mm, respectively). Animals were randomized into three groups of eight animals each based on tumor volume. To evaluate efficacy, Compound-210 was administered orally using 70% PEG400 (Sigma-Aldrich, P3265) in distilled water as a vehicle. The mean tumor size was approximately 160 mm 3Upon reaching 100 mg / kg, animals were randomized and treated daily (every 24 hours / once a day schedule) with vehicle, 20 mg / kg, or 40 mg / kg Compound-210 for 25 days. Statistical analysis of differences in tumor volume between groups was performed on data obtained for PG-D25. All data were analyzed using Graphpad Prism (GraphPad, Prism 6.00). p<0.05 was considered statistically significant. The results are shown in the graph (Figure 1).

[0074] Example 5: Derivatization of the pyrazolo-triazine and pyrazolo-pyrimidine general scaffolds Compounds of the present invention were derivatized according to the methods outlined below (Schemes 1-56). The resulting derivatives were tested for enzyme-linked cellular activity (HCT116, H460, MV4-11, MM.1S, MOLT-4, RPMI-8226, A2780, and OVCAR-3), CDK7 selectivity among CDK families, and in vivo efficacy studies (OVCAR-3) using the assays described above (Examples 1, 2, 3, and 4), with the results summarized in Tables 1-10 and Figure 1. Compounds 1-279 synthesized are listed in Table 11.

[0075] Scheme 1-a: General synthetic route [ka]

[0076] A method for preparing compounds I-3 and I-4 is shown in Scheme 1-a. Route I: Compound C7 can be synthesized by treating it in the presence of POCl. Compound C7 can be further treated with Group B in the presence of DIPEA to give Compound I-1. Compound I-1 can be further treated with m-CPBA to give Compound I-2. Compound I-2 can be synthesized by treating it with Group A to give Compound I-3.

[0077] Route II: Route II has similar reaction conditions but a different sequence compared to Route I. Compound C13 can be synthesized by treating with m-CPBA. Compounds of formula II-1 can be synthesized by treating compound C13 with the appropriate group A. Compound II-2 can be synthesized by treating with POCl. Compounds of formula I-3 can be synthesized by treating compound II-2 with DIPEA and group B.

[0078] Deprotection step: Compounds of formula I-4 can be prepared by using compounds of formula I-3 in the presence of an acid (such as TFA, HBr, and AcOH) or a base (such as hydrazine).

[0079] Scheme 1-b: General synthetic route [ka] A method for preparing compounds III-2 and III-3 is shown in Scheme 1-b.

[0080] Route III: Compound E1 can be synthesized by treatment in the presence of NaOEt. Compound E2 can be synthesized by treatment in the presence of POCl. Compound E2 can be further treated with Group B in the presence of KCO to give Compound III-1. Compound III-1 can be further treated with Group A to give Compound III-2. Compound III-3 can be prepared by using Compound III-2 in the presence of an acid (such as TFA, HBr, and AcOH) or a base (such as hydrazine).

[0081] Procedure for the synthesis of E1 Na (859 mg, 37.4 mmol) was added to anhydrous EtOH (100 mL) at 10° C., and the resulting mixture was stirred under a N atmosphere at 10° C. for 1 hour. Compound C3 (3.90 g, 31.1 mmol) and diethylpropanedioate (5.99 g, 37.4 mmol) were then added to the mixture. The mixture was heated at 80° C. and stirred under a N atmosphere for an additional 15 hours to give a yellow solution. TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated to give a residue. The residue was dissolved in water (60 mL), acidified to pH=3 with 3 M HCl, and filtered to give compound E1 (3.60 g) as an off-white solid.

[0082] Procedure for the synthesis of E2 To a solution of compound E1 (3.60 g, 18.6 mmol) in POCl3 (57.1 g, 373 mmol) was added N,N-diethylaniline (2.78 g, 18.6 mmol). The resulting mixture was heated at 100 °C and stirred under a N2 atmosphere for 2 h, resulting in a red solution. TLC showed that the reaction was complete, with one major spot forming. The reaction mixture was concentrated to remove most of the solvent, poured into H2O (40 mL), and extracted with DCM (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica column to give compound E2 (2.85 g) as a yellowish solid.

[0083] General scheme of group A Scheme 2: Synthetic route for A1 [ka] Procedure for the synthesis of A1 A mixture of 4-aminophenol (1.00 g, 9.16 mmol) and 1,4-dibromobutane (9.89 g, 45.8 mmol) in DMF (100 mL) was stirred at 65 °C for 18 hours. Saturated NaHCO (150 mL) was carefully added dropwise to the reaction mixture to quench the reaction. The mixture was diluted with EtOAc (100 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (100 mL × 2). The combined organic phase was washed with water (70 mL × 4), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude compound was purified by Combi-Flash® to obtain compound A1 (110 mg) as a brown powder.

[0084] Scheme 3: Synthetic route for A5 [ka] Procedure for the synthesis of A4 To a solution of compound A2 (1.00 g, 5.76 mmol), compound A3 (2.16 g, 11.5 mmol), and PPh3 (3.02 g, 11.5 mmol) in anhydrous THF (15 mL) was added DEAD (2.01 g, 11.5 mmol), and the mixture was stirred at 20 °C for 17 hours. TLC showed the reaction was complete. The reaction was quenched with water (50 mL) and extracted with EtOAc (50 mL × 3). The combined extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give 1.60 g of compound A4 as a white powder.

[0085] Procedure for the synthesis of A5 To a suspension of compound A4 (800 mg, 2.33 mmol) and NH4Cl (1.25 g, 23.3 mmol) in EtOH (15 mL) was added Zn (1.53 g, 23.3 mmol), and the mixture was stirred at 50 °C for 17 h. TLC and LCMS showed the reaction was complete. The mixture was filtered, the filter cake was washed with DCM (50 mL × 2), and the combined organic phase was concentrated under reduced pressure to give a residue, which was dissolved in DCM (100 mL), washed with water (50 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 650 mg of compound A5 as a yellow gum.

[0086] Scheme 4: Synthetic Route for A9 [ka] Procedure for the synthesis of A8 To a solution of compound A6 (1.00 g, 5.78 mmol) in HO (5 mL) and dioxane (10 mL) was added compound A7 (2.14 g, 6.94 mmol), KCO (2.00 g, 14.5 mmol), and Pd(dppf)Cl (422 mg, 0.578 mmol). The reaction mixture was stirred at 90 °C under a N atmosphere for 16 hours. LCMS showed 50.4% of the desired MS. The mixture was partitioned between DCM (50 mL) and HO (50 mL). The aqueous material was extracted with DCM (50 mL). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound A8 (1.30 g) as a white powder.

[0087] Procedure for the synthesis of A9 To a suspension of compound A8 (1.30 g, 4.72 mmol) in MeOH (2 mL) was added Pd / C (0.13 g, 50% wet, 10% Pd), and the mixture was stirred under a H balloon (15 psi) at 25 °C for 2 h to give a black suspension. LCMS showed that compound A8 was consumed and the desired MS was observed. The mixture was filtered and concentrated under reduced pressure to give compound A9 (1.20 g) as a yellow powder.

[0088] Scheme 5: Synthetic route for A13 [ka] Procedure for the synthesis of A11 To a mixture of EtN (21 mL) in MeNO (50 mL) was added compound A10 (5 g, 25.1 mmol). The mixture was stirred at 10-15 °C for 48 h to give a yellow suspension. The suspension was diluted with EtOAc (100 mL), washed with water (100 mL), saturated NHCl (100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give compound A11 (7.6 g) as a yellow solid.

[0089] Procedure for the synthesis of A12 To a mixture of compound A11 (2 g, 7.68 mmol) and imidazole (2.62 g, 38.4 mmol) in DMF (5 mL) was added chloro(triethyl)silane (10 mL). The mixture was stirred at 70-80 °C for 12 h to give a yellow mixture. The mixture was cooled to room temperature and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 3). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound A12 (5 g) as a yellow oil.

[0090] Procedure for the synthesis of A13 To a mixture of Pd / C (1 g, 10%) in MeOH (100 mL) was added compound A12 (4.9 g, 13.08 mmol). The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 25 °C for 30 h to give a black mixture. Crude HNMR showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a yellow gum, which was purified by Combi flash® to give compound A13 (2.3 g) as a yellow oil.

[0091] Scheme 6: Synthetic route for A16 [ka] Procedure for the synthesis of A15 A mixture of A14 (1.5 g, 9.54 mmol), N-benzylhydroxylamine (2.28 g, 14.3 mmol), (HCHO)n (2.15 g, 23.8 mmol), and TEA (1.45 g, 14.3 mmol, 2.0 mL) in toluene (100 mL) was refluxed for 20 h. A large amount of white solid was observed. LCMS showed the reaction was complete. Most of the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and HO (50 mL). The aqueous phase was extracted with EtOAc (50 mL × 2). The organic extract was washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by combi flash® to give compound A15 (2.05 g) as a pale yellow solid.

[0092] Procedure for the synthesis of A16 To a solution of A15 (1.5 g, 5.13 mmol) in EtOH (10 mL) was added Pd(OH)2 / C (0.5 g, 20% purity). The reaction suspension was purged with H2 (balloon, 15 psi) several times and stirred at 15 °C for 16 h to give a black mixture. TLC (PE / EA = 1 / 1) showed a new spot. The reaction was diluted with MeOH (200 mL) and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give A16 (1.15 g, crude) as a white solid.

[0093] Scheme 7: Synthetic route for A18 [ka] Procedure for the synthesis of A18 To a mixture of A17 (500 mg, 5.61 mmol) in DCM (10 mL) was added BocO (1.35 g, 6.17 mmol), and the mixture was stirred at 25 °C for 16 h to give a colorless oil. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to give compound A18 (1.2 g, crude) as a colorless oil.

[0094] Scheme 8: Synthetic Route for A21 [ka] Procedure for the synthesis of A20 To a solution of compound A19 (500 mg, 2.46 mmol) in DMF (5 mL) was added NaN (319 mg, 4.92 mmol) and NH Cl (158 mg, 2.95 mmol). The mixture was stirred at 80 °C for 3 h to give a yellow mixture. LCMS showed the reaction was complete. The mixture was partitioned between EtOAc (30 mL) and H O (20 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic extracts were dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give compound A20 (820 mg, crude) as a yellow oil.

[0095] Procedure for the synthesis of A21 To a mixture of compound A20 (820 mg, 3.33 mmol) in MeOH (10 mL) was added Pd / C (100 mg). The mixture was stirred at 25° C. for 16 hours to give a black mixture. TLC and LCMS showed that the reaction was complete. The mixture was filtered. The filtrate was concentrated under reduced pressure to give compound A21 (680 mg, crude) as a yellow oil.

[0096] Scheme 9: Synthetic route for A26 [ka] Procedure for the synthesis of A24 To a mixture of A23 (3.34 g, 18.0 mmol) and TMBAC (335 mg, 1.80 mmol) in IPA (50 mL) was added A22 (5.00 g, 54.1 mmol), and the mixture was stirred at 20 °C for 72 h to form a white mixture. TLC (eluent: PE / EtOAc = 2 / 1) showed a new spot. The mixture was partitioned between EtOAc (80 mL) and HO (80 mL). The aqueous phase was extracted with EtOAc (80 mL × 2). The combined organic extracts were washed with brine (80 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by combi flash® to give A24 (1.1 g) as a white solid.

[0097] Procedure for the synthesis of A25 To a mixture of compound A24 (1 g, 4.92 mmol) in THF (10 mL), TEA (597 mg, 5.91 mmol, 822 μL) and 2-hydroxy-2-methyl-propanenitrile (502 mg, 5.91 mmol) were added, and the mixture was stirred at 75° C. for 12 hours to give a yellow mixture. LCMS showed that the reactant remained. The mixture was stirred for another 16 hours to give a brown mixture. TLC showed that the reaction was complete. The mixture was partitioned between EtOAc (30 mL) and H2O (20 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by combi flash® to give compound A25 (450 mg) as an off-white solid.

[0098] Procedure for the synthesis of A26 To a mixture of compound A25 (40 mg, 0.17 mmol) in EtOH (10 mL), PtO (4.0 mg, 0.017 mmol, 0.1 equiv) and HCl (0.05 mL) were added, and the mixture was stirred at 25 °C for 1 h to give a black mixture. TLC showed the reaction was complete. The mixture was filtered and concentrated under reduced pressure to give compound A26 (40 mg, crude) as an off-white gum.

[0099] Scheme 10: Synthetic route for A29 [ka] Procedure for the synthesis of A29 To a solution of compound A27 (200 mg, 0.979 mmol), TEA (409 μL) and DCM (5 mL) was added CbzOSu (217 mg, 0.870 mmol) at 0-10°C, and the mixture was stirred at 20°C for 1 h to give a yellow mixture. TLC showed the reaction was complete. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with water (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil, which was washed with PE (10 mL) to give compound A29 (310 mg) as a yellow oil.

[0100] Procedure for the synthesis of A30 Following the same procedure as for B14 with compound A29 (290 mg), 270 mg of compound A30 was obtained as a yellow gum.

[0101] Commercially available reagents (tert-butyl piperidin-3-ylcarbamate, tert-butyl 4-aminopiperidine-1-carboxylate, piperidine-4-carboxamide, tert-butyl (4-methylpiperidin-4-yl)carbamate, tert-butyl piperidin-4-ylcarbamate, benzyl piperidin-4-ylcarbamate, piperidin-4-ol, piperazine, piperazin-2-one, tetrahydro-2H-pyran-4-amine, tert-butyl 3-methylpiperazine-1-carboxylate, N-(piperidin-4-yl)amine) were used. Cetoamide, 1-methylpiperidin-4-ol, tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate, tert-butyl (morpholin-2-ylmethyl)carbamate, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate, tert-butyl (R)-3-hydroxypiperidine-1-carboxylate, tert-butyl 4-(piperidin-4-yl)piperazine-1-carboxylate, tert-butyl (piperidin-4-ylmethyl)carbamate, 1,2,3,4-tetrahydro-2,6 naphthyridine, tert-butyl (4-methylpiperidin-4-yl)carbamate, tert-butyl ((4-fluoropiperidin-4-yl)methyl)carbamate, (S)-2-(piperidin-2-yl)ethan-1-ol, (S)-piperidin-2-ylmethanol, (1s,4s)-4-aminocyclohexan-1-ol, (1r,4r)-4-aminocyclohexan-1-ol, 4-methoxycyclohexan-1-amine, (tetrahydro-2H-pyran-4-yl)methanamine, morpholine, cyclohexane-1,4-diol, tert-butyl (S)-3-(hydroxymethyl)piperazine-1-carboxylate, tert-butyl 2-(aminomethyl)morpholine-4-carboxylate, 1H-indol-4-amine, 4-(trifluoromethoxy)piperidine, 4-ethoxypiperidine, 4-isopropoxypiperidine, 4-methoxycyclohexane-1-amine, 4-isopropoxycyclohexane-1-amine, 1H-pyrrol-3-amine, and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate, etc., were used for Group A.

[0102] General scheme of group B Scheme 11: Synthetic Route for B3 [ka] Procedure for the synthesis of B2 To a solution of compound B1 (5.00 g, 41.3 mmol) and phenol (5.80 g, 61.9 mmol) in DMA (50 mL) was added 18-crown-6 (1.10 g, 4.13 mmol) and K2CO3 (11.4 g, 82.6 mmol), and the reaction mixture was stirred at 110 °C for 16 hours to give a brown mixture. LCMS showed that the reaction was complete. HO (50 mL) was added to the reaction mixture, and the reaction mixture was extracted with EtOAc (50 mL × 3). The combined organic phase was washed with HO (40 mL × 2) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a brown oil, which was purified by Combi Flash® to give compound B2 (9.80 g) as a yellow oil.

[0103] Procedure for the synthesis of B3 To a solution of compound B2 (1.00 g, 5.12 mmol) in MeOH (30 mL), Raney-Ni (43.9 mg, 0.512 mmol) and NH3·H2O (3 mL) were added, and the reaction mixture was stirred under a H2 balloon (15 psi) at 15 °C for 16 h to give a black suspension. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove MeOH. The residue was diluted with DCM (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound B3 (820 mg) as a yellow oil.

[0104] Scheme 12: Synthetic Route for B7 [ka] Procedure for the synthesis of B6 To a solution of 2-hydroxybenzonitrile B4 (200 mg, 1.68 mmol) and 2-chloroquinoline B5 (261 mg, 1.60 mmol) in DMA (3.0 mL) was added Cs2CO3 (1.04 g, 3.20 mmol). The reaction mixture was stirred at 100 °C for 5 h. TLC showed the reaction was complete. The residue was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was washed with water (10 mL × 2), brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound B6 (80 mg) as a yellow powder.

[0105] Procedure for the synthesis of B7 Following the same procedure as for B3 with compound B6 (80 mg), 64 mg of compound B7 was obtained as a yellow powder.

[0106] Scheme 13: Synthetic route for B10 [ka] Procedure for the synthesis of B9 To a mixture of NaH (198 mg, 4.96 mmol, 60% in mineral oil) in THF (3 mL) was added dropwise a solution of compound B8 (571 mg, 4.96 mmol) in THF (3 mL). After stirring the reaction mixture for 5 minutes, 2-fluorobenzonitrile (500 mg, 4.13 mmol) was added to the mixture. The reaction mixture was stirred at 40° C. for 2 hours. LCMS showed the reaction was complete. The reaction mixture was quenched with water (10 mL) and extracted with DCM (10 mL×2). The organic layer was washed with water (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by Combi flash® to give compound B9 (432 mg) as a light brown oil.

[0107] Procedure for the synthesis of B10 Following the same procedure as for B102 with compound B9 (430 mg), 410 mg of compound B10 was obtained as a white powder.

[0108] Scheme 14: Synthetic route for B14 [ka] Procedure for the synthesis of B13 To a solution of compound B11 (150 mg, 0.675 mmol) and compound B12 (114 mg, 0.81 mmol) in DCM (10 mL) was added DIPEA (174 mg, 1.35 mmol). The resulting mixture was stirred at 20° C. for 12 hours to give a yellowish liquid. TLC showed that the reaction was complete and one major spot was formed. The reaction mixture was quenched by adding HO (30 mL) and extracted with DCM (30 mL×2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound B13 (200 mg) as a white solid.

[0109] Procedure for the synthesis of B14 To a solution of compound B13 (200 mg, 0.613 mmol) in DCM (7 mL) was added TFA (3 mL). The resulting mixture was stirred at 20° C. for 1 hour to give a yellow solution. TLC showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give compound B14 (130 mg) as a yellow oil.

[0110] Scheme 15: Synthetic route for B18 [ka] Procedure for the synthesis of B17 To a solution of compound B15 (1.00 g, 3.49 mmol) and compound B16 (536 mg, 4.19 mmol) in DME (10 mL) was added Pd(dppf)Cl (128 mg, 0.174 mmol) and NaCO (370 mg, 3.49 mmol) in HO (2.5 mL), and the reaction mixture was stirred at 90 °C for 3 hours to give a black suspension. TLC showed that the reaction was complete. HO (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (10 mL × 2). The organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a brown oil, which was purified by Combi Flash® to give compound B17 (705 mg) as a yellow oil.

[0111] Procedure for the synthesis of B18 Following the same procedure as for B14 with compound B17 (350 mg), 220 mg of compound B18 was obtained as a yellow powder.

[0112] Scheme 16: Synthetic route for B21 [ka] Procedure for the synthesis of B20 A mixture of compound B19 (2.00 g, 16.5 mmol), pyrrolidine (1.29 g, 18.1 mmol), and K2CO3 (4.56 g, 33.0 mmol) in DMF (10 mL) was stirred at 60 °C for 16 hours. TLC showed that the reaction was complete. The mixture was poured into water (100 mL). The mixture was extracted with EtOAc (30 mL × 3), and the combined mixture was washed with water (50 mL × 2), brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound B20 (2.78 g) as a colorless oil.

[0113] Procedure for the synthesis of B21 Following the same procedure as for B3 with compound B20 (1.5 g), 1.5 g of compound B21 was obtained as a colorless oil.

[0114] Scheme 17: Synthetic route for B24 [ka] Procedure for the synthesis of B23 To a solution of compound B22 (5 g, 35.7 mmol) and CsCO (29.1 g, 89.2 mmol) in DMF (50 mL) was added 2-fluorobenzonitrile (6.48 g, 53.5 mmol, 5.69 mL). The reaction mixture was stirred at 25 °C for 16 hours to give a yellow mixture. TLC showed the reaction was complete. The reaction mixture was quenched by the addition of HO (200 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column to give compound B23 (5 g) as a white powder.

[0115] Procedure for the synthesis of B24 To a solution of compound B23 (200 mg, 0.829 mmol) in THF (2 mL) was added LiAlH (126 mg, 3.32 mmol) at 0 °C under a N atmosphere. The reaction mixture was stirred at 25 °C for 2 hours to give a yellow solution. LCMS showed that the reaction of the mixture was complete. The reaction was slowly quenched with water (1 mL) and aqueous NaOH (1 mL, 2.0 M) at 5 °C. The mixture was stirred at 5 °C for 10 minutes. The mixture was filtered, and the filtrate was extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude compound B24 (180 mg) as a pale yellow gum.

[0116] Scheme 18: Synthetic route for B28 [ka] Procedure for the synthesis of B26 To a solution of compound B25 (5 g, 35.7 mmol) in THF (50 mL) was added MeMgBr (3 M, 47.6 mL) dropwise at 0-5 °C under a N atmosphere. The resulting mixture was stirred at 10 °C for 15 h, forming a white suspension. TLC showed the reaction was complete. The mixture was poured into saturated aqueous NH4Cl (50 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic extracts were washed with brine (80 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound B26 (2.6 g) as a white solid.

[0117] Procedure for the synthesis of B27 To a mixture of compound B26 (2.6 g, 20.6 mmol) and 2-fluorobenzonitrile (3.00 g, 24.7 mmol) in DMF (50 mL) was added CsCO (13.4 g, 41.2 mmol). The mixture was stirred at 15 °C for 15 hours, forming a white suspension. TLC showed the reaction was complete. The mixture was partitioned between EtOAc (150 mL) and HO (150 mL). The aqueous phase was extracted with EtOAc (150 mL × 2). The combined organic extracts were washed with brine (100 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by combi flash® to give compound B27 (3.6 g) as a white solid.

[0118] Procedure for the synthesis of B28 To a solution of compound B27 (3.6 g, 15.84 mmol) in MeOH (100 mL) was added Raney-Ni (1 g in water) under a N atmosphere. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (15 psi) at 20 °C for 15 h, resulting in the formation of a black suspension. TLC showed the reaction was complete. The reaction mixture was filtered through a pad of Celite. The filter cake was washed with MeOH (80 mL). The filtrate was concentrated under reduced pressure to give compound B28 (3.5 g) as a colorless gum.

[0119] Scheme 19: Synthetic route for B31 [ka] Procedure for the synthesis of B30 To a mixture of morpholine (2.63 g, 30.2 mmol) and compound B29 (500 mg, 2.02 mmol) in toluene (5 mL), XPhos (192 mg, 0.403 mmol), CsCO (1.64 g, 5.04 mmol), and Pd(dba) (185 mg, 0.202 mmol) were added, and the reaction mixture was stirred at 110 °C under a N atmosphere for 16 hours to give a black suspension. LCMS (Rt = 0.908 min) indicated that the reaction was complete. The reaction mixture was partitioned between EtOAc (80 mL) and water (80 mL). The aqueous phase was extracted with EtOAc (70 mL × 2). The combined organic layers were washed with water (100 mL × 2), brine (100 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The reaction mixture was purified by Combi flash® to give compound B30 (190 mg) as a brown gum.

[0120] Procedure for the synthesis of B31 Following the same procedure as for B3 with compound B30 (190 mg), 170 mg of compound B31 was obtained as a colorless gum.

[0121] Scheme 20: Synthetic route for B38 [ka] Procedure for the synthesis of B33 To a mixture of compound B31 (10 g, 37.7 mmol) in DMF (5 mL) was added compound B32 (9.13 g, 75.3 mmol). The mixture was stirred at 50° C. for 12 hours to give a yellow suspension. LCMS showed the reaction was complete. Water (30 mL×2) was added to the mixture, which was filtered and concentrated under reduced pressure to give a yellow powder, which was washed with PE (50 mL) to give compound B32 (7 g) as a brown powder.

[0122] Procedure for the synthesis of B34 To a mixture of compound B33 (4 g, 18.7 mmol) in MeOH (30 mL) was added NH4Cl (9.99 g, 186 mmol) and Zn (12.2 g, 186 mmol). The mixture was stirred at 25 °C for 15 hours to give an off-white suspension. LCMS showed the reaction was complete. After filtration, the filter cake was washed with MeOH (50 mL), and the filtrate was partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (50 mL × 2), and the combined extracts were washed with water (50 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound B34 (2 g) as a yellow powder.

[0123] Procedure for the synthesis of B36 To a mixture of compound B34 (2 g, 10.8 mmol) in n-BuOH (20 mL) was added compound B35 (1.94 g, 10.8 mmol). The reaction was refluxed at 117° C. for 48 hours to give a yellow suspension. LCMS showed the reaction was complete. To the mixture was added NaOH (868 mg, 21.7 mmol) and HO (10 mL), dioxane (10 mL), and tert-butoxycarbonyl tert-butyl carbonate (3.56 g, 16.2 mmol). The mixture was stirred at 25° C. for 2 hours to give a yellow suspension. LCMS (Rt=1.268 min) showed the reaction was complete. The mixture was partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (50 mL × 2), and the combined extracts were washed with water (50 mL × 2), dried over anhydrous NaSO and concentrated under reduced pressure to give a yellow gum, which was purified by Combi flash® to give compound B36 (400 mg) as a yellow oil.

[0124] Procedure for the synthesis of B37 Following the same procedure as for B72 with compound B36 (1.0 g), 400 mg of compound B37 was obtained as a yellow solid.

[0125] Procedure for the synthesis of B38 Following the same procedure as for B3 with compound B37 (200 mg), 200 mg of compound B38 was obtained as a yellow powder.

[0126] Scheme 21: Synthetic route for B42 [ka] Procedure for the synthesis of B41 To a mixture of compound B39 (423 mg, 2.88 mmol), compound B40 (500 mg, 2.40 mmol), and K2CO3 (663 mg, 4.80 mmol) in dioxane (5 mL) / HO (1 mL) was added Pd(dppf)Cl2 (175 mg, 0.24 mmol). The mixture was stirred at 110 °C for 16 hours. TLC showed a new spot. The mixture was poured into water (20 mL). The mixture was extracted with DCM (30 mL × 3). The combined mixture was washed with water (50 mL × 2), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue (brown gum). The residue was purified by Combi Flash® to give compound B41 (200 mg) as a red powder.

[0127] Procedure for the synthesis of B42 Following the same procedure as for B3 with compound B41 (200 mg), 200 mg of compound B42 was obtained as a brown oil.

[0128] Scheme 22: Synthetic route for B46 [ka] Procedure for the synthesis of B45 A solution of compound B43 (300 mg, 1.37 mmol) and compound B44 (335 mg, 1.51 mmol) in i-PrOH (10 mL) was heated at 80° C. and stirred for 4 hours. Then, tributylphosphane (1.39 g, 6.85 mmol) was added to the mixture and stirred for another 12 hours to give a yellow solution. LCMS and TLC showed that the reaction was complete. The reaction mixture was quenched by adding HO (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (20 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound B45 (524 mg) as a yellow solid.

[0129] Procedure for the synthesis of B46 Following the same procedure as for B14 with compound B45 (524 mg), 430 mg of compound B46 was obtained as a yellow solid.

[0130] Scheme 23: Synthetic route for B50 [ka] Procedure for the synthesis of B49 To a solution of compound B47 (500 mg, 3.70 mmol) in AcOH (10 mL) was added compound B48 (1.11 g, 4.44 mmol), Pd(OAc) (415 mg, 1.85 mmol), and the reaction mixture was stirred under O (15 psi) at 25 °C for 16 hours to give a black suspension. LCMS and TLC showed the reaction was complete. The reaction was poured into water (50 mL) and partitioned between EtOAc (100 mL) and water (100 mL). The aqueous phase was extracted with EtOAc (100 mL × 2), and the combined organic layers were washed with water (100 mL × 2), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound B49 (240 mg, 0.705 mmol) as a yellow gum.

[0131] Procedure for the synthesis of B50 Following the same procedure as for B14 with compound B49 (240 mg), 170 mg of compound B50 was obtained as a yellow gum.

[0132] Scheme 24: Synthetic route for B56 [ka] Procedure for the synthesis of B53 To a solution of compound B51 (600 mg, 3.35 mmol) in i-PrOH (10 mL) was added compound B52 (744 mg, 3.35 mmol). The reaction solution was heated to 80 °C and stirred for 3 h, resulting in a yellow solution. The reaction was cooled to 30-40 °C, and tributylphosphane (2.03 g, 2.48 mL) was added. The mixture was stirred at 80 °C for an additional 16 h, resulting in a black solution. TLC showed the reaction was complete. The reaction mixture was quenched by the addition of HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated NH Cl (50 mL) and brine (10 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound B53 (784 mg) as a yellow solid.

[0133] Procedure for the synthesis of B54 To a solution of compound B53 (784 mg, 2.06 mmol) in MeOH (5 mL) and HO (1 mL) was added LiOH·HO (431 mg, 10.3 mmol). The resulting mixture was stirred at 20 °C for 12 h to give a yellow suspension. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove most of the MeOH and then acidified with 1 M HCl to approximately pH 4, precipitating a large amount of white solid. The mixture was filtered under reduced pressure to give the filter cake, compound B54 (724 mg), as a white solid.

[0134] Procedure for the synthesis of B55 To a solution of compound B54 (625 mg, 1.70 mmol) and methanamine (230 mg, 3.40 mmol) in DMF (10 mL) was added EtN (516 mg, 5.10 mmol) and HATU (647 mg, 1.70 mmol, 1 equiv.). The resulting mixture was stirred at 20 °C for 2 h to give a yellow solution. TLC showed that the reaction was complete and one major new spot had formed. The reaction mixture was quenched with HO (20 mL) to precipitate a large amount of white solid, which was then filtered under reduced pressure to give the filter cake, compound B55 (693 mg), as a white solid.

[0135] Procedure for the synthesis of B56 Following the same procedure as for B14 with compound B55 (200 mg), 130 mg of compound B56 was obtained as a yellow oil.

[0136] Scheme 25: Synthetic Route for 61 [ka] Procedure for the synthesis of B59 Following the same procedure as for B41 with compound B57 (500 mg), 840 mg of compound B59 was obtained as a yellow solid.

[0137] Procedure for the synthesis of B60 To a solution of compound B59 (350 mg, 1.08 mmol) in MeOH (10 mL) was added Pd / C (20 mg, 10% purity, wet) under a N atmosphere. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 20 °C for 12 h to give a black suspension; LCMS showed no reaction; acetic acid (0.1 mL) was added to the reaction, and the suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (50 psi) at 20 °C for 12 h to give a black suspension; LCMS showed the reaction was complete. The reaction mixture was filtered through padded Celite and concentrated under reduced pressure to give compound B60 (450 mg, crude) as a yellowish oil; the crude product was used in the next step without purification.

[0138] Procedure for the synthesis of B61 Following the same procedure as for B14 with compound B60 (450 mg), 330 mg of compound B61 was obtained as a yellow oil.

[0139] Scheme 26: Synthetic route for B66 [ka] Procedure for the synthesis of B63 A solution of compound B62 (1.00 g, 8.84 mmol) in DMF / DMA (20 mL) was heated at 110° C. and stirred for 2 h to give a red solution. The reaction mixture was concentrated under reduced pressure to give crude compound B63 (1.20 g) as a red solid.

[0140] Procedure for the synthesis of B64 To a solution of compound B63 (700 mg, 4.16 mmol) in EtOH (10 mL) was added NHNH·H0 (208 mg, 4.16 mmol). The resulting mixture was heated at 100 °C and stirred for 16 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give compound B64 (550 mg) as a yellow solid.

[0141] Procedure for the synthesis of B65 Following the same procedure as for B33 with compound B64 (400 mg), 445 mg of compound B65 was obtained as a yellow solid.

[0142] Procedure for the synthesis of B66 Following the same procedure as for B3 with compound B65 (100 mg), 91 mg of compound B66 was obtained as a white powder.

[0143] Scheme 27: Synthetic route for B70 [ka] Procedure for the synthesis of B69 To a mixture of compound B67 (300 mg, 1.41 mmol), compound B68 (710 mg, 2.83 mmol), and CsCO (1.15 g, 3.54 mmol) in dioxane (3 mL) and HO (0.9 mL) was added Pd(dppf)Cl (104 mg, 0.141 mmol). The mixture was stirred at 100 °C under a N atmosphere for 12 h to give a brown suspension. LCMS showed the reaction was complete. The mixture was cooled to room temperature and partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (30 mL × 2). The combined extracts were washed with water (30 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product as a red oil, which was purified by Combi flash® to give compound B69 (108 mg) as a brown oil.

[0144] Procedure for the synthesis of B70 To a mixture of compound B69 (100 mg, 0.296 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at 15° C. for 20 minutes to give a yellow mixture. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give compound B70 (90 mg) as a yellow oil.

[0145] Scheme 28: Synthetic route for B75 [ka] Procedure for the synthesis of B72 To a mixture of compound B71 (1 g, 5.68 mmol) in DCM (5 mL) was added BocO (1.49 g, 6.82 mmol). The mixture was stirred at 25 °C for 2 h to give a yellow mixture. LCMS showed the reaction was complete. The mixture was partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (30 mL × 2), and the combined extracts were washed with water (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound B72 (950 mg) as a white powder.

[0146] Procedure for the synthesis of B74 To a mixture of compound B72 (850 mg, 3.08 mmol), compound B73 (804 mg, 3.08 mmol), and CsCO (2.51 g, 7.69 mmol) in dioxane (5 mL) and HO (1.5 mL) was added Pd(dppf)Cl (225 mg, 0.308 mmol), and the mixture was stirred at 100 °C under a N atmosphere for 12 hours to give a red mixture. LCMS showed that the reaction was complete. The mixture was cooled to room temperature and partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was extracted with DCM (50 mL × 2). The combined extracts were washed with water (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by Combi flash® to give compound B74 (420 mg) as a white powder.

[0147] Procedure for the synthesis of B75 Following the same procedure as for B14 with compound B74 (230 mg), 170 mg of compound B75 was obtained as a yellow oil.

[0148] Scheme 29: Synthetic route for B81 [ka] Procedure for the synthesis of B77 To a mixture of compound B76 (8.00 g, 56.3 mmol) in MeOH (60 mL) was added TEA (11.4 g, 113 mmol) and methylhydrazine (8.11 g, 56.3 mmol). The mixture was stirred at 60° C. for 15 hours, forming a brown mixture. The desired MS value was detected by LC-MS. The mixture was cooled to 5° C. and allowed to stand for 2 hours until white crystals precipitated, which were filtered, washed with ethanol, and dried to give compound B77 (3.5 g) as a white solid.

[0149] Procedure for the synthesis of B78 A mixture of compound B77 (750 mg, 4.80 mmol) and TEA (1.34 mL) in DCM (5 mL) was cooled to 0 °C in a brine / ice bath. TfO (2.71 g, 9.61 mmol) was then added dropwise while maintaining the temperature at 0 °C. After the addition was complete, the reaction mixture was warmed to 20 °C and stirred for 1 h to form a colorless mixture. LCMS showed that the starting material was completely consumed. The reaction mixture was quenched with water (30 mL) and the layers were separated. The aqueous phase was extracted with DCM (50 mL × 2). The combined organic extracts were washed with brine (80 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by Combi flash® to give compound B78 (530 mg) as a yellow oil.

[0150] Procedure for the synthesis of B80 To a mixture of compound B78 (430 mg, 1.49 mmol) and compound B79 (544 mg, 2.24 mmol) in dioxane (4 mL) and HO (1 mL), CsCO (1.22 g, 3.73 mmol) and Pd(dppf)Cl (109 mg, 0.15 mmol) were added, and the mixture was stirred at 80 °C under a N atmosphere for 12 hours, forming a brown mixture. LCMS showed the reaction was complete. The mixture was filtered through a pad of Celite. The filtrate was partitioned between EtOAc (30 mL) and HO (30 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (80 mL × 3), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by Combi flash® to give compound B80 (200 mg) as a white solid.

[0151] Procedure for the synthesis of B81 To a mixture of methyl compound B80 (150 mg, 0.58 mmol) in THF (4 mL) was added LiAlH (111 mg, 2.94 mmol) at 0 °C, and the mixture was stirred at 10 °C for 12 h to form a white mixture. LCMS showed the reaction was complete. The mixture was quenched with saturated NH Cl (10 mL). The mixture was filtered through a pad of Celite and washed with EtOAc (10 mL). The filtrate was partitioned between EtOAc (30 mL) and H O (30 mL). The aqueous phase was extracted with EtOAc (30 mL × 2). The combined organic extracts were washed with brine (50 mL × 3), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give compound B81 (100 mg) as a white solid, which was used for the next step without further purification.

[0152] Scheme 30: Synthetic route for B88 [ka] Procedure for the synthesis of B84 To a mixture of compound B82 (1 g, 7.14 mmol), CsCO (5.81 g, 17.8 mmol) in DMF (15 mL) was added compound B83 (6.14 g, 35.68 mmol). The mixture was stirred at 20 °C for 12 hours to give a yellow suspension. TLC showed the reaction was complete. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the aqueous phase was extracted with EtOAc (80 mL × 2), and the combined extracts were washed with water (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by Combi flash® to give compound B84 (1.9 g) as a white solid.

[0153] Procedure for the synthesis of B85 To a mixture of compound B84 (300 mg, 1.09 mmol) in THF (2 mL), MeOH (2 mL), and HO (1 mL) was added LiOH (130 mg, 5.44 mmol). The mixture was stirred at 15 °C for 12 h to give a yellow mixture. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to remove MeOH. The aqueous phase was diluted with water (30 mL), acidified to pH = 4-5 with HCl (3 M), and lyophilized to give compound B85 (201 mg) as a white solid.

[0154] Procedure for the synthesis of B87 To a mixture of compound B85 (200 mg, 0.808 mmol), HOBt (131 mg, 0.969 mmol), and EDCI (186 mg, 0.969 mmol) in DMF (3 mL) was added DIEA (313 mg, 2.42 mmol) and compound B86 (324 mg, 1.62 mmol). The mixture was stirred at 20 °C for 12 hours to give a yellow mixture. LCMS showed the reaction was complete. The reaction mixture was quenched with HO (20 mL), and a large amount of white solid precipitated, which was then filtered under reduced pressure to give compound B87 (205 mg) as a white powder.

[0155] Procedure for the synthesis of B88 Following the same procedure as for B3 with compound B87 (200 mg), 254 mg of compound B88 was obtained as a yellow solid.

[0156] Scheme 31: Synthetic Route for B95 [ka] Procedure for the synthesis of B90 To a solution of compound B89 (5 g, 41.3 mmol), pyridine (8.33 mL) in DCM (50 mL) was added TFAA (7.17 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h to give a yellow mixture. LCMS showed the reaction was complete. The reaction mixture was poured into 0.5 N HCl (30 mL) and stirred vigorously for 5 min. The layers were separated, and the aqueous layer was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with 0.5 N HCl (20 mL), H0 (2 × 20 mL), and saturated NaHCO (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound B90 (9.3 g, crude) as a yellow gum.

[0157] Procedure for the synthesis of B91 To a solution of CFSOH (2.44 mL) in DCM (50 mL) was added HNO (622 μL) at 0 °C and stirred at 0 °C for 30 min. The mixture was cooled to -70 °C, and a solution of compound B90 (3.00 g, 13.8 mmol) in DCM (20 mL) was added over 1 h. The mixture was then stirred at -70 °C for 30 min. The mixture was stirred at -40 °C for 12 h to give a yellow mixture. LCMS indicated the reaction was complete. The yellow-orange reaction mixture was poured onto ice (50 g) and stirred vigorously for 10 min. The layers were separated, and the aqueous layer was extracted with CHCl (3 × 25 mL). The organic layers were combined, washed with H2O (3 x 50 mL), saturated NaHCO3 (50 mL), and H2O (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to provide compound B91 (3.12 g) as a yellow solid.

[0158] Procedure for the synthesis of B92 To a mixture of compound B91 (500 mg, 1.91 mmol) in EtOH (10 mL) was added Pd / C (0.1 g, 10% purity, 50% water). The suspension was degassed under vacuum and purged with H atmosphere several times. The mixture was stirred under H atmosphere (15 psi) at 15 °C for 12 hours to give a black suspension. LCMS showed the reaction was complete. The combined batch mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound B92 (480 mg) as a yellow oil.

[0159] Procedure for the synthesis of B94 To a solution of compound B92 (390 mg, 2.58 mmol) in i-PrOH (15 mL) was added compound B93 (600 mg, 2.58 mmol). The reaction solution was heated to 80 °C and stirred for 3 h, resulting in a yellow solution. The reaction was cooled to 30-40 °C, and P(n-Bu) (1.57 g, 7.74 mmol) was added and stirred at 80 °C for an additional 12 h, resulting in a dark brown solution. LCMS showed the reaction was complete. The reaction mixture was quenched by the addition of HO (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with saturated NH Cl (50 mL) and brine (10 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue that was purified by Combi flash® to give compound B94 (200 mg) as a yellow gum.

[0160] Procedure for the synthesis of B95 To a solution of compound B94 (200 mg, 0.600 mmol) in MeOH (8 mL) was added K2CO3 (415 mg, 3.00 mmol). The resulting mixture was stirred at 60-70 °C for 2 h to give a yellow solution. TLC indicated that the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to give compound B95 (141 mg) as a yellow gum.

[0161] Scheme 32: Synthetic route for B98 [ka] Procedure for the synthesis of B97 To a solution of compound B96 (4.00 g, 32.8 mmol) in DMA (50 mL) was added 1H-pyrazole (2.68 g, 39.3 mmol) and CsCO (10.7 g, 32.8 mmol). The reaction mixture was stirred at 80° C. for 5 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between water (250 mL) and EtOAc (250 mL). The organic layer was washed with water (100 mL×2), brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash® to give compound B97 (4.76 g) as a white powder.

[0162] Procedure for the synthesis of B98 To a solution of compound B97 (1.3 g, 7.64 mmol) in MeOH (30 mL) was added Raney-Ni (497 mg, 5.81 mmol). The reaction mixture was stirred under H atmosphere (15 psi) at 20° C. for 3 hours. TLC showed the reaction was complete. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to give 560 mg of a dark brown gum as a crude product. The crude product was purified by Combi Falsh to give compound B98 (350 mg) as a light purple oil.

[0163] Scheme 33: Synthetic route for B102 [ka] Procedure for the synthesis of B100 To a solution of compound B99 (1.00 g, 8.05 mmol) and CuBr (2.16 g, 9.66 mmol) in CHCN (10 mL) was added tert-butyl nitrite (1.25 g, 12.1 mmol) at 0 °C, and the reaction mixture was stirred at 15 °C for 3 hours to give a brown solution. TLC showed the reaction was complete. 2 M HCl (50 mL) was added to the reaction mixture, which was extracted with EtOAc (30 mL × 3). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a brown oil. The product was purified by Combi Flash to give compound B100 (380 mg) as a yellow oil.

[0164] Procedure for the synthesis of B101 To a solution of compound B100 (380 mg, 2.02 mmol) in dioxane (6 mL), CuI (115 mg, 0.606 mmol), K2CO3 (559 mg, 4.04 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (86.2 mg, 0.606 mmol), and 1H-pyrazole (165 mg, 2.42 mmol) were added, and the reaction was stirred at 80 °C for 16 h to give a brown suspension. TLC showed a new spot. 1H-pyrazole (500 mg) was added to the reaction solution, and the solution was stirred at 110 °C for 8 h. TLC showed that the reaction was not complete. The mixture was filtered. The filtrate was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with 28% NH H O (30 mL × 2), brine (20 mL × 2), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a yellow oil. The product was purified by Combi Flash to give compound B101 (180 mg) as a white solid.

[0165] Procedure for the synthesis of B102 Following the same procedure as for B3 with compound B102 (180 mg), 143 mg of compound B101 was obtained as a yellow oil.

[0166] Scheme 34: Synthetic route for B105 [ka] Procedure for the synthesis of B104 To a mixture of compound B103 (1.00 g, 4.81 mmol) and Pd(PPh3)4 (556 mg, 0.481 mmol) in anhydrous DMF (10 mL) was added Zn(CN)2 (678 mg, 5.77 mmol). The reaction mixture was heated at 80 °C under a N2 atmosphere for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was cooled to room temperature, and then poured into water (50 mL). The crude product was extracted with EtOAc (100 mL). The organic layer was washed with water (50 mL x 2), brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by Combi Flash® to give compound B104 (700 mg) as a white powder.

[0167] Procedure for the synthesis of B105 Following the same procedure as for B102 with compound B104 (700 mg), 660 mg of compound B105 was obtained as a brown oil.

[0168] Scheme 35: Synthetic route for B111 [ka] Procedure for the synthesis of B107 To a mixture of compound B106 (10.0 g, 45.4 mmol) in DMF (5 mL) was added MeNH (2 M in THF, 68.2 mL), followed by KCO (9.42 g, 68.2 mmol), and the resulting mixture was stirred at 25 °C for 12 hours to give a yellow suspension. TLC showed that the reaction was complete. The mixture was diluted with EtOAc (300 mL), washed with water (200 mL × 3) and brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound B107 (13.0 g) as a yellow oil, which was used directly for the next step without further purification.

[0169] Procedure for the synthesis of B108 To a mixture of compound B107 (6.00 g) in MeOH (60 mL) was added AcOH (15.6 g, 259 mmol), followed by Fe powder (7.25 g, 129.9 mmol), and the resulting mixture was stirred at 25 °C for 12 h. Crude LCMS showed a complete reaction. The suspension was filtered and washed with MeOH (80 mL). The filtrate was concentrated under reduced pressure. The residue was basified to pH 9-10 with saturated NaHCO and extracted with EtOAc (200 mL × 2). The combined organic phase was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound B108 (4.60 g) as a brown oil. The crude product was used directly for the next step.

[0170] Procedure for the synthesis of B109 To compound B108 (4.60 g, crude) was added HCOOH (20 mL), and the resulting mixture was stirred at 90 °C for 12 h. LCMS showed a sufficient reaction. The reaction was quenched by adding 50 mL of water and neutralized with saturated NaHCO to adjust the pH to 8-9. The resulting mixture was extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound B109 (3.70 g, 83.6% yield for three steps) as a brown solid.

[0171] Procedure for the synthesis of B110 Following the same procedure as for B104 with compound B109 (2.0 g), 900 mg of compound B110 was obtained as a purple powder.

[0172] Procedure for the synthesis of B111 Following the same procedure as for B3 with compound B110 (1.2 g), 1.0 g of compound B111 was obtained as a white powder.

[0173] Scheme 36: Synthetic route for B115 [ka] Procedure for the synthesis of B113 A mixture of compound B112 (1.00 g, 5.32 mmol) in 1,1,1-triethoxyethane (4.40 g, 27.1 mmol) was stirred under N at 120 °C for 2 h to form a dark red solution. LCMS showed 91.7% of the desired MS. Most of the MeC(OEt) was removed under reduced pressure to give compound B113 (950 mg) as a red powder.

[0174] Procedure for the synthesis of B114 Following the same procedure as for B104 with compound B113 (950 mg), 230 mg of compound B114 was obtained as a pink powder.

[0175] Procedure for the synthesis of B115 Following the same procedure as for B3 with compound B114 (257 mg), 250 mg of compound B115 was obtained as a yellow gum.

[0176] Scheme 37: Synthetic route for B122 [ka] Procedure for the synthesis of B118 To a stirred solution of compound B116 (6.80 g, 53.5 mmol) in DCM (50 mL) was added compound B117 (8.38 g, 48.6 mmol) dissolved in DCM (50 mL) dropwise at −5 to 0° C. The mixture was then stirred at 1 to 11° C. for 64 h. TLC showed that compound B116 was completely consumed. The mixture was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give compound B118 (10.0 g) as a brown solid.

[0177] Procedure for the synthesis of B119 Compound B118 (10.0 g, 38.0 mmol) and AlCl (12.7 g, 95.2 mmol) were stirred at 120° C. under a N atmosphere for 4 hours. TLC showed that compound B90 was completely consumed. The mixture was dissolved in DCM (30 mL), poured into ice water (50 mL), and separated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product as a brown oil. The crude product was purified by Combi flash® to give compound B119 (1.10 g) as a yellow solid.

[0178] Procedure for the synthesis of B120 To a stirred solution of compound B119 (1.10 g, 4.87 mmol) in DMSO (30 mL) was added KOH (1.09 g, 19.4 mmol) and MeI (2.07 g, 14.5 mmol). The mixture was then stirred at 10° C. for 64 hours. LCMS showed that compound B119 was completely consumed. The mixture was poured into water (100 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate, and concentrated to give the crude product as a brown oil. The crude product was purified by Combi flash® to give compound B120 (840 mg) as a yellow oil.

[0179] Procedure for the synthesis of B121 Following the same procedure as for B104 with compound B120 (600 mg), 450 mg of compound B121 was obtained as a yellow solid.

[0180] Procedure for the synthesis of B122 Following the same procedure as for B3 with compound B121 (400 mg), 180 mg of compound B122 was obtained as a red oil.

[0181] Scheme 38: Synthetic route for B125 [ka] Procedure for the synthesis of B124 To a solution of 2,2,6,6-tetramethylpiperidine (1.23 g, 8.72 mmol) in THF (18 mL) was added n-BuLi (2.5 M, 2.91 mL) under a N2 atmosphere at −10 °C for 10 min. Then, a solution of B123 (1 g, 7.27 mmol) in THF (10 mL) was added to the mixture, and the reaction mixture was stirred at −78 °C for 10 min. Then, acetone (844 mg, 14.5 mmol, 1.07 mL) was added to the reaction mixture. The reaction mixture was stirred at 15 °C for 16 h to give a brown mixture. TLC showed a new spot. The reaction mixture was quenched with NH4Cl (200 mL) and extracted with EA (150 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The residue was purified by column chromatography to give compound B124 (1.3 g) as a pale yellow oil.

[0182] Procedure for the synthesis of B125 To a solution of B124 (1.3 g, 6.64 mmol) in THF (15 mL) was added BH3·THF (1 M, 33.2 mL) under a N2 atmosphere at 0 °C and stirred for 30 min. The reaction mixture was then stirred at 60 °C for 16 h to give a colorless mixture. LCMS showed that the desired MS and R1 were consumed. The reaction mixture was quenched with MeOH (20 mL) and adjusted to pH = 2 with 0.5 M aqueous HCl. The mixture was then extracted with DCM (100 mL × 2). The aqueous phase was basified to pH = 8 with 2 M NaOH and extracted with DCM (100 mL × 2). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B125 (800 mg, crude) as a white solid.

[0183] Scheme 39: Synthetic route for B129 [ka] Procedure for the synthesis of B127 To a solution of B126 (1 g, 6.60 mmol) in CCl4 (10 mL) was added NBS (1.29 g, 7.25 mmol) and BPO (16 mg, 66 μmol). The reaction mixture was stirred at 85 °C for 16 h to give a pale yellow mixture. TLC showed a new spot. The reaction mixture was filtered, and the filter cake was washed with CCl4 (100 mL). The filtrate was concentrated to give a residue. The residue was purified by column chromatography to give B127 (1.5 g) as a pale yellow solid.

[0184] Procedure for the synthesis of B128 To a solution of B127 (1.5 g, 6.51 mmol) in DMF (15 mL) was added NaN3 (570 mg, 8.77 mmol). The reaction mixture was then stirred at 60 °C under a N2 atmosphere for 16 h to give a pale yellow mixture. TLC showed a new spot. The reaction mixture was quenched with brine (150 mL) and extracted with MTBE (150 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give B128 (1.1 g, crude) as a pale yellow oil.

[0185] Procedure for the synthesis of B129 To a solution of B128 (1.1 g, 5.71 mmol) in THF (9 mL) / HO (1 mL) was added PPh (2.25 g, 8.57 mmol). The reaction mixture was stirred at 80 °C for 16 h to give a brown mixture. LCMS showed the desired MS values. The reaction mixture was diluted with water (100 mL), adjusted to pH = 3 with HCl (0.5 M), and then extracted with EtOAc (100 mL × 2). The aqueous phase was adjusted to pH = 8 with aqueous NaHCO and extracted with EtOAc (100 mL). TLC showed no product in the organic extracts. The aqueous phase was concentrated to give B129 (2.3 g, crude) as a brown solid.

[0186] Scheme 40: Synthetic route for B136 [ka] Procedure for the synthesis of B131 Following the same procedure as for B41 with compound B130 (100 mg), 87 mg of compound B131 was obtained as a brown solid.

[0187] Procedure for the synthesis of B132 Following the same procedure as for B26 with compound B131 (87 mg), 90 mg of compound B132 was obtained as a brown gum.

[0188] Procedure for the synthesis of B133 Following the same procedure as for B28 with compound B132 (90 mg), 80 mg of compound B133 was obtained as a brown solid.

[0189] Scheme 41: Synthetic route for B138 [ka] Procedure for the synthesis of B135 To a solution of SOCl (2.07 g, 17.4 mmol, 1.26 mL) in MeOH (20 mL) at 0 °C was added B134 (1 g, 8.69 mmol). The reaction mixture was stirred at 20 °C for 3 h to give a colorless mixture. TLC showed a new spot. The reaction mixture was concentrated under reduced pressure to give B135 (1.3 g) as a colorless oil.

[0190] Procedure for the synthesis of B136 Following the same procedure as for B21 with compound B135 (1.3 g), 1.8 g of compound B136 was obtained as a white solid.

[0191] Procedure for the synthesis of B137 Following the same procedure as for B26 with compound B136 (1.8 g), 1.81 g of compound B137 was obtained as a yellow gum.

[0192] Procedure for the synthesis of B138 Following the same procedure as for B125 with compound B137 (1 g), 600 mg of compound B138 was obtained as a yellow gum.

[0193] Scheme 42: Synthetic route for B143 [ka] Procedure for the synthesis of B140 To a solution of compound B139 (3 g, 11.9 mmol) in MeOH (20 mL) was added H2SO4 (2.38 g, 23.8 mmol, 1.29 mL). The mixture was refluxed for 17 hours, forming a brown solution. TLC showed the reaction was complete. The mixture was partitioned between EtOAc (30 mL) and HO (30 mL). The aqueous phase was extracted with EtOAc (30 mL x 2). The combined organic extracts were washed with brine (50 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound B140 (2.8 g) as a yellow solid.

[0194] Procedure for the synthesis of B141 Following the same procedure as for B26 with compound B140 (500 mg), 910 mg of compound B141 was obtained as a yellow powder.

[0195] Procedure for the synthesis of B142 Following the same procedure as for B104 with compound B141 (910 mg), 560 mg of compound B142 was obtained as a pale yellow powder.

[0196] Procedure for the synthesis of B143 Following the same procedure as for B28 with compound B142 (100 mg), 100 mg of compound B143 was obtained as a pale yellow powder.

[0197] Scheme 43: Synthetic route for B147 [ka] Procedure for the synthesis of B146 To a solution of compound B144 (792.88 mg, 3.06 mmol) and compound B145 (500 mg, 3.06 mmol) in dioxane (10 mL) and HO (2 mL) was added Pd(dppf)Cl (111.95 mg, 153.00 mmol) and CsCO (1.99 g, 6.12 mmol) under N. The resulting mixture was heated at 100 °C and stirred for 3 h, resulting in a gray suspension. LCMS indicated that the reaction was not complete. The reaction mixture was then stirred at 100 °C for 18 h, at which point LCMS indicated that the reaction had 32% desired product and 36% material. The mixture was partitioned between EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil, which was purified by column chromatography to give compound B146 (236 mg) as a yellow oil.

[0198] Procedure for the synthesis of B147 Following the same procedure as A30 with compound B146 (236 mg), 200 mg of compound B147 was obtained as a yellow oil.

[0199] Scheme 44: Synthetic route to compound 209 via Route I [ka] Procedure for the synthesis of C2 To a mixture of diisopropylamine (6.69 g, 66.2 mmol) in anhydrous THF (20 mL), n-BuLi (2.5 M, 27.7 mL) was added at 0° C. and stirred at 0° C. for 0.5 h. The mixture was then cooled to −70° C., and C1 (5.00 g, 60.2 mmol) in THF (20 mL) was added to the mixture at −70° C. and stirred at −70° C. for 0.5 h. The mixture was then poured into a mixture of ethyl formate (4.90 g, 66.2 mmol) in THF (20 mL) at −70° C. under a N atmosphere at −70° C. The resulting mixture was stirred at −70° C. for 0.5 h, then warmed to 15° C., and stirred at 15° C. for 17 h. TLC (silica gel, PE / EtOAc = 2 / 1) showed the reaction was complete. The reaction mixture was poured into aqueous HCl (150 mL, 1 M) at 0° C. and stirred at 0° C. for 0.5 hours, and then the mixture was extracted with EtOAc (150 mL×3). The organic layer was washed with brine (250 ml), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give compound G2 (5.0 g) as a yellow oil. The crude product was used directly in the next step without further purification.

[0200] Procedure for the synthesis of C3 To a solution of compound C2 (8.82 g, 67.5 mmol) and AcOH (7.09 g, 118 mmol) in EtOH (5 mL), NH2-NH2·H2O (4.39 g, 87.7 mmol) was added, and the resulting mixture was stirred at 78 °C for 17 h to give a pale yellow solution. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to give a residue. The pH of the residue was then adjusted to 9 with aqueous NaOH (1 M), diluted with water (50 mL), and extracted with EtOAc (100 mL × 3). The organic layer was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound C3 (10.0 g, crude) as a yellow gum. The crude product was used directly in the next step without further purification.

[0201] Procedure for the synthesis of C4 To a mixture of compound C3 (5.00 g, 40.0 mmol) in anhydrous DCM (25 mL) was added a mixture of ethoxycarbonyl isothiocyanate (4.72 g, 36.0 mmol) in anhydrous DCM (25 mL) at -70 °C, and the mixture was stirred at -70 °C for 1 h, resulting in the appearance of a large amount of white solid. TLC showed that the reaction was complete. The mixture was then warmed to -10 °C and filtered, and the filter cake was washed with DCM (15 mL) to give 4.50 g of the desired compound as a white solid, the structure of which was confirmed by HNMR. The filtrate was purified using a silica gel column to give compound C4 (1.80 g) as a white solid.

[0202] Procedure for the synthesis of C5 To a mixture of compound C4 (6.30 g, 24.6 mmol) in MeCN (50 mL) was added KCO (6.79 g, 49.2 mmol), and the mixture was stirred at 80 °C for 8 hours. Crude LCMS showed that the reaction was complete. The mixture was cooled to room temperature, and then AcOH (15 mL) was added to the mixture and stirred at 15 °C for 20 minutes. The resulting mixture was then concentrated under reduced pressure to give a residue, which was washed with water (50 mL × 3) to give compound C5 (4.20 g) as a white solid.

[0203] Procedure for the synthesis of C6 To a mixture of compound C5 (4.20 g, 20.0 mmol) in EtOH (40 mL) was added NaOH (2.00 g, 50.0 mmol) in HO (20 mL) at 15 °C, and then MeI (2.84 g, 20.0 mmol) was added to the mixture, and the resulting mixture was stirred at 15 °C for 2 hours. Crude LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a residue, which was treated with ice water (50 mL) and aqueous HCl (20 mL, 6 M) for 30 minutes, whereby a large amount of white solid appeared, which was filtered to give the crude product. The crude product was poured into MeCN (50 mL) to give a suspension, which was then concentrated under reduced pressure to give compound C6 (3.60 g) as a white solid.

[0204] Procedure for the synthesis of C7 To a solution of compound C6 (500 mg, 2.23 mmol) in POCl3 (5 mL) was added N,N-diethylaniline (998 mg, 6.69 mmol) dropwise. The reaction mixture was stirred at 90 °C for 2 hours. The reaction solution was concentrated under reduced pressure to give crude compound C7 (710 mg) as a dark oil, which was used directly in the next step without further purification.

[0205] Procedure for the synthesis of C8 To a mixture of compound B42 (700 mg, 2.99 mmol) in CHCN (20 mL) was added DIEA (772 mg, 5.98 mmol) and compound C7 (652 mg, 2.69 mmol), and the mixture was stirred at 15° C. for 2 hours to give a yellow mixture. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash® to give compound C8 (650 mg) as a yellow gum.

[0206] Procedure for the synthesis of C9 To a mixture of compound C8 (650 mg, 1.48 mmol) in DCM (10 mL) was added m-CPBA (659 mg, 3.25 mmol) in portions at 15° C. The reaction mixture was stirred under a N atmosphere at 15° C. for 2 hours to give a yellow mixture. LCMS showed the reaction was complete. The reaction mixture was filtered, and the filtrates were combined and concentrated under reduced pressure to give the crude product. The crude product was purified by Combi flash® to give compound C9 (350 mg) as a yellow gum.

[0207] Procedure for the synthesis of C11 A mixture of compound C9 (350 mg, 0.740 mmol) and compound C10 (317 mg, 1.48 mmol) in NMP (10 mL) was stirred at 140° C. for 16 hours to give a brown mixture. LCMS showed the reaction was complete. The reaction was quenched with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (100 mL×2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by Combi flash® to give compound C11 (220 mg) as a yellow gum.

[0208] Procedure for the synthesis of compound 209 A solution of compound C11 (220 mg, 0.362 mmol) in HCl / MeOH (3 mL, 4 M) was stirred at 15 °C for 16 hours to give a yellow solution. LCMS showed the reaction was complete. The solution was concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC (0.1% TFA), and the fraction was basified with saturated NaHCO to pH = 8, extracted with DCM (20 mL x 2), and the separated organic layer was washed with brine (20 mL x 2), dried over anhydrous NaSO, filtered, and lyophilized to give compound 209 (62 mg) as a white powder.

[0209] Scheme 45: Synthetic route for compound 245 via Route I [ka] Procedure for the synthesis of C12 Following the same procedure as for C11 with compound C9 (1.46 g) and compound A30 (680 mg), 110 mg of compound C12 was obtained as a yellow solid.

[0210] Procedure for the synthesis of compound 245 To a mixture of compound C12 (110 mg, 0.179 mmol) in EtOH (5 mL) was added NH 4·HO (12.7 mg, 12.3 uL, 85% purity) was added. The mixture was stirred at 25 °C for 2 hours to give a colorless mixture. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove EtOH, and the residue was diluted with HO and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude product, which was purified by preparative TLC to give compound 245 (17.6 mg) as a white powder.

[0211] Scheme 46: Synthetic route for compound 48 via Route II [ka] Procedure for the synthesis of C13 To a mixture of compound C6 (5.00 g, 22.3 mmol) in DCM (100 mL) was added m-CPBA (10.1 g, 46.8 mmol) in portions at 25 °C. The mixture was stirred under a N2 atmosphere at 25 °C for 2 hours. A large amount of white solid appeared. TLC showed that the reaction was complete. The reaction mixture was filtered. Most of the DCM was removed under reduced pressure, and then the mixture was filtered. The filter cake was washed with cold DCM (15 mL × 2). This process was repeated twice. The filtrate was dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give compound C13 (5.7 g) as a white powder. The crude product was used directly for the next step without further purification.

[0212] Procedure for the synthesis of C15 To a solution of compound C13 (6.62 g, 25.83 mmol) in NMP (100 mL) was added compound C14 (18.15 g, 77.5 mmol). The reaction mixture was stirred at 140° C. for 16 hours. TLC showed the reaction was complete. The reaction mixture was partitioned between brine (500 mL) and EtOAc (400 mL). The organic layer was washed with water (100 mL×2), brine (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash® to give a brown gum, which was triturated with CHCN (50 mL) to give compound C15 (2.06 g) as an off-white powder.

[0213] Procedure for the synthesis of C16 To a mixture of compound C15 (89 mg, 0.22 mmol) in POCl (4.41 g, 28.7 mmol) was added N,N-diethylaniline (97 mg, 0.65 mmol) at 20 °C. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give compound C16 (93 mg) as a crude product as a brown gum. The crude product was used directly in the next step without further purification.

[0214] Procedure for the synthesis of C17 To a mixture of compound C16 (100 mg, 0.233 mmol) and DIPEA (60.3 mg, 0.466 mmol) in MeCN (3 mL) was added compound B42 (109 mg, 0.466 mmol). The mixture was stirred at 15° C. for 2 hours. TLC showed that the reaction was complete. The mixture was filtered. The filter cake was washed with MeCN (1 mL×2) and PE (1 mL×2) to give compound C17 (100 mg) as a yellow powder.

[0215] Procedure for the synthesis of compound 48 A mixture of compound C17 (90 mg, 0.143 mmol) in HBr / HOAc (2.5 mL, purity 35%) was stirred at 15° C. for 20 minutes. TLC showed a new spot. The mixture was concentrated under reduced pressure to give a residue. Saturated NaHCO solution was added to the residue to pH=8. The mixture was extracted with DCM (30 mL×2). The combined extracts were washed with water (40 mL×2), dried over anhydrous NaSO, then filtered and concentrated under reduced pressure to give a residue (as a yellow gum). The residue was purified by preparative HPLC, and the remaining solvent was removed by lyophilization to give compound 48 (24.3 mg) as a white powder.

[0216] Scheme 47: Synthetic route for compound 73 via Route III [ka] Procedure for the synthesis of C18 To a solution of compound E2 (300 mg, 1.30 mmol) in CHCN (20 mL) was added compound B42 (305 mg, 1.30 mmol) and KCO (180 mg, 1.30 mmol). The resulting mixture was heated at 80 °C and stirred for 3 h, resulting in a yellow suspension. TLC showed the reaction was complete. The reaction mixture was quenched by the addition of HO (50 mL) and 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 crude product was purified by silica column, and the fractions were concentrated to give compound C18 (420 mg) as a yellow solid.

[0217] Procedure for the synthesis of C20 To a solution of compound C18 (200 mg, 0.467 mmol) in NMP (20 mL) was added compound C19 (468 mg, 2.34 mmol). The resulting mixture was heated at 140 °C and stirred for 12 hours to give a yellow solution. TLC showed that most of compound 5 was consumed and one major spot was formed. The reaction mixture was quenched by the addition of HO (100 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica column to give compound C20 (168 mg) as an off-white solid.

[0218] Procedure for the synthesis of compound 73 To a solution of compound C20 (168 mg, 0.284 mmolq) in DCM (14 mL) was added TFA (6 mL). The resulting mixture was stirred at 20 °C for 1.5 hours to give a yellow solution. LCMS and HPLC showed the reaction was complete. The reaction mixture was concentrated to remove most of the TFA, then basified with saturated aqueous NaHCO to pH 9 and extracted with EtOAc (50 mL × 5). The combined organic layers were washed with brine (5 mL × 5), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by trituration with MTBE (20 mL) and filtered under reduced pressure to give compound 73 (122.3 mg) as an off-white solid.

[0219] Unusual synthetic route Scheme 48: Synthetic route for compound 178 [ka] Procedure for the synthesis of D2 To a mixture of (2-bromophenyl)methanamine (5.14 g, 27.7 mmol) in CHCN (50 mL) was added compound D1 (4.00 g, 25.1 mmol). The mixture was stirred at 85° C. for 12 hours to give a yellow mixture. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a yellow residue, which was purified by Combi flash® to give compound D2 (3.2 g) as a yellow powder.

[0220] Procedure for the synthesis of D3 To a solution of compound D2 (1 g, 3.23 mmol) in DMA (8 mL) was added Pd2(dba)3 (296 mg, 0.323 mmol), DPPF (359 mg, 0.647 mmol), Zn(CN)2 (228 mg, 1.94 mmol), and Zn (21.2 mg, 0.323 mmol). The reaction was stirred at 150 °C under microwave conditions under a N2 atmosphere for 0.5 h to give a red-brown suspension. TLC showed the reaction was complete. The mixture was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined extracts were washed with brine (30 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a brown oil, which was purified by Combi flash® to give compound D3 (530 mg) as a yellow gum.

[0221] Procedure for the synthesis of D4 To a mixture of Raney-Ni (100 mg in water) in MeOH (30 mL) was added compound D3 (500 mg, 1.96 mmol) and NH3·H2O (2 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (15 psi) at 15 °C for 2 h to give a black suspension. TLC showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound D4 (500 mg) as a yellow powder.

[0222] Procedure for the synthesis of D5 To a mixture of compound D4 (500 mg, 1.93 mmol) in MeCN (5 mL) was added DIEA (1 mL) and compound C16 (827 mg, 1.93 mmol). The mixture was stirred at 15° C. for 12 hours to give a yellow mixture. TLC showed the reaction was complete. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous material was extracted with EtOAc (50 mL×2). The combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by Combi flash® to give compound D5 (830 mg) as a yellow powder.

[0223] Procedure for the synthesis of D6 To a mixture of tetrahydro-2H-pyran-4-amine (111 mg, 1.10 mmol) in DCM (2 mL) was added Al(CH) (2 M, 405 μL) at −60° C. under a N atmosphere. The mixture was stirred at 20° C. for 1 hour. Then, a solution of compound D5 (100 mg, 0.162 mmol) in dry DCM (1 mL) was added dropwise. The mixture was stirred at 20° C. for 12 hours to give a yellow suspension. LCMS showed the reaction was complete. The reaction mixture was filtered through Celite and concentrated under reduced pressure to give a yellow residue, which was purified by preparative TLC to give compound D6 (53 mg) as a yellow gum.

[0224] Procedure for the synthesis of compound 178 A mixture of compound D6 (53.0 mg, 0.0750 mmol) in HBr / HOAc (1 mL, 35% HBr in HOAc) was stirred at 0-10 °C for 0.5 h to give a yellow mixture. TLC (PE / EA = 1 / 1) showed the reaction was complete. MTBE (10 mL) was added to the reaction mixture, causing the precipitation of a red powder. The red material was collected by filtration and washed with MTBE (5 mL × 2). The red solid was purified by cation exchange resin eluted with 5% NH₃·H₂O and then lyophilized to give a white powder, which was purified by preparative TLC and lyophilized to give compound 178 (20.5 mg) as a white powder.

[0225] Scheme 49: Synthetic route for compound 24 [ka] Procedure for the synthesis of D8 A mixture of compound D7 (50.0 g, 430 mmol) in SOCl2 (328 g, 2.76 mol) was stirred at 78 °C for 2 h to give a pale yellow solution. The solution was concentrated under reduced pressure to give the acyl chloride (65.0 g, crude) as a pale yellow oil. The crude product was used directly in the next step. To a solution of NH3·HO (109 g, 22%) in DCM (300 mL) was added the acyl chloride (65.0 g, crude) dropwise. The reaction mixture was stirred at 15 °C for 0.5 h. The mixture was extracted with DCM (150 mL × 3), and the combined organic layers were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound D8 (20.5 g) as a white powder.

[0226] Procedure for the synthesis of D9 To a solution of compound D8 (10.0 g, 86.8 mmol) in DCM (150 mL), TEA (43.9 g, 434 mmol) and TFAA (45.6 g, 217 mmol) were added dropwise sequentially under a N atmosphere. The reaction mixture was stirred at 15 °C for 16 h. The reaction was quenched with saturated NH Cl (200 mL) and then extracted with DCM (100 mL × 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give compound D9 (16.2 g, crude) as a yellow oil.

[0227] Procedure for the synthesis of D10 To a solution of n-BuLi (2.5 M, 56.8 mL) in anhydrous THF (200 mL) was added N-isopropylpropan-2-amine (13.7 g, 135 mmol) dropwise at −70° C. under a N atmosphere. The mixture was stirred at 15° C. under a N atmosphere for 1 hour. Compound D9 (12.0 g, 123 mmol) in anhydrous THF (20 mL) was then added to the mixture at −70° C. under a N atmosphere, and the resulting mixture was stirred at −70° C. under a N atmosphere for 2 hours. HC0Et (12.8 g, 173 mmol) in anhydrous THF (20 mL) was added dropwise at −70° C. under a N atmosphere, and the reaction mixture was stirred at 15° C. for 16 hours. TLC showed a new spot. The reaction was quenched with aqueous HCl (10%), adjusted to pH=3-4, extracted with EtOAc (120 mL×2), and the combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give compound D10 (13.0 g, crude) as a brown oil. The crude product was used in the next step without any purification.

[0228] Procedure for the synthesis of D11 To a solution of compound D10 (900 mg, 7.19 mmol) in EtOH (15 mL), NH2NH2·HO (478 mg, 9.35 mmol) and AcOH (734 mg, 12.2 mmol) were added dropwise, successively. The solution was stirred at 78 °C for 16 h. TLC showed a new spot. The solution was concentrated under reduced pressure to give a yellow oil. EtOAc (20 mL) and HO (50 mL) were added to the residue, and the aqueous phase was neutralized with 1 M NaOH, adjusted to pH 9, and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound D11 (550 mg, crude) as a yellow oil, which was used in the next step without any purification.

[0229] Procedure for the synthesis of D12 To a solution of compound D11 (550 mg, 3.95 mmol) in DCM (10 mL) at −78° C., EtOC-NCS (518 mg, 3.95 mmol) was added dropwise under a N atmosphere. The reaction solution was stirred at −78° C. for 10 minutes. TLC showed that the starting material was consumed and several new spots had formed. The reaction solution was concentrated under reduced pressure to give a crude yellow oil, which was purified by CombiFlash® to give the intermediate (230 mg) as a yellow solid. To a solution of the intermediate (230 mg, 0.850 mmol) in MeCN (4 mL), KCO (235 mg, 1.70 mmol) was added in one portion. The suspension was stirred at 80° C. for 1 hour. LCMS showed the reaction was complete. The suspension was neutralized with AcOH, adjusted to pH 4, and concentrated under reduced pressure to give a yellow oil. DCM (20 mL) was added to dissolve the product and washed with HO (2 x 20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound D12 (300 mg) as a yellow solid.

[0230] Procedure for the synthesis of D13 To a solution of compound D12 (300 mg, 1.34 mmol) in EtOH (7 mL) and NaOH (2 M, 1.34 mL), MeI (190 mg, 1.34 mmol) was added dropwise. The mixture was stirred at 15 °C for 0.5 h. LCMS showed the reaction was complete. The mixture was concentrated in vacuo to give a residue, DCM (15 mL) was added, and 6 M HCl (2 mL) was added, and the resulting mixture was stirred for 10 min. The mixture was extracted with DCM (20 mL × 2), and the combined organic layers were washed with water (20 mL × 2) and brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give compound D13 (160 mg) as a yellow solid, which was used in the next step without any purification.

[0231] Procedure for the synthesis of D14 To a solution of compound D13 (500 mg, 2.10 mmol) in N,N-diethylaniline (1.57 g, 10.5 mmol) was added POCl (16.5 g, 107 mmol), and the reaction mixture was stirred at 90 °C for 2 h to give a brown solution. The mixture was concentrated under reduced pressure to remove POCl. The product was used for further purification.

[0232] Procedure for the synthesis of D16 To a solution of compound D14 (500 mg, 1.95 mmol) in MeCN (2.00 mL) was added DIEA (1.26 g, 9.75 mmol), and then compound D15 (675 mg, 3.90 mmol) was added to the above mixture, and the resulting mixture was stirred at 20 ° C. for 2 hours. LCMS showed the desired MS value. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3), and the combined extracts were washed with brine (100 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by Combi flash® to obtain compound D16 (524 mg) as a white powder.

[0233] Procedure for the synthesis of D17 To a solution of compound D16 (524 mg, 1.33 mmol) in CHCl (5.00 mL) was added m-CPBA (573 mg, 2.66 mmol), and the mixture was stirred at 20 °C for 1 h. LCMS indicated that compound D16 was consumed and the desired MS was obtained. The reaction was quenched with saturated aqueous NaSO (20 mL), and the mixture was extracted with DCM (30 mL × 3). The combined extracts were washed with saturated aqueous NaHCO (30 mL) and water (30 mL × 2). The organic phase was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give compound D17 (450 mg) as a yellow oil.

[0234] Procedure for the synthesis of D18 To a mixture of compound D17 (450 mg, 1.06 mmol) in NMP (5.00 mL) was added compound D5 (423 mg, 2.12 mmol) in one portion at 120° C. under N2. The mixture was stirred at 120° C. for 3 h to give a yellow solution. TLC showed that compound D17 was consumed and a new spot was formed. The mixture was poured into water (10 mL) to give a large amount of white solid. The mixture was filtered, and the filter cake was washed with water (10 mL) and dried under high vacuum to give compound D18 (390 mg) as a white powder.

[0235] Procedure for the synthesis of compound 24 To a mixture of compound D18 (390 mg, 0.714 mmol) in CHCl (10.0 mL), TFA (4.84 g, 42.4 mmol) was added in one portion. The mixture was stirred at 25 °C for 2 h to give a yellow solution. LCMS showed the reaction was complete. The reaction solution was adjusted to pH 7-8 by adding saturated aqueous NaHCO, extracted with DCM (10 mL × 2), and the combined organic phase was concentrated under reduced pressure to give a brown oil. The crude product was purified by preparative HPLC (0.01% TFA). Most of the MeCN was removed under reduced pressure. The remaining solvent was removed by lyophilization to give compound 24 (161.1 mg) as a white powder.

[0236] Scheme 50: Synthetic route for compound 18 [ka] Procedure for the synthesis of D20 To a mixture of compound D19 (5.00 g, 30.9 mmol) in anhydrous DMF (30 mL), a mixture of ethyl ethoxycarbonyl isothiocyanate (3.64 g, 27.8 mmol) was added at 0 °C and stirred at 0 °C for 1 hour, after which a large amount of white solid appeared. Crude LCMS showed that the reaction was complete. The mixture was then poured into water (200 mL), after which a large amount of white solid appeared, and the mixture was filtered to obtain the crude product. The crude product was washed with EtOH (30 mL) to obtain compound D20 (4.50 g) as a white powder.

[0237] Procedure for the synthesis of D21 To anhydrous EtOH (40 mL) was added Na (686 mg, 30.0 mmol), and the mixture was stirred at 20° C. for 0.5 hours. Then, compound D20 (3.50 g, 11.9 mmol) was added to the above mixture, and the resulting mixture was stirred at 80° C. for 3 hours. Crude LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a residue, and then the pH value of the residue was adjusted to 5 with aqueous HCl (1 M) to give a suspension. The mixture was then filtered to give compound D21 (2.10 g) as a white powder.

[0238] Procedure for the synthesis of D22 To a mixture of compound D21 (900 mg, 3.64 mmol) in EtOH (20 mL) was added NaOH (364 mg, 9.11 mmol) in HO (10 mL), and then MeI (517 mg, 3.64 mmol) was added to the mixture, and the resulting mixture was stirred at 20 °C for 17 h. The two batches of reaction were combined, and crude LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The pH value of the residue was adjusted to 5 with aqueous HCl (1 M), and a large amount of white solid appeared, which was filtered to give compound D22 (1.80 g) as a white powder.

[0239] Procedure for the synthesis of D23 To a mixture of compound D22 (800 mg, 3.06 mmol) in POCl (6 mL) was added N,N-diethylaniline (2.74 g, 18.4 mmol) and the mixture was stirred at 90° C. for 2 hours. The mixture was concentrated under reduced pressure to give 4.20 g (crude) of compound D23 as a yellow gum.

[0240] Procedure for the synthesis of D24 To a solution of compound D23 (4.20 g, crude) and DIPEA (11.7 g, 90.1 mmol) in MeCN (10 mL) was added compound D15 (1.20 g, 6.91 mmol), and the mixture was stirred at 20° C. for 17 hours. Crude LCMS showed insufficient reaction, so DIPEA (11.7 g, 90.1 mmol) was added to the above mixture, and the mixture was stirred at 20° C. for 17 hours. Crude LCMS showed the reaction was complete. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Combi flash® to give 300 mg of compound D24 as a yellow gum.

[0241] Procedure for the synthesis of D25 To a solution of compound D24 (300 mg, 0.721 mmol) in DCM (10 mL) was added m-CPBA (326 mg, 1.51 mmol, 80% purity), and the mixture was stirred at 20 °C for 1 h. A large amount of white solid appeared. Crude LCMS showed the reaction was complete. The reaction was quenched with saturated aqueous NaSO (3 mL), and then the mixture was poured into DCM (100 mL) and washed with saturated aqueous NaHCO (100 mL × 3) and brine (100 mL × 2). The organic phase was dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 250 mg of compound D25 as a white powder.

[0242] Procedure for the synthesis of D26 To a solution of compound D25 (250 mg, 0.558 mmol) in NMP (3 mL) was added compound D5 (223 mg, 1.12 mmol), and the mixture was stirred at 120 °C under a N atmosphere for 1 h. Crude LCMS showed the reaction was complete. After cooling to room temperature, the mixture was poured into water (30 mL) and a large amount of white solid appeared. The mixture was filtered, and the filter cake was washed with water (50 mL) to give 153 mg of compound D26 as a yellow powder.

[0243] Procedure for the synthesis of compound 18 To a solution of compound D26 (150 mg, 0.264 mmol) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol), and the mixture was stirred at 20 °C for 20 min. Crude LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The pH of the residue was adjusted to 8 with saturated aqueous NaHCO3 and diluted with water (20 mL). The mixture was extracted with DCM (30 mL × 3). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (0.05%, HCl salt). Most of the CH3CN was removed by evaporation under reduced pressure, and the remaining solvent was removed by lyophilization to give 78.6 mg of compound 18 as a white powder.

[0244] Scheme 51: Synthetic route for compound 35 [ka] Procedure for the synthesis of D28 To a mixture of compound D26 (500 mg, 0.879 mmol) in dioxane (5 mL) was added compound D27 (952 mg, 2.64 mmol) and Pd(PPh3)4 (101 mg, 0.0879 mmol) in one portion at 120 °C under a N2 atmosphere. The mixture was stirred at 120 °C for 16 hours to give a yellow solution. LCMS showed 10.4% of the desired MS. The mixture was poured into aqueous NH4Cl (50 mL) and stirred for 10 minutes. The mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous material was extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by Combi Flash® to give compound D28 (91.6 mg) as a white powder.

[0245] Procedure for the synthesis of compound 35 To a mixture of compound D28 (110 mg, 0.206 mmol) in CHCl (2 mL), TFA (1.40 g, 12.3 mmol) was added in one portion. The mixture was stirred at 25 °C for 1 h to give a yellow solution. LCMS showed the reaction was complete, with 52.8% of the desired MS. The reaction solution was adjusted to pH 7-8 by adding saturated aqueous NaHCO and extracted with DCM (10 mL × 2). The combined organic phase was concentrated under reduced pressure to give a brown oil, which was purified by preparative HPLC (0.01% TFA). Most of the MeCN was removed under reduced pressure. The remaining solvent was removed by lyophilization to give compound 35 (10.40 mg) as a white powder.

[0246] Scheme 52: Synthetic route for compound 30 [ka] Procedure for the synthesis of D29 To a mixture of compound D26 (50 mg, 0.088 mmol), 1-pentenylboronic acid (50 mg, 0.44 mmol), Na2CO3 (19 mg, 0.18 mmol) in HO (0.5 mL) and dioxane (2 mL) was added Pd(dppf)Cl2 (13 mg, 0.018 mmol), the mixture was purged with N2 once, and then the mixture was stirred under a N2 atmosphere at 110 °C in a microwave for 1 h. Crude LCMS showed the desired MS values. The mixture was poured into water (30 mL) and extracted with DCM (30 mL × 3). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give 150 mg of compound D29 as a yellow gum.

[0247] Procedure for the synthesis of D30 To a solution of compound D29 (120 mg, 0.215 mmol) in MeOH (10 mL) was added Pd / C (20 mg), and the mixture was purged with H three times and stirred at 20 °C under a H balloon (15 psi) for 3 h. Crude LCMS showed the reaction was complete. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 100 mg of compound D30 as a yellow gum.

[0248] Procedure for the synthesis of compound 30 To a solution of compound D30 (100 mg, 0.179 mmol) in DCM (3 mL) was added TFA (2 mL), and the mixture was stirred at 20 °C for 1 h. Crude LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a residue, and the pH value of the residue was adjusted to 8 with saturated aqueous NaHCO3, extracted with DCM (30 mL × 3), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (0.05% HCl). Most of the CH3CN was removed by evaporation under reduced pressure, and the remaining solvent was removed by lyophilization to give 10.5 mg of compound 30 as a white powder.

[0249] Scheme 53: General synthetic route for compound 163 [ka] Procedure for the synthesis of D33 To a solution of compound D31 (1.00 g, 2.43 mmol) in anhydrous THF (10 mL) was added compound D32 (1.28 g, 6.08 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 hours. Crude LCMS showed the reaction was complete. The reaction was quenched with brine (100 mL), and the mixture was extracted with EtOAc (100 mL × 2). The combined extracts were washed with brine (100 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by combi flash® to give 600 mg of compound D33 as a yellow gum.

[0250] Procedure for the synthesis of D34 To a solution of compound D33 (550 mg, 1.25 mmol) in DCM (3 mL) was added BBr3 (627 mg, 2.50 mmol) at 0 °C, and the mixture was then warmed to 20 °C and stirred at 20 °C for 3 hours. Crude LCMS showed a sufficient reaction. The reaction was quenched with saturated aqueous NH4Cl (30 mL), the pH value of the mixture was adjusted to 8 with saturated aqueous NaHCO3, extracted with EtOAc (50 mL × 3), the combined extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 600 mg of crude product, which was confirmed by HNMR. 100 mg was used in the next step but did not react. The crude product was then purified by Combi flash® to give 360 ​​mg of compound D34 as a yellow gum.

[0251] Procedure for the synthesis of D36 To a mixture of compound D34 (310 mg, 0.729 mmol), compound D35 (409 mg, 2.19 mmol), and PPh3 (382 mg, 1.46 mmol) in anhydrous THF (2 mL) was added DEAD (254 mg, 1.46 mmol) at 0 °C, and the mixture was then warmed to 20 °C and stirred at 20 °C for 17 hours. Crude LCMS showed a complete reaction. The reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give 150 mg of compound D36 as a yellow gum.

[0252] Procedure for the synthesis of compound 163 To a solution of compound D36 (150 mg, 0.252 mmol) in DCM (3 mL) was added TFA (3 mL), and the mixture was stirred at 20 °C for 0.5 h. Crude LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The pH value of the mixture was then adjusted to pH = 8 with saturated aqueous NaHCO3, then diluted with water (15 mL), extracted with DCM (30 mL x 3), the combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (0.05% HCl). Most of the CH3CN was removed by evaporation under reduced pressure, and the remaining solvent was removed by lyophilization to give 27.8 mg of compound 163 as a yellow gum.

[0253] Scheme 54: Synthetic route for compound 23 [ka] Procedure for the synthesis of D37 To a solution of compound D31 (1.00 g, 2.43 mmol) in dioxane (10 mL), NaOH (800 mg, 20.0 mmol) and HO (10 mL) were added, and the mixture was stirred at 50 °C for 16 hours to give a yellow solution. TLC showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove dioxane, and then 6 M HCl was added dropwise to the reaction mixture until pH = 5. The mixture was extracted with DCM (20 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound D37 (952 mg) as a yellow solid.

[0254] Procedure for the synthesis of D38 To a solution of compound D37 (952 mg, 2.72 mmol) in POCl (10 mL) was added N,N-diethylaniline (1.2 g, 8.16 mmol), and the reaction mixture was stirred at 90 °C for 2 hours to give a brown solution. LCMS showed that the reaction was complete. The mixture was concentrated under reduced pressure to remove POCl, and the residue was then partitioned between DCM (20 mL) and saturated NaHCO (20 mL). The aqueous phase was extracted with DCM (20 mL × 2), and the combined organic phase was washed with brine (40 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a brown oil. The crude product was purified by Combi Flash to give compound D38 (828 mg) as a yellow oil.

[0255] Procedure for the synthesis of D40 To a solution of compound D38 (200 mg, 0.544 mmol) and compound D39 (202 mg, 0.652 mmol) in dioxane (4 mL) was added KCO (188 mg, 1.36 mmol) and Pd(dppf)Cl (20 mg, 0.272 mmol) in HO (1 mL), and the mixture was stirred under a N balloon at 90 °C for 16 hours to give a black solution. LCMS showed a desired MS value of 43.8%. HO (10 mL) was added to the solution, extracted with EtOAc (10 mL × 2), and the combined organic phase was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a brown oil, which was purified by Combi Flash® to give compound D40 (119 mg) as a yellow oil.

[0256] Procedure for the synthesis of D41 To a suspension of compound D40 (181 mg, 0.352 mmol) in MeOH (5 mL) was added Pd / C (50% wet, 10% Pd), and the mixture was stirred under a H balloon (15 psi) at 25 °C for 16 h to give a black suspension. LCMS showed the reaction was complete. The suspension was filtered through a pad of Celite, and the combined filtrate was concentrated under reduced pressure to give compound D41 (121 mg) as a yellow oil.

[0257] Procedure for the synthesis of compound 23 To a solution of compound D41 (121 mg, 0.234 mmol) in DCM (4 mL) was added TFA (1 mL), and the reaction solution was stirred at 25 °C for 2 hours to give a yellow solution. LCMS showed the reaction was complete. Saturated aqueous NaHCO3 (10 mL) was added to the reaction solution, which was then extracted with DCM (10 mL x 2). The combined organic phase was concentrated under reduced pressure to give a brown oil. The crude product was purified by preparative HPLC (0.05% HCl). The eluent containing the desired product was added with saturated NaHCO3 until pH = 7, extracted with DCM (20 mL x 3), and the combined organic phase was concentrated under reduced pressure. The remaining aqueous solution was lyophilized to give compound 23 (3.9 mg) as a white powder.

[0258] Scheme 55: Synthetic route for compound 165 [ka] Procedure for the synthesis of D43 To a solution of compound D38 (120 mg, 0.326 mmol), compound D42 (235 mg, crude, approximately 0.489 mmol), Pd(PPh3)4 (65 mg, 0.056 mmol) in dioxane (3 mL) and HO (750 μL) was added Na2CO3 (86 mg, 0.82 mmol). The reaction mixture was stirred at 110 °C for 1 h under N2 microwave conditions. TLC (PE / EtOAc = 5 / 1, SiO2) showed the reaction was complete. The reaction mixture was diluted with DCM (10 mL) and water (10 mL) and then filtered. The filtrate was separated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as a brown gum, which was purified by Combi flash® to give compound D43 (126 mg) as a colorless oil. The impure product was used directly in the next step without further purification.

[0259] Procedure for the synthesis of compound 165 To a solution of compound D43 (133 mg, crude) in DCM (1.6 mL) was added TFA (400 μL). The reaction solution was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The reaction solution was diluted with DCM (10 mL) and water (5 mL). Aqueous ammonia (0.5 mL, 28%) was added to the mixture until the aqueous layer reached a pH greater than 7. The organic layer was separated, washed with water (10 mL), and then concentrated under reduced pressure to give the crude product as a brown oil, which was purified by preparative HPLC (0.05% HCl as additive). Most of the MeCN was removed under reduced pressure; the remaining solvent was removed by lyophilization to give compound 165 (35.9 mg) as an off-white powder.

[0260] Scheme 56: Synthetic route for compound 171 [ka] Procedure for the synthesis of D45 To compound D38 (200 mg, 0.54 mmol) and KCO (187 mg, 1.36 mmol) in dioxane (1 mL) and HO (0.5 mL) was added compound D44 (176 mg, 0.979 mmol) and Pd(dppf)Cl (39.7 mg, 0.54 mmol). The reaction mixture was stirred at 110 °C under a N atmosphere for 16 hours. LCMS showed a desired MS value of 82.4%. The mixture was partitioned between EtOAc (100 mL) and HO (100 mL). The aqueous material was extracted with EtOAc (100 mL). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give compound D45 as a red powder.

[0261] Procedure for the synthesis of D46 To a solution of compound D45 (100 mg, 0.221 mmol) and compound D5 (53 mg, 0.26 mmol) in anhydrous DMF (1 mL) was added HATU (104 mg, 0.276 mmol) and TEA (37 mg, 0.36 mmol) under N atmosphere. The mixture was stirred at 25 °C under N atmosphere for 16 hours. LCMS showed a desired MS value of 74.3%. The mixture was partitioned between EtOAc (50 mL) and H O (50 mL). The aqueous material was extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Combi flash® to give compound D46 (95.0 mg) as a yellow oil.

[0262] Procedure for the synthesis of compound 171 To a mixture of compound D46 (95 mg, 0.15 mmol) in CHCl (4 mL), TFA (1 mL) was added in one portion. The mixture was stirred at 25 °C for 1 h to give a yellow solution. LCMS showed the reaction was complete, with 98.7% of the desired MS value. The reaction solution was adjusted to pH 7-8 by adding saturated aqueous NaHCO and extracted with DCM (10 mL × 2). The combined organic phase was concentrated under reduced pressure to give a yellow oil, which was purified by preparative HPLC (0.05% HCl). Most of the MeCN was removed under reduced pressure. The remaining solvent was removed by lyophilization to give compound 171 (41.8 mg) as a yellow powder.

[0263] References

number

number

[0264] [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

[0265] Table 2

[0266] Table 3-1 Table 3-2

[0267] Table 4

[0268] Table 5-1 Table 5-2

[0269] Table 6

[0270] Table 7

[0271] Table 8

[0272] Table 9

[0273] Table 10

[0274] Table 11-1 Table 11-2 Table 11-3 Table 11-4 Table 11-5 Table 11-6 Table 11-7 Table 11-8 Table 11-9 Table 11-10 Table 11-11 Table 11-12 Table 11-13 Table 11-14 Table 11-15 Table 11-16 Table 11-17 Table 11-18 Table 11-19 Table 11-20 Table 11-21 Table 11-22 Table 11-23 Table 11-24 Table 11-25 Table 11-26 Table 11-27 Table 11-28 Table 11-29 Table 11-30 Table 11-31 Table 11-32 Table 11-33 Table 11-34 Table 11-35 Table 11-36 Table 11-37 Table 11-38 Table 11-39 Table 11-40 Table 11-41 Table 11-42 Table 11-43 Table 11-44 Table 11-45 Table 11-46

Claims

1. General formula I 【Chemistry 79】 or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or a pharmaceutically acceptable salt thereof, wherein X is independently selected at each occurrence from CH and N; L １ is absent or independently, at each occurrence, —NH—, —NH(CH ２ )-, -NH(C=O)-, -NHSO ２ -, -O-, -O(CH ２ )—, —(C═O)—, —(C═O)NH—, and —(C═O)(CH ２ )-selected from the group consisting of; Q, in each occurrence, is independently selected from the group consisting of C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl, where C1-C6 alkyl is selected from the group consisting of -OR ５ , -N(R ５ ) R ５ , aryl, heteroaryl, and heterocyclyl; C3-C8 cycloalkyl is R ３ and R ４ and —(C═O)R ５ may be substituted with one or two of Heterocyclyl is R ３ and R ４ and —(C═O)R ５ may be substituted with one or two of Aryl or heteroaryl is C1-C6 alkyl, -OR ５ , -N(R ５ ) R ５ , -(C=O)R ５ , halogen, heteroaryl, and heterocyclyl; R １ is, at each occurrence, independently selected from the group consisting of hydrogen and methyl; R ２ is C1-C6 alkyl; R ３ is independently, at each occurrence, hydrogen, -OR ５ , halogen, —N(R ５ ) R ５ , -NR ９ R １２ , -NH(C=O)R ５ , -(C=O)NH ２ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with; R ４ is independently, at each occurrence, hydrogen, halogen, -OR ５ , -N(R ５ ) R ５ , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with; R ５ is, at each occurrence, hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl; halogen, —OR １１ , -N(R １１ ) R １１ , C1-C6 alkyl, and —OH or —NH ２ heteroaryl substituted with one or two of C1-C6 alkyl substituted with -OR; halogen, -OR １１ , -N(R １１ ) R １１ , C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with Z is 【Chemistry 80】 and R ６ is, in each existence, 【Chemistry 81】 are independently selected from R ７ is hydrogen; R ８ is hydrogen; R ９ is hydrogen; R １０ is, at each occurrence, independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; R １１ is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C3-C10 cycloalkyl; R １２ is absent or independently, at each occurrence, C1-C6 alkyl, —OR ５ or -N(R ５ ) R ５ C1-C6 alkyl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C9 heteroaryl substituted with 1 to 4 halogens or C1-C3 alkyl, C3-C6 heterocyclyl substituted with 1 to 4 halogens and / or 1 to 4 -NH(C=O)R １３ C6-C10 aryl substituted with; R １３ is, at each occurrence, hydrogen, C1-C6 alkyl; —CN, —OH, —OR ５ , -NH ２ , -NHR ５ , or -N(R ５ ) R ５ and C3-C10 cycloalkyl; R １４ and R １５ is, at each occurrence, hydrogen, C1-C6 alkyl substituted with —OH, —(C═O)R ５ , -(C=O)NHR ２１ , C3-C10 heterocyclyl, C6-C10 aryl and —(C═O)NHR ２１ aryl substituted with R ２１ is, at each occurrence, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl, C1-C3 haloalkyl, aryl, phenyl, benzyl; —CN, —OH, —OR ５ , -NH ２ , -NHR ５ , or -N(R ５ ) R ５ C1-C6 alkyl substituted with; aryl substituted with halogen or C1-C3 haloalkyl, C3-C10 heteroaryl substituted with 1-4 halogen or C1-C3 alkyl, and R ４ independently selected from the group consisting of C3-C10 heterocyclyl substituted with However, R ６ but 【Chemistry 101】 If R １４ and R １５ One of the is not H; A compound or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof of said compound.

2. R １ is hydrogen, and the compound has the general formula II 【Chemical 84】 wherein X, Q, L １ , R ２ and Z are as defined in claim 1.

3. General formula III 【Chemical 85】 wherein X, L １ , R １ , R ２ and Z are as defined in claim 1; Q １ is absent or independently at each occurrence aryl, heteroaryl, heterocyclyl; C1-C6 alkyl, -OR ５ , -N(R ５ ) R ５ aryl substituted with one or two of the following: - and halogen; C1-C6 alkyl, -OR ５ , -N(R ５ ) R ５ and heteroaryl substituted with one or two of halogen; and R ２９ and R ３０ heterocyclyl substituted with one or two of: R ２９ is absent or independently at each occurrence hydrogen, -OR ５ , halogen, —N(R ５ ) R ５ , -NR ９ R １２ , -NH(C=O)R ５ , -(C=O)NH ２ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with; R ３０ is independently, at each occurrence, hydrogen, halogen, -OR ５ , -N(R ５ ) R ５ , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with; Here, R ５ , R ９ , and R １２ is as defined in claim 1; L ２ is absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)—, and —(C═O)NH—; Y １ is independently selected at each occurrence from CH, C(OH), and N; Y ２ is independently in each occurrence CH, CR ３０ , O, and N; m is independently selected in each occurrence from 0, 1, and 2; n is independently selected in each occurrence from 0 and 1; 10. The compound of claim 1, or an enantiomer, stereoisomer, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate, or pharmaceutically acceptable salt thereof.

4. General formula IV 【Chemical 86】 wherein X, L １ , and R ２ is as defined in claim 1; Here, m, n, Y １ , Y ２ , L ２ , R ２９ , R ３０ , and Q １ is as defined in claim 3; Here, Z １ teeth, 【Transformation 87】 and In the formula, R ６ , R ７ , R ８ , R ９ , and R １０ The compound according to any one of claims 1 to 3, wherein is as defined in claim 1.

5. General formula VII 【Chemistry 91】 wherein X, L １ , R ２ , and R ６ is as defined in claim 1; m, n, Y １ , Y ２ , L ２ , R ２９ , R ３０ , and Q １ is as defined in claim 3; R ２２ is hydrogen; R ２３ is hydrogen; R ２４ is, at each occurrence, independently selected from the group consisting of hydrogen, halogen, and C1-C6 alkyl; R ２５ is hydrogen, The compound according to any one of claims 1 to 3.

6. General formula VIII 【Chemistry 92】 wherein X, L １ , R ２ , R ６ , and R １０ 3. A compound according to any one of claims 1 and 2, wherein:

7. General formula IX 【Chemistry 93】 wherein X ３ is CR １０ and L １ , R ２ , R ６ , R １０ is as defined in claim 1; R ２２ is hydrogen; R ２３ is hydrogen; R ２５ is hydrogen; Here, Q ２ is the following F group: 【Chemical 94】 any structure of R ３１ and R ３２ is absent or independently at each occurrence hydrogen, -OR ５ , halogen, —N(R ５ ) R ５ , -NR ９ R １２ , -NH(C=O)R ５ , -(C=O)NH ２ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl, and —OH or —NH ２ C1-C6 alkyl substituted with; Here, R ５ , R ９ , and R １２ The compound according to any one of claims 1 to 3, wherein is as defined in claim 1.

8. The table below Table 20-1 Table 20-2 Table 20-3 Table 20-4 Table 20-5 Table 20-6 Table 20-7 Table 20-8 Table 20-9 2. The compound of claim 1 having a structure selected from structures 99, 151, 152, 154-156, 177, 179-181, 192, 193, 195-205, 207, 210, 214, 217, 220, 221, 223, 224, 227-233, 236, 238, 244, 246, 252, 253, 256, 258, 259, 276, and 277 as defined in

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

10. A composition comprising a compound according to any one of claims 1 to 8 for use as a pharmaceutically active agent, wherein the pharmaceutically active agent preferably has inhibitory activity against cyclin-dependent kinase 7 (CDK7).

11. 10. A composition comprising a compound according to any one of claims 1 to 8 for use in a method for preventing and / or treating a disease associated with inhibition of apoptosis, aberrant transcriptional activity, and / or cell cycle arrest due to aberrant activity and / or overexpression of one or more cyclin-dependent kinases (CDKs), in particular cyclin-dependent kinase 7 (CDK7), wherein the disease is selected from proliferative diseases, infectious diseases including opportunistic diseases, immunological diseases, autoimmune diseases, and inflammatory diseases.

12. The proliferative disease is cancer, preferably adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and -independent breast cancer, Burkitt's lymphoma, corpus cancer, carcinoma of unknown primary site (CUP syndrome), colorectal cancer, small intestine cancer, small intestine tumor, ovarian cancer, endometrial cancer, ependymoma, epithelial carcinoma type, Ewing's tumor, gastrointestinal tumor, gastric cancer cancer), gallbladder cancer, gallbladder cancer, uterine cancer, cervical cancer, cervix, glioblastoma, gynecological tumors, ear, nose and throat tumors, hematological tumors, hairy cell leukemia, urethral cancer, skin cancer, skin testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumors, carcinoid, Kaposi's sarcoma, laryngeal cancer, germ cell tumors, bone cancer, colorectal cancer, head and neck tumors (tumors of the ear, nose, and pharyngeal area), colon cancer, craniopharyngioma, oral cancer (cancer in the mouth and above the lips), cancers of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumors, lung cancer, lymphoma, stomach cancer cancer), malignant melanoma, malignant neoplasia, malignant tumors of the gastrointestinal tract, breast cancer, rectal cancer, medulloblastoma, melanoma, meningioma, Hodgkin / non-Hodgkin lymphoma, mycosis fungoides, nasal cancer, schwannoma, neuroblastoma, kidney cancer, renal cell carcinoma, oligodendroglioma, esophageal cancer, osteolytic and osteoplastic carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal cancer, retinoblastoma, vaginal cancer, thyroid cancer, esophageal cancer, T-cell lymphoma, thymoma, ductal carcinoma, eye tumors, urethral cancer, urinary tract tumors, urothelial carcinoma, vulvar cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, nephroblastoma, cervical cancer, tongue Cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung cancer, non-small cell lung cancer, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brainstem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal gland tumor, uterine sarcoma, salivary gland cancer, anal gland adenocarcinoma, mast cell tumor, pelvic tumor, ureteral tumor, hereditary papillary renal carcinoma, sporadic papillary renal carcinoma, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer12. The composition for use of claim 11, wherein the cancer is selected from the group comprising or consisting of: squamous cell carcinoma, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma.

13. The infectious diseases including the opportunistic diseases include AIDS, adenovirus infection, alveolar hydatid disease (AHD), amebiasis, angiostrongyliasis, anisakiasis, anthrax, babesiosis, balantidiosis, Baylis ascaris infection, bilharzia (schistosomiasis), Blastocystis hominis infection, Lyme borreliosis, botulism, Brainerd diarrhea, brucellosis, bovine spongiform encephalopathy (BSE), candidiasis, capillary disease, chronic fatigue syndrome (CFS), Chagas disease, chicken pox, Chlamydia pneumoniae, pneumoniae infection, cholera, chronic fatigue syndrome, Creutzfeldt-Jakob disease (CJD), clonorchiasis, cutaneous larva migrans (CLM), coccidioidomycosis, conjunctivitis, Coxsackievirus A16 (CoxA16), cryptococcosis, cryptosporidiosis, West Nile fever, cyclosporosis, neurocysticercosis, cytomegalovirus infection, dengue fever, Dipylidium caninum infection, Ebola hemorrhagic fever (EHF), alveolar echinococcosis (AE), encephalitis, Entamoeba coli infection, Entamoeba dispar infection, Entamoeba Hartmannii infection, hartmannii infection, Entamoeba poreckiipollecki infection, pinworm infection, enterovirus infection (polio / non-polio), Epstein-Barr virus infection, E. coli infection, foodborne infection, foot-and-mouth disease, fungal dermatitis, fungal infection, gastroenteritis, group A streptococcal disease, group B streptococcal disease, leprosy, hantavirus pulmonary syndrome, head lice infestation (pediculosis), Helicobacter pylori infection, blood disorders, Hendra virus infection, hepatitis (HCV, HBV), shingles (herpes zoster), HIV infection, human ehrlichiosis, human parainfluenza virus infection, influenza, isosporosis, Lassa fever, leishmaniasis, visceral leishmaniasis (VL) ), malaria, Marburg hemorrhagic fever, measles, meningitis, Mycobacterium avium complex (MAC) infection, Naegleria infection, nosocomial infection, non-pathogenic intestinal ameba infection, onchocerciasis, opisthorchiasis, papillomavirus infection, parvovirus infection, plague, Pneumocystis jiroveci pneumonia (PCP), polyomavirus infection, Q fever, rabies, respiratory syncytial virus (RSV) infection, rheumatic fever, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, scabies, shigellosis, herpes zoster, sleeping sickness, smallpox, streptococcal infection, tapeworm infection, tetanus, toxic shock syndrome, tuberculosis, duodenal ulcer, Vibrio parahaemolyticus 12. The composition for use of claim 11, wherein the infection is selected from the group consisting of: Bacillus subtilis (B. parahaemolyticus) infection, Vibrio septicemia, viral hemorrhagic fever, warts, waterborne diseases, varicella zoster virus infection, whooping cough, and yellow fever.

14. The immunological and / or autoimmune disease may be asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary disease, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, allergic disease manifestations, primary immunodeficiency, antibody deficiency states, cell-mediated immunodeficiency, severe combined immunodeficiency, DiGeorge syndrome, hyper IgE syndrome (HIES), Wiskott syndrome, 12. The composition for use of claim 11, comprising or selected from the group consisting of Aldrich syndrome (WAS), ataxia-telangiectasia, immune-mediated cancer, white blood cell deficiency, autoimmune disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or type 1 diabetes mellitus, immune-mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel disease, Crohn's disease, psoriasis, autoimmune thyroid disease, Hashimoto's disease, dermatomyositis, Goodpasture's syndrome (GPS), myasthenia gravis (MG), sympathetic ophthalmia, phakogene uveitis, chronic invasive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia, and Verhof's disease.

15. 12. The composition for use according to claim 11, wherein the inflammatory disease is caused, induced, initiated and / or enhanced by bacteria, viruses, prions, parasites, fungi and / or is caused by irritating, traumatic, metabolic, allergic, autoimmune or idiopathic factors.

16. 16. The composition for use according to claim 11 or 15, wherein the inflammatory disease comprises or is selected from the group consisting of inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory uveitis, and inflammatory diseases of the larynx.

17. The inflammatory disease is selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory uveitis, and inflammatory diseases of the larynx, and preferably, the inflammatory disease is selected from abscess formation, acanthamoeba infection, acne vulgaris, actinomycosis, acute inflammatory skin diseases, acute adult laryngeal infection, acute multifocal macular pigment epitheliopathy, acute (burn) injuries, acute retinal necrosis, acute suppurative otitis media, and algal viral disorders. disorder), allergic contact dermatitis, amyloidosis angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, pseudorabies, autoantibodies in vasculitis, bacterial disorders, bacterial laryngitis, bacterial meningitis, Behcet's disease (BD), birdshot choroidopathy, Gilchrist's disease, Borna's disease, brucellosis, bullous tympanocytosis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in young animals, canine hemorrhagic fever, canine herpesvirus encephalomyelitis, cholesteatoma, chronic granulomatous disease (CGD), chronic inflammatory skin diseases, chronic relapsing encephalomyelitis, chronic Suppurative otitis media, ocular cicatricial pemphigoid (OCP), common upper respiratory tract infections, granulomas, Crohn's disease, cryptococcal disease, dermatomyositis, diphtheria, discoid lupus erythematosus (DLE), drug-induced vasculitis, drug or hypersensitivity reactions, encephalitozoonosis, eosinophilic meningoencephalitis, erythema multiforme (EM), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalitis, feline spongiform encephalopathy, fibromyalgia, Fuchs heterochromia irido-uveitis, gastroesophageal (laryngopharyngeal) reflux disease, giant cell arteritis, glanders, glaucoma, cyclitis, gonococcal granulomatous myringitis granular myringitis), granulomatous meningoencephalitis (GME), herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune and idiopathic disorders, infections in immunocompromised hosts, infectious canine hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki disease, La Crosse virus encephalitis, laryngeal abscess, laryngotracheobronchitis, leishmaniasis, lens-induced uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lymphoma, meningitis, greyhound meningoencephalitis, various meningitis / meningoencephalitis, microscopic polyangiitis, multifocal choroiditis, multifocal distemper encephalomyelitis in adult animals, multiple sclerosis,Myotonic dysphonia (MTD), mycoses (fungal diseases), mycoses of the CNS, necrotizing encephalitis, neosporosis, geriatric encephalitis, onchocerciasis, parasitic encephalomyelitis, parasitic infections, pars planitis, parvoviral encephalitis, pediatric laryngitis, pollution and inhalant allergies, polymyositis, post-vaccine canine distemper encephalitis, prion protein-induced disease, protothecosis, protozoan encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug encephalitis, radiation injury, radiation laryngitis, Radiation necrosis, relapsing polychondritis, Reiter's syndrome, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, rickettsial disorders, Rocky Mountain spotted fever, salmon toxic disease (SPD), sarcocystosiosis, sarcoidosis, schistosomiasis, scleroderma, rhinosclerosis, geographic choroiditis, Shaker dog disease, Sjogren's syndrome, spastic croup, spirochetal (syphilitic) disease, spongiotic dermatitis, sporotrichosis, steroid-responsive meningitis-arteritis, Stevens-Johnson syndrome group (SJS, severe erythema multiforme), epiglottitis, sympathetic ophthalmia, singamus, syphilis, systemic vasculitis in sarcoidosis, Takayasu's arteritis, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's disease), tick-borne encephalitis in dogs, toxic epidermal necrolysis (TEN), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, urticaria (hives) 17. The composition for use according to any one of claims 11, 15, or 16, wherein the composition is selected from the group comprising vasculitis, vasculitis and complications of malignant diseases, vasculitis and complications of rheumatoid arthritis, vasculitis in idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal, and parasitic infections, viral disorders, viral laryngitis, vitiligo, vocal cord abuse, vocal cord hemorrhage, Vogt-Koyanagi-Harada syndrome (VKH), Wegener's granulomatosis, and Whipple's disease.

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