RU2818563C2 - Pharmaceutically active derivatives of pyrazolotriazine and/or pyrazolopyrimidine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazolo [1,5-a][1,3,5] triazine and pyrazolo [1,5-a]pyrimidine derivatives and/or their pharmaceutically acceptable salts, use of these derivatives as pharmaceutically active agents. Present invention also relates to pharmaceutical compositions containing at least one of pyrazolo [1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof.

EFFECT: prevention and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases.

10 cl, 6 tbl, 3 ex

Description

Field of technology to which the invention relates

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

State of the art

Elements of the cyclin-dependent kinase (CDK) family, which trigger cell cycle progression, are considered promising therapeutic targets, especially in cancer. Elements of the CDK family that control other processes, such as transcription and RNA processing, have received less attention so far, although experimental evidence for their involvement in various pathological processes is emerging. It has also been established that CDK/cyclin complexes, along with cell cycle control, are conserved components of the RNA polymerase II (Pol II) transcription machinery ( Bregman et al. , 2000, Front Biosci. 5:244-257). Currently, 20 mammalian CDKs are known. While CDK7-13 were associated with transcription, only CDKs 1, 2, 4, and 6 showed obvious association with the cell cycle. Unique among mammalian CDKs, CDK7 has consolidated kinase activities, regulating both cell cycle progression and transcription ( Desai et al., 1995, Mol. Cell Biol. 15, 345-350).

The general transcription factor TFIIH, purified from mammalian cells, consists of ten subunits, seven of which (p62, p52, p44, p34, XPD, XPB, and TTDA) form the core complex. Three subunits (cyclin H, MAT1 and CDK7) of CDK-activating kinase (CAK), which is associated with the TFIIH core through a subunit of the XPD (ATP-dependent helicase) complex. During the transcription initiation process, TFIIH helicase activity exposes the DNA of the core promoter, with CDK7 phosphorylating the C-terminal domain (CTD) of Pol II at serines 5 and 7 (Akhtar et al., 2009, Mol. Cell 34, 387-393), and also other transcription factors that control the transition from initiation to elongation (Larochelle et al., 2012, Nat. Strut. Mol. Biol. 19, 1108-1115). Thus, CDK7 is an important factor in the transcription process, suggesting that CDK7 is a target for cancer treatment, especially transcription-dependent cancers.

It has long been argued that CDK7 plays an important role in cell metabolism and viability. CDK transcriptional inhibitors reduce the activity of a large number of short-lived anti-apoptotic proteins, such as myeloid cell leukemia-1 (Mcl-1) anti-apoptotic proteins, B-cell lymphoma extra-long molecule (Bcl-xL) and XIAP (X-linked inhibitor of apoptosis protein), D- cyclins, c-Myc, Mdm-2 (providing stabilization of p53), p21 ^waf1 proteins, the transcription of which is mediated by transcription factor (NF-kB), and hypoxia-induced VEGF ( Shapiro GI. 2006, J Clin Oncol; 24(11):1770 -83). The transcriptional nonselective cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and downregulation of Mcl-1. These findings confirmed previous suggestions that CDK7 may be a valuable drug target for the treatment of malignancies and cell cycle-related diseases ( Lolli G and Johnson LN. 2005. Cell Cycle 4:572–577).

The function of CDK7 as a regulator of general transcription and the use of CDK7 as a therapeutic target for the treatment of many diseases and syndromes are associated with mutations in regulatory regions and transcription factors, cofactors, chromatin regulators and non-coding RNAs. These mutations may contribute to the development of cancer, autoimmunity, neurological disorders, developmental syndromes, diabetes, cardiovascular disease and obesity, among other conditions. Several transcription factors control the initiation of pausing and elongation of RNA polymerase II and, when their expression or function is altered, can produce aggressive tumor cells (c-Myc) or some forms of autoimmunity (AIRE) ( Tong Ihn Lee and Richard A. Young, Cell , 2013, 152:1237-1251). Thus, inhibition of human CDK7 kinase activity is likely to result in suppression of proliferation through the function of cell cycle progression and transcriptional regulation by inhibiting certain oncogene-associated transcription factors by inhibiting the overall transcription process. More importantly, CDK7 has been shown to regulate the exponential expression of oncogenic transcription factors more significantly than it does for other constitutive genes in cancer cells. Thus, inhibition of CDK7 may differentially affect the transcription of specific oncogenes and constitutive gene, hence a therapeutic window may be provided. For this reason, transcriptional regulation and pharmacological inhibition can be used to treat proliferative disorders, including cancer, through appropriate general transcriptional inhibition by CDK7. As a general transcriptional regulator, CDK7 represents a therapeutic target for the treatment of diseases such as inflammation, replication of viruses such as HIV, Epstein-Barr virus, cancer and cardiac hypertrophy.

HIV-1 gene expression is regulated by the viral transactivator (Tat) protein, which induces transcriptional elongation of the HIV-1 long tandem repeat. This induction requires hyperphosphorylation of the C-terminal repeat domain of RNA polymerase II. To archive this hyperphosphorylation, Tat stimulates CTD kinases associated with general promoter complex transcription factors, in particular TFIIH-associated CDK7 (Nekhai et al.; Biochem J. (2002) 364, 649-657). The authors of US 615968 also described that Tat binds to CDK7 and this interaction increases the ability of CAK to phosphorylate the CTD. In addition, the authors of US 615968 describe that Tat transcriptional activation is dependent on the kinase activity of CDK7. Additionally, Young Kyeung Kim et al concluded that TFIIH recruitment and activation represents a rate-limiting step for HIV emergence from latency (Young Kyeung Kim, EMBO (2006) 25, 3596-3604).

Levels of CDK7 and CDK9, as well as other components of the kinase complexes, MAT-1/cyclin H, are up-regulated during human cytomegalovirus infection. In addition, there is an increase in the kinase activity of CDK7 and CDK9 (Tamrakar et al., Journal of Virology, 2005, 79; 15477-15493).

The targets of many antiviral drugs are viral proteins. The disadvantage of such antiviral drugs is that viruses often develop resistance to these drugs. Antiviral drugs that target cellular proteins essential for the viral process, such as CDK7, may circumvent this deficiency. These drugs may also be effective against several unrelated viruses and should complement traditional antiviral agents. Inhibitors of CDK7, which has dual functions as CDK activating kinase and transcriptional regulation, are very effective in treating several viruses.

Disclosure of the Invention

An object of the present invention is to provide compounds and/or pharmaceutically acceptable salts thereof which can be used as pharmaceutically active agents, especially for the prevention and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases, as well as compositions containing at least one of these compounds and/or pharmaceutically acceptable salts thereof as pharmaceutically active ingredients.

In one aspect, the present invention relates to pyrazolotriazine or pyrazolopyrimidine compounds, which are defined by the general formula I

Formula I

Where

X is independently selected from CH and N in each case;

Q is either absent or independently in each case selected from the group consisting of -NH-, -NH(CH ₂ )-, -NH(CH ₂ ) ₂ -, -NH(C=O)-, -NHSO ₂ -, -O-, -O(CH ₂ )-, -(C=O)-, -(C=O)NH- and -(C=O)(CH ₂ )-;

Y is independently in each case selected from the group consisting of C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl and C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or two -OR ⁵ , -N(R ⁵ )R ⁵ , aryl , heteroaryl and heterocyclyl,

C3-C8-cycloalkyl may be substituted by one or two R ³ , R ⁴ and -(C=O)R ⁵ ,

heterocyclyl may be substituted with one or two R ³ , R ⁴ and -(C=O)R ⁵ , and

aryl or heteroaryl may be substituted with one or two R ³ , C1-C6 alkyl, -OR ⁵ , -N(R ⁵ )R ⁵ , -(C=O)R ⁵ , halogen, heteroaryl and heterocyclyl,

R ¹ is independently in each case selected from the group consisting of hydrogen and methyl;

R ² is independently in each instance selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH ₃ and C1-C3 haloalkyl, any of which is optionally substituted;

R ³ is either absent or independently in each case selected from the group consisting of hydrogen, -OR ⁵ , halogen, -N(R ⁵ )R ⁵ , -NH(C=O)R ⁵ , -(C=O)NH ₂ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with -OH or -NH ₂ ;

R ⁴ is independently in each case selected from the group consisting of hydrogen, halogen, -OR ⁵ , -N(R ⁵ )R ⁵ , (=O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl, substituted -OH or -NH ₂ ;

R ⁵ is in each instance independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C3 haloalkyl, heteroaryl, heterocyclyl, heteroaryl substituted with one or two halogens, -OR ¹¹ , -N(R ¹¹ )R ¹¹ , C1-C6 alkyl, and C1-C6 alkyl substituted with -OH, -NH ₂ , heterocyclyl substituted with one or two halogens, -OR ¹¹ , -N(R ¹¹ )R ¹¹ , C1-C6 alkyl and C1 -C6 alkyl substituted with -OH or -NH ₂ ;

Z - any structure of the next group A;

Group A

where n = 1, 2 or 3; m = 1 or 2;

R ⁶ and R ⁷ are in each case independently selected from the group consisting of hydrogen, -NH(C=O)R ¹⁴ , -NHR ¹⁴ , -OR ¹⁴ and any structure of the following group B, with the proviso that when Z is , one of R ⁶ and R ⁷ is not H;

Group B

where o is independently selected from 1, 2 and 3 in each case;

W - any structure of the following group C;

Group C

L is absent or independently in each case selected from the group consisting of -O- and -NH-;

where n is independently selected from 1, 2 and 3 in each case;

R ⁸ , R ⁹ and R ¹⁰ are independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR ⁵ , -CN and C1-C6 alkyl substituted -OH, -OR ⁵ or -NHR ⁵ ;

R ¹¹ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above;

R ¹² is independently in each case selected from the group consisting of hydrogen and W as defined above;

wherein if R ¹¹ represents W, R ¹² represents hydrogen;

R ¹³ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ , -CN and W, as defined above;

wherein if R ¹³ represents W, R ¹² represents hydrogen;

R ¹⁴ - any structure of group D;

Group D

R ¹⁵ is independently in each case selected from the group consisting of hydrogen and W as defined above;

R ¹⁶ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ , -CN and W, as defined above;

wherein if R ¹⁶ represents W, R ¹² represents hydrogen;

R ¹⁷ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C3 haloalkyl;

R ¹⁸ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ and -CN;

R ¹⁹ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above;

wherein if R ¹⁹ represents W, R ¹⁵ represents hydrogen;

R ²⁰ and R ²¹ are independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR ⁵ , heterocyclyl and -CN;

R ²² is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N( ^R5 ) ₂ ^{, -NR19R20 ,} _-NR19CH2 (CO) _NH2 , heterocyclyl, -OR ⁵ and -CN;

or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate of the above compounds or a pharmaceutically acceptable salt thereof.

The present invention also relates to enantiomers, stereoisomeric forms, mixtures of enantiomers, diastereomers, mixtures of diastereomers, racemates of the above compounds and pharmaceutically acceptable salts thereof.

In one embodiment of the compounds of general formula I above, the compounds have the general formula Ia

Formula Ia

Where

X is independently selected from CH and N in each case;

Y ¹ is independently selected in each case from CH, C(OH) and N;

Y ² is independently selected in each case from CH, C(OH) and N;

Q is either absent or independently in each case selected from the group consisting of -NH-, -NH(CH ₂ )-, -NH(C=O)-, -NHSO ₂ -, -O-, -O(CH ₂ )-, -(C=O)- and -(C=O)(CH ₂ )-;

R ¹ is independently in each case selected from the group consisting of hydrogen and methyl;

R ² is independently in each instance selected from the group consisting of halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -CN, -(C=O)CH ₃ and C1-C3 haloalkyl, any of which is optionally substituted;

R ³ is independently in each case selected from the group consisting of hydrogen, -OH, halogen, -N(R ⁵ ) ₂ , -NH(C=O)R ⁵ , -(C=O)NH ₂ , C1-C6 alkyl and C1-C6 alkyl substituted -OH or -NH ₂ ;

R ⁴ is in each case absent or independently selected from the group consisting of hydrogen, halogen, -OH, -OR ⁵ , -NH ₂ , C1-C6 alkyl and C1-C6 alkyl substituted -OH or -NH ₂ ;

R ⁵ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C3 haloalkyl;

Z - any structure of the next group A;

Group A

where n = 1, 2 or 3; m = 1 or 2;

R ⁶ and R ⁷ are in each case independently selected from the group consisting of hydrogen, -NH(C=O)R ¹⁴ , -NHR ¹⁴ , -OR ¹⁴ and any structure of the following group B, with the proviso that when Z is , one of R ⁶ and R ⁷ is not H;

Group B

where o = 1, 2 or 3;

W - any structure of the following group C;

Group C

L is absent or independently in each case selected from the group consisting of -O- and -NH-;

R ⁸ , R ⁹ and R ¹⁰ are independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR ⁵ , -CN and C1-C6 alkyl substituted -OH, -OR ⁵ or -NHR ⁵ ;

R ¹¹ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W as defined above;

R ¹² is independently in each case selected from the group consisting of hydrogen and W as defined above;

Moreover, if R ¹¹ represents W, then R ¹² represents hydrogen;

R ¹³ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ , -CN and W, as defined above;

wherein if R ¹³ represents W, R ¹² represents hydrogen;

R ¹⁴ - any structure of group D;

Group D

R ¹⁵ is independently in each case selected from the group consisting of hydrogen and W as defined above;

R ¹⁶ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ , -CN and W, as defined above;

Moreover, if R ¹⁶ represents W, then R ¹² represents hydrogen;

R ¹⁷ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C3 haloalkyl;

R ¹⁸ is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -NH ₂ , -OR ⁵ and -CN;

R ¹⁹ is independently in each case selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C10 cycloalkyl and W, as defined above;

Moreover, if R ¹⁹ represents W, then R ¹⁵ represents hydrogen;

R ²⁰ and R ²¹ are independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, -OR ⁵ , heterocyclyl and -CN;

R ²² is independently in each case selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C3-C10 cycloalkyl, -N(R ⁵ ) ₂ , -NR ¹⁹ R ²⁰ , heterocyclyl, -OR ⁵ and -CN.

In one embodiment of the compounds of general formula I or formula Ia above, at least one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above for general formula I, or is a structure containing W as defined above for general formula I.

In one embodiment of the compounds of general formula I or formula Ia above, only one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above for the general formula I, or is a structure containing W as defined above for general formula I.

In one embodiment, at least one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above or is a structure containing W as defined above for general formula Ia.

In one embodiment, only one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above or is a structure containing W as defined above for the general formula Ia.

In one embodiment of the compounds of general formula I above, R ¹ is hydrogen and the compound has general formula II

Formula II

where X, Y, Z, R ² and Q have the meaning given above for the general formula I.

In one embodiment of the compounds of general formula I above, the compounds have the general formula III

Formula III

where X, Y, Z, R ² and Q have the meaning given above for the general formula I, and

Y ^{a is} either absent or, in each case, independently selected from the group consisting of aryl, heteroaryl, heterocyclyl, aryl substituted with one or two of C1-C6 alkyl, -OR ⁵ , -N(R ⁵ )R ⁵ , and halogen, heteroaryl substituted with one or two of C1-C6 alkyl, OR ⁵ , -N(R ⁵ )R ⁵ and halogen, heterocyclyl substituted with one or two of R ²³ and R ²⁴ ;

R ²³ is either absent or independently in each case selected from the group consisting of hydrogen, -OR ⁵ , halogen, -N(R ⁵ )R ⁵ , -NH(C=O)R ⁵ , -(C=O)NH ₂ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with -OH or -NH ₂ ;

R ²⁴ is independently in each case selected from the group consisting of hydrogen, halogen, -OR ⁵ , -N(R ⁵ )R ⁵ , (=O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl, substituted -OH or -NH ₂ ;

where R ⁵ has the meaning defined in claim 1 of the claims;

L ¹ is either absent or independently in each case selected from the group consisting of -NH-, -NH(CH ₂ )-, -NH(C=O)-, -NHSO ₂ -, -O-, -O(CH ₂ )-, -(C=O)-, -(C=O)NH- and -(C=O)(CH ₂ )-;

Y ¹ is independently selected in each case from CH, C(OH) and N;

Y ² is independently in each case selected from CH, C(OH), O and N;

q is independently selected from 0, 1 and 2 in each case;

r is independently selected from 0, 1, 2 and 3 in each case;

In one embodiment of the compounds of general formula I or general formula Ia above,

Z represents Z ¹ where Z ¹ represents any structure of the following group E;

Group E

where m is independently selected from 1 and 2 in each case; And

n has the meaning given above for General Formula I;

R ⁸ , R ⁹ , R ¹² and R ¹³ have the meanings defined above for the general formula I;

R ⁶ represents any group B structure defined above for general formula I.

In one embodiment of the compounds of general formula Ia above,

Z represents Z ¹ where Z ¹ represents any structure of the following group E;

Group E

where n = 1, 2 or 3; m = 1 or 2;

R ⁸ , R ⁹ , R ¹² and R ¹³ have the meanings defined above; A

R ⁶ represents any group B structure defined above.

In one embodiment of the compounds of general formula I or general formula Ia above,

Z represents

p is independently selected from 0, 1, 2 and 3 in each case;

X ¹ is independently in each case selected from CR ⁸ and N;

R ⁶ represents any group B structure defined above for general formula I; And

R ⁸ has the meaning defined above for general formula I.

In one embodiment of the compounds of general formula Ia above,

Z represents

p equals 0, 1, 2 or 3

X ¹ is independently selected from CR ⁸ and N in each case;

R ⁶ represents any group B structure defined above; And

R ⁸ has the meaning defined above.

In one embodiment of the compounds of general formula I or general formula Ia above,

Z represents or Z represents

where R ⁶ - R ⁸ have the meanings defined above for the general formula I.

In one embodiment of the compounds of general formula Ia above,

Z represents or Z represents

where R ⁶ - R ⁸ have the meanings defined above.

In one embodiment of the compounds of general formula I above,

Z represents

where R ⁶ and R ¹⁰ have the meanings defined above for general formula I.

In one embodiment of the compounds of general formula I above, the compounds have the general formula IV

Formula IV

where X, X ¹ , R ⁶ , R ⁸ and Q have the meanings given above for the general formula I, and

X ¹ has the meaning defined above;

where Y ^b is any structure of the next group F;

Group F

R ²⁶ and R ²⁷ are either absent or independently in each case selected from the group consisting of hydrogen, -OR ⁵ , halogen, -N(R ⁵ )R ⁵ , -NH(C=O)R ⁵ , -(C= O)NH ₂ , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted -OH or -NH ₂ ;

where R ⁵ has the meaning defined above for general formula I.

In one embodiment of the compounds of general formula I above,

R ² represents C1 -C6 alkyl.

In one embodiment of the compounds of general formula Ia above,

R ² represents C1-C6 alkyl.

In one embodiment of the compounds of general formula I or general formula Ia above,

R ⁶ and R ⁷ are in each case independently selected from the group consisting of -NH(C=O)R ¹⁴ , -NHR ¹⁴ , -OR ¹⁴ , any structure of the following group B'

Group B'

where R ¹⁴ is selected from the group consisting of , where R ⁵ , R ⁸ , R ¹² , R ¹⁶ , R ¹⁷ , R ¹⁸ and W have the meanings defined above.

In one embodiment of the compounds of general formula I or general formula Ia above,

W is selected from the group consisting of

R ²⁰ - R ²² and L have the meanings defined above.

In one embodiment of the compounds of general formula Ia or general formula III above,

Y ¹ is N, Y ² is CH, and R ³ is -N(R ⁵ ) ₂ where R ⁵ is as defined above.

In one embodiment, the present invention also provides pharmaceutically acceptable salts of the compounds of the present invention, as defined above.

In one embodiment, the compound of the present invention is a compound selected from structures 1-88, which are listed below in Table 7.

In a further aspect, the present invention also provides a pharmaceutical composition containing a compound of the present invention, as defined herein, as an active ingredient together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.

In one aspect, the present invention also provides a compound of the present invention, as defined herein, for use as a pharmaceutical or pharmaceutically active agent, wherein said pharmaceutical or pharmaceutically active agent preferably has cyclin-dependent kinase 7 (CDK7) inhibitory activity. .

In one aspect, the present invention also provides a compound of the present invention, as defined herein, for use in a method of preventing and/or treating a disease that is associated with inhibition of apoptosis, abnormal transcriptional activity, and/or cell cycle arrest due to abnormal 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 .

In one embodiment, a disease associated with inhibition of apoptosis, abnormal transcriptional activity, and/or cell cycle arrest due to abnormal activity and/or overexpression of one or more cyclin-dependent kinases (CDKs), particularly cyclin-dependent kinase 7 (CDK7), is a disease associated with, accompanied by, caused by and/or provoked by dysfunction and/or hyperfunction of CDK7. In one embodiment, a disease associated with inhibition of apoptosis, abnormal transcriptional activity, and/or cell cycle arrest due to abnormal activity and/or overexpression of one or more cyclin-dependent kinases (CDKs), particularly cyclin-dependent kinase 7 (CDK7), is proliferative disease. In one embodiment, said proliferative disease is cancer.

In one embodiment, said cancer is one of the following: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurilemmoma, amplular colon carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and estrogen-independent breast cancer, Burkitt's lymphoma, body cancer, tumor of unknown primary site of carcinoma (CUP syndrome), colorectal cancer, small intestinal cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial types of cancer , Ewing tumors, gastrointestinal tract tumors, stomach cancer, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer, cervical glioblastomas, gynecological tumors, ear, nose and throat tumors, hematological tumor, hairy cell leukemia, urethral cancer , skin cancer, testicular skin cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, embryonal cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer of the mouth and lips), central nervous system cancer, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymphomas, cancer stomach, malignant melanoma, malignant neoplasm, malignant neoplasms of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastoma, melanoma, meningiomas, Hodgkin's lymphoma / non-Hodgkin's lymphoma, fungoid granuloma, nasal cancer, neuroma, neuroblastoma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, cancer esophagus, T-cell lymphoma, thymoma, tubal carcinoma, eye tumors, urethral cancer, urological tumors, urothelial carcinoma, vulvar cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, nephroblastoma, cervical carcinoma, tongue cancer, invasive ductal carcinoma breast, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung carcinoma, non-small cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brainstem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, small tumor , pineal gland tumors, uterine sarcoma, salivary gland cancers, anal gland adenocarcinomas, mastocytomas, renal pelvis tumor, ureteral tumor, hereditary papillary renal cancers, sporadic papillary renal cancers, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma a, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, subpharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer, squamous cell carcinoma, oral melanoma, AIDS-associated lymphoma, cutaneous T-cell lymphoma, central nervous system lymphoma, malignant fibrous histiocytoma, lymph node sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma and feline mammary carcinoma.

In one embodiment, said infectious disease, including opportunistic diseases, is selected from the following diseases: AIDS, adenovirus infection, alveolar hydatid echinococcosis (AHD), amoebiasis, angiostrongyliasis, anisakiasis, anthrax, babesiosis, balantidiasis, Baylisascaris nematode infection, bilharzia (schistosomiasis), blastocytosis, Lyme borreliosis, botulism, Brainerd's diarrhea, brucellosis, bovine spongiform encephalopathy (BSE), candidiasis, capillariasis, chronic fatigue syndrome (CFS), Chagas disease, chickenpox, chlamydia pneumoniae infection, cholera, chronic fatigue syndrome, Creutzfeldt disease -Jacoba (CJD), clonorchiasis, cutaneous larva migrans (CLM), coccidiridomycosis, conjunctivitis, coxsackie infection (Cox A16), cryptococcal disease, cryptosporidiosis, West Nile fever, cyclosporiasis, neurocysticercosis, cytomegalovirus infection, dengue fever, Dipylidium caninum infection, ragic Ebola fever (EHF), alveolar echinococcosis (AE), encephalitis, intestinal amoeba infection, Entamoeba dispar infection, Entamoeba hartmanni infection, Entamoeba polecki infection, enterobiasis, enterovirus infection (polio/non-polio), Epstein-Barr virus infection, E. coli infection, food infection, foot and mouth disease, fungal dermatitis, fungal infections, gastroenteritis, group A streptococcal disease, group B streptococcal disease, Hansen's disease (leprosy), hantavirus pulmonary syndrome, lice (lice), Helicobacter pylori infection, hematological disease, Hendra virus infection, hepatitis (HCV, HBV), herpes zoster (shingles), HIV, human ehrlichiosis, parainfluenza virus infection, influenza, isosporiasis, Lassa fever, leishmaniasis, visceral leishmaniasis (VL), malaria, Marburg hemorrhagic fever, measles, meningitis, Mycobacterium complex infection avium (MAC), infection with amoeba Naegleria Fowler, nosocomial infection, infection with non-pathogenic intestinal amoebae, onchocerciasis, opisthorchiasis, papillomavirus infection, parvovirus infection, plague, Pneumocystis pneumonia (PCP), polyomavirus infection, Q fever, rabies, respiratory syncytial infection virus, rheumatoid arthritis, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, scabies, shigellosis, shingles, encephalitis lethargica, smallpox, streptococcal infection, tapeworm infection, tetanus, toxic shock syndrome, tuberculosis, duodenitis, parague infection prayerful vibrio, vibrio common purulent infection, viral hemorrhagic fever, warts, waterborne infections, varicella zoster virus infection, whooping cough and amaryllium fever.

In one embodiment, the immunological disease and/or autoimmune disease is selected from the following diseases: asthma, diabetes, rheumatic diseases, organ and tissue transplant rejection, 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, manifestations of allergic diseases, primary immunodeficiencies, antibody deficiency conditions, cell-mediated immunodeficiencies, severe combined immunodeficiency, DiGeorge syndrome, IgE hyperproduction syndrome (HIES), Wiskott syndrome -Aldrich's (WAS), ataxia-telangiectasia, immune-mediated cancers, white blood cell defects, autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated diabetes 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 thyroiditis, dermatomyositis, Goodpasture syndrome (GPS), myasthenia gravis (MG), sympathetic ophthalmia, phacogenic uveitis , chronic aggressive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia and Werlhof's disease.

In one embodiment, the inflammatory disease is caused, induced, initiated and/or enhanced by bacteria, viruses, prions, parasites, fungi and/or caused by irritant, traumatic, metabolic, allergic, autoimmune or idiopathic agents.

In one embodiment, the inflammatory disease is selected from the following diseases: 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 diseases of uveitis, and inflammatory diseases of the larynx.

In one embodiment, said inflammatory disease is selected from the following diseases: 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 diseases of uveitis, inflammatory diseases of the larynx, wherein said inflammatory diseases are preferably diseases from the group that includes: abscess, Acanthamoeba infection, juvenile acne, actinomycosis, acute inflammatory dermatoses, acute laryngeal infections in adults, acute multifocal placoid pigment epitheliopathy, acute (thermal) injury, acute retinal necrosis , acute suppurative otitis media, algae diseases, allergic contact dermatitis, amyloidosis, angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, pseudorabies, autoantibodies in vasculitis, bacterial diseases, bacterial laryngitis, bacterial meningitis, Behçet's disease (BD), shotgun. choroidopathy, Gilchrist blastomycosis, Born's disease, brucellosis, bullous myringitis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in immature animals, canine hemorrhagic fever, canine herpes virus encephalomyelitis, cholesteatoma, chronic granulomatous diseases ( CGD), chronic inflammatory dermatoses, chronic recurrent encephalomyelitis, chronic suppurative otitis media, ocular cicatricial pemphigoid (OCP), common upper respiratory tract infection, granuloma, Crohn's disease, cryptococcal disease, dermatomyositis, diphtheria, discoid lupus erythematosus (DLE), drug vasculitis, drug reaction or hypersensitivity reaction, encephalitic zoonosis, eosinophilic meningoencephalitis, erythema multiforme (EM), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalitis, feline spongiform encephalopathy, fibromyalgia, heterochromic Fuchs uveitis, gastroesophageal (laryngopharyngeal) reflux disease giant cell arteritis , glanders, glaucomatocyclic crisis, gonorrheal granular myringitis, granulomatous meningoencephalitis (GME), herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune and idiopathic disorders, immunodeficient host infections, infectious canine hepatitis, inhalational laryngitis, interstitial nephritis, irritant contact dermatitis curses , juvenile rheumatoid arthritis, Kawasaki syndrome, La Crosse viral encephalitis, laryngeal abscess, laryngotracheobronchitis, leishmaniasis, phacogenic uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lymphoma, meningitis, greyhound meningoencephalitis, other meningitis/ goencephalitis, microscopic polyangiitis , multifocal choroiditis, canine distemper multifocal encephalomyelitis in mature animals, multiple sclerosis, muscle tension dysphonia (MTD), mycotic (fungal) diseases, mycotic diseases of the central nervous system, necrotizing encephalitis, neosporosis, encephalitis of old dogs, onchocerciasis, parasitic encephalomyelitis, parasitic infections, Parksplanet, parcel encephalitis, children's laryngitis, environmental pollution allergies and inhalation allergies, polymiositis, puscinal caused by the plague of dogs, diseases, induced by outline, prototicosis, protozoan encephalomia, psoriasis, psoriatic arthritis, encephalitis of Mopsov, rayevo e defeat, radiation laryngitis, radiation necrosis, relapsing polychondritis, Reiter's syndrome, retinal pigmentary degeneration, retinoblastoma, rheumatoid arthritis, rickettsial diseases, Rocky Mountain spotted fever, salmon poisoning disease (SPD), sarcocystosis, sarcoidosis, schistosomatosis, scleroderma, rhinoscleroma, creeping choroiditis, idiopathic cerebellitis , Sjögren's syndrome, spasmodic croup, spirochetal (syphilis) diseases, spongiotic dermatitis, sporotrichosis, steroid-responsive meningitis-arteritis, Stevens-Johnson syndrome (SJS, erythema multiforme), epiglottitis, sympathetic ophthalmia, syngamosis, syphilis, systemic vasculitis in sarcoidosis, Takayasu syndrome, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's disease), canine tick-borne viral encephalitis, toxic epidermal necrolysis (TEN), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, allergic rash ( urticaria), vasculitis, vasculitis and malignancies, vasculitis and rheumatoid arthritis, vasculitis in idiopathic inflammatory myopathies, central nervous system vasculitis, vasculitis secondary to bacterial, fungal and parasitic infections, viral diseases, viral laryngitis, vitiligo, voice abuse, vocal cord hemorrhage, Vogt-Koyanagi-Harada (VKH) syndrome, Wegener's granulomatosis and Whipple's disease.

In one aspect, the present invention also relates to the treatment and/or prevention of a disease that is associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest due to abnormal activity and/or overexpression of one or more cyclin-dependent kinases (CDKs), in 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, wherein said method of treatment and/or prophylaxis comprises administering a compound at the present invention, as defined herein, to a patient in need of such treatment and/or prophylaxis.

In yet another embodiment, the patient in need of such treatment and/or prophylaxis is a mammal. In one embodiment, the patient in need of such treatment and/or prophylaxis is a human. In yet another embodiment, the patient in need of such treatment is a non-human animal.

In one embodiment, the disease being prevented or treated by the method is a disease as defined herein.

In one aspect, the present invention also relates to the use of a compound of the present invention, as defined herein, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest due to abnormal 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 diseases, the definition of which is given in this description.

Carrying out the invention

Additional useful features, aspects and details of the invention will be apparent from the dependent claims, description, examples and drawings.

The compounds of the present invention are highly potent inhibitors of the threonine/serine kinase CDK7 and/or its complex, CDK7/MAT1/CycH. The compounds of the invention are suitable for use as a pharmaceutically active agent. The compounds of the invention are suitable for the treatment of disorders associated with, accompanied by, caused and/or induced by CDK7 and its complex, in particular its hyperfunction or dysfunction. Thus, the compounds of the invention are suitable for the treatment of diseases or disorders associated with CDK7 and disorders induced by the CDK7 complex.

The compounds of the invention can also be used for the manufacture of a medicament or pharmaceutical composition for the treatment of disorders associated with, accompanied by, caused and/or induced by CDK7 and its complex, in particular its hyperfunction or dysfunction. The compounds of the invention are further used for the manufacture of a medicament or pharmaceutical composition for the treatment and/or prevention of disorders induced by CDK7 and its complex.

The present inventors have found that, in particular, in those embodiments of the present invention in which the compounds of the invention contain a W group as defined above, they can covalently bind to the -SH groups of cysteine residues in cyclin-dependent kinase(s), in particular , CDK7, thereby forming a covalent bond and adduct between the compound and the kinase and thereby inhibiting the kinase(s). This applies in particular to those embodiments in which at least one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above or is is a structure containing W as defined above.

This also applies to those embodiments in which only one of Z, R ⁶ , R ⁷ , R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ and R ¹⁹ is W as defined above or is a structure containing W as defined above. This is because all W structures defined above contain a double or triple bond allowing the reaction with the sulfhydryl group in the kinase to form an adduct between the compound and the kinase. Inhibition of the kinase occurs due to covalent binding of the compound of the invention. When used in this context, the term “only one” means that only one (and no more) of the listed groups/residues is W or a structure containing W as defined above.

As used herein, the term "optionally substituted" means that a hydrogen atom, if present and attached to an element atom in the group, or more of such hydrogen atoms may be replaced by a suitable group such as halogen, including fluorine, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, methylhydroxyl, COOMe, C(O)H, COOH, OMe or OCF ₃ ;

The term "alkyl" refers to a straight, branched or cyclic monovalent saturated aliphatic hydrocarbon radical with a number of carbon atoms in the range indicated. Thus, for example, “C ₁ -C ₆ -alkyl” means any of the hexylalkyl and pentylalkyl isomers, as well as n-, iso-, sec- and tert-butyl, n- and isopropyl, cyclic propyl, ethyl and methyl.

The term "alkenyl" means a straight or branched monovalent aliphatic hydrocarbon radical with one or more carbon-carbon double bonds and a number of carbon atoms in the range indicated. Thus, for example, "C ₂ -C ₆ -alkenyl" means all hexenyl and pentenyl isomers, as well as 1-butenyl, 2-butenyl, 3-butenyl, isobutenyl, 1-propenyl, 2-propenyl and ethenyl (or vinyl) .

The term "cycloalkyl", alone or in combination with any other term, means a group such as, for example, an optionally substituted or unsubstituted cyclic hydrocarbon having from three to eight carbon atoms, unless otherwise specified. Thus, for example, "C ₃ -C ₈ cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "haloalkyl" means an alkyl group, as defined herein, that is substituted with at least one halogen. Examples of straight or branched chain "haloalkyl" groups used in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl, independently substituted with one or more halogens. It should be understood that the term "haloalkyl" includes substituents such as -CHF ₂ , -CF ₃ , -CH ₂ -CH ₂ -F, -CH ₂ -CF ₃ and the like.

The term "heteroalkyl" means an alkyl group in which one or more carbon atoms are replaced by a heteroatom, such as O, N, or S. For example, if the carbon atom of an alkyl group that is attached to the parent molecule is replaced by a heteroatom (such as O, N, or S ), the resulting heteroalkyl groups are respectively an alkoxy group (eg -OCH ₃ etc.), an amine (eg -NHCH ₃ , -N(CH ₃ ) ₂ etc.) or a thioalkyl group (eg , -SCH ₃ , etc.). If the non-terminal carbon atom of an alkyl group that is not attached to the parent molecule is replaced by a heteroatom (for example, O, N or S) and the resulting heteroalkyl groups are, respectively, an alkyl ether (for example, -CH ₂ CH ₂ -O-CH ₃ and etc.), an alkyl amine (eg -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , etc.) or a thioalkyl ether (eg -CH ₂ -S-CH ₃ ).

The term "halogen" means fluorine, chlorine, bromine or iodine.

As used herein, the term “phenyl” means an optionally substituted or unsubstituted phenyl group.

As used herein, the term “benzyl” means an optionally substituted or unsubstituted benzyl group.

The term "heteroaryl" means (i) optionally substituted 5- and 6-membered heteroaromatic rings and (ii) optionally substituted 9- and 10-membered bicyclic fused ring systems in which at least one ring is aromatic, wherein the heteroaromatic ring or the bicyclic fused ring system contains from 1 to 4 heteroatoms independently selected from N, O and S, each N optionally being in oxide form and each S in the non-aromatic ring optionally being S(O) or S(O) ₂ . Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, 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, tetrahydroisoquinolinyl, isoindolyl, benzodioxolyl, benzofuryl, imidazo[1,2-a]pyridinyl, benzotriazolyl, dihydroindolyl, dihydroisoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, 2,3-dihydrobenzofuranyl and 2,3-dihydrobenzo-1,4-dioxynyl.

The term "heterocyclyl" means (i) optionally substituted 4-8 membered, saturated and unsaturated but non-aromatic monocyclic rings containing at least one carbon atom and from 1 to 4 heteroatoms, (ii) optionally substituted bicyclic ring systems containing from 1 to 6 heteroatoms, and (iii) optionally substituted tricyclic ring systems, wherein each ring in (ii) or (iii) is independently fused or bridged to another ring or rings, and each ring is saturated or unsaturated but non-aromatic, and wherein each heteroatom in (i), (ii) and (iii) is independently selected from N, O and S, wherein each N is optionally in oxide form and each S is optionally oxidized to S(O) or S(O) ₂ . Suitable 4-8 membered saturated heterocyclyls include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, , thiazinanil, thiazipanil, thiazepanil, azepanil , diazepanil, tetrahydropyranyl, tetrahydrothiopyranyl, dioxanil and azacyclooctyl. Suitable unsaturated heterocyclic rings include rings that correspond to the saturated heterocyclic rings listed in the sentence above, in which the single bond is replaced by a double bond. It should be understood that the 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 provided as examples only.

Pharmaceutically acceptable salts

Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic addition salts of inorganic and organic acids, for example, acetate derived from acetic acid, aconate derived from aconitic acid, ascorbate derived from ascorbic acid, benzenesulfonate derived from benzenesulfonic acid, benzoate, derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enanthate derived from enanthic acid, formate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from from glutamic acid, glycolate derived from glycolic acid, hydrochloride derived from hydrochloric acid, hydrobromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelic acid salt, methanesulfonate derived from methanesulfonic acid, naphthalene-2-sulfonate derived from naphthalene-2-sulfonic acid, nitrate derived from nitric acid, perchlorate derived from perchloric acid, phosphate derived from phosphoric acid, phthalate derived from phthalic acid, salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate derived from succinic acid, sulfate derived from sulfuric acid, tartrate derived from tartaric acid, toluene-p-sulfonate derived from p-toluenesulfonic acid, etc. Such salts can be prepared by methods well known and described in the art.

Other acids, such as oxalic acid, although not themselves pharmaceutically acceptable, may be useful in the preparation of salts as intermediates in the preparation of the chemical compound of the invention and its pharmaceutically acceptable salt.

In yet another embodiment, the compounds of the invention are used in their respective free base form of the present invention.

Metal salts of the chemical compound of the invention include alkali metal salts such as a sodium salt of the chemical compound of the invention containing a carboxyl group.

The chemical compounds of the invention may be presented in unsolvated or solvated forms together with pharmaceutically acceptable solvent(s) such as water, ethanol and the like. Solvated forms may also include hydrated forms such as monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, etc. In general, for purposes of the present invention, solvated forms are considered equivalent to non-solvated forms.

Additional aspects of the present invention are illustrated and explained by reference to the following diagrams, examples, tables, and procedural descriptions, which are provided solely by way of illustration and not by way of limitation of the present invention. The scope of protection of the present invention is limited only by the appended claims.

Tables

The following are links to the attached tables, where

Table 1 shows enzyme assay activity data for CDK1, CDK2, CDK5 and CDK7 for selected compounds of the invention. Inhibition is given as IC ₅₀ with the following symbols: A = IC ₅₀ less than 100 nM; B = IC ₅₀ greater than 100 nM but less than 1000 nM; C = IC ₅₀ greater than 1000 nM. Also shown in Table 1 are selectivity data for CDK1/CDK7, CDK2/CDK7 and CDK5/CDK7 for selected compounds of the invention. Selectivities are reported as CDK1/CDK7*, CDK2/CDK7**, and CDK5/CDK7*** with the following legend: A = greater than 500-fold; B = less than 500 times but more than 50 times; C = less than 50 times.

Table 2 shows activity data in the H460 cell viability assay for selected compounds of the invention. Inhibition is given as IC ₅₀ with the following legend: A = IC ₅₀ less than 1 μM; B = IC ₅₀ greater than 1 µM but less than 10 µM; C = IC ₅₀ greater than 10 µM.

Table 3 shows activity data in the MV4-11 cell viability assay for selected compounds of the invention. Inhibition is given as IC ₅₀ with the following symbols: A = IC ₅₀ less than 1 μM; B = IC ₅₀ greater than 1 µM but less than 10 µM; C = IC ₅₀ greater than 10 µM.

Table 4 provides activity data in the A2780 viability assay for selected compounds of the invention. Inhibition is given as IC ₅₀ with the following legend: A = IC ₅₀ less than 1 μM; B = IC ₅₀ greater than 1 µM but less than 10 µM; C = IC ₅₀ greater than 10 µM.

Table 5 provides activity data in the OVCAR-3 viability assay for selected compounds of the invention. Inhibition is given as IC ₅₀ with the following symbols: A = IC ₅₀ less than 1 μM; B = IC ₅₀ greater than 1 µM but less than 10 µM; C = IC ₅₀ greater than 10 µM.

Table 6 lists compounds 1-88 in terms of their structures and related characteristics.

Examples

The invention will now be further described by reference to the following examples, which are provided by way of illustration and not limitation of the present invention.

Example 1: Enzymatic Assay of CDK1, CDK2, CDK5 and CDK7

Protocol for Enzymatic Binding Assay of CDK1, CDK2, CDK5 and CDK7

The inhibitory activity of the corresponding compound against CDK kinase at the Km value of ATP was tested using a LANCE® Ultra kinase assay based on the fluorescence resonance energy transfer method (Perkin Elmer), which uses a ULight™ labeled peptide substrate and the corresponding europium labeled antiphospholipid antibody. Test compounds were prepared in DMSO solutions and then 4-fold serial dilutions were prepared for 8 doses using an automated liquid handler (POD™ 810, Labcyte), and diluted compound solutions were placed into 384-well plates at a volume of 80 nL/well (Greiner, catalog no. 784075). 68 nM ULight-MBP peptide (Perkin Elmer, Cat. No. TRF0109-M) and ATP in a volume of 5 μl/well (Sigma, Cat. No. A7699) were then added to the plate. After centrifugation for 1 min at 1000 rpm, purified CDK/cyclin complex was added at the following concentrations, respectively. Each corresponding plate for CDK1, CDK2, CDK5 and CDK7 was supplemented with 24 μM for CDK1/cyclin B (Invitrogen, catalog no. PR4768C), 22 μM for CDK2/ cyclin A (Invitrogen, catalog no. PV6290), 10 μM for CDK5/ p25 (Invitrogen, cat. no. PR8543B) and 400 μM for CDK7/cyclin H/MNAT1 (Invitrogen, cat. no. PR6749B). Incubate at 23°C for 60 minutes, then a mixture of europium-labeled antiphospholipid myelin basic protein (PE, cat. no. TRF0201-M) and EDTA (Invitrogen, cat. no. 15575038) in Lance Detection Buffer (Perkin Elmer) was added to each well. , part no. CR97100). After an additional incubation at 23°C for 60 minutes, the fluorescence of the test samples was measured using an Envision leader (Perkin Elmer, USA) [laser as excitation light; APC 615 nm and Europium 665 as the first and second emission filters]. Data were analyzed using XLfit software.

Example 2: Viability Analysis of H460, MV4-11, A2780 and OVCAR-3 Cells

Cell culture

From the American Type Culture Collection (ATCC), we obtained the human T-lymphocyte acute lymphoblastic leukemia cell line MV4-11 (ATCC, catalog no. CRL-9591), the NSCLC (non-small cell lung cancer) cell line H460 (ATCC, catalog no. HTB-177 ), A2780 (ECACC, part no. 93112519) and OVCAR-3 (ATCC, part no. HTB-161). Cells were grown in RPMI-1640 medium (Invitrogen, catalog no. 22400-089) supplemented with 10% fetal bovine serum (Invitrogen, catalog no. 10099141) and 1% penicillin/streptomycin (Invitrogen, catalog no. 15070063) and cultured at 37 °C, 5% CO ₂ in the humidification chamber. All cell lines were routinely tested for mycoplasma.

H460, MV4-11, A2780 and OVCAR-3 cell viability assay protocol

To ensure that the CDK7 inhibitor inhibits the growth of target cancer cells, the viability assay was performed for 72 hours. Schematically, the candidate cell line was seeded in a 96-well plate at the following cell densities, respectively. 1 X 10 ⁴ cells/well for MV4-11, 5 X 10 ³ for H460 and OVCAR-3 and 1 X 10 ³ for A2780. After 24 hours, cells were treated with various concentrations of the compound (from 0.0015 μM to 10 μM). DMSO solvent without compound was used as a control with a final DMSO concentration of less than 0.1%. After 72 hours of incubation at 37°C in a 5% CO ₂ incubator, cell viability was analyzed using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Cat. No. G7570). All viability assays were performed in duplicate, and luminescence values were obtained using Envision (Perkin Elmer, USA). Data were analyzed using XLfit software.

Example 3: Preparation of pyrazole-triazine general framework derivatives

Derivatives of the presented compounds were prepared using the methods described below ( Scheme 1-37 ). The resulting derivatives were tested for enzymatic binding and cellular activity (H460, MV4-11, A2780 and OVCAR-3) using the assays described above (Examples 1 and 2), and the results are summarized in Tables 1-5 . Synthesized compounds 1-88 are shown in Table 6 .

Scheme 1: General mechanism of synthesis 1

The method for preparing compounds of formula I-2, II-3 and III-4 is shown in Scheme 1.

Route I: Compound G10 can be treated with group A in the presence of diisopropylethylamine to give compounds I-1. Compounds I-2 can be treated with HBr/AcOH to obtain compounds of formula I-2.

Route II: Compound G10 can be treated with Group B in the presence of diisopropylethylamine to give Compounds II-1. Compound II-1 can be treated with the group C described in claim 1 in the presence of diisopropylethylamine and acyl chloride to obtain compounds II-2. Compounds II-2 can be treated with HBr/AcOH to obtain compounds of formula II-3.

Route III: Compound G10 can be treated with group D in the presence of diisopropylethylamine to give compounds III-1. Compound III-1 can be treated with trifluoroacetic acid to give compound III-2. Compound III-2 can be treated with Group C, described in claim 1, in the presence of diisopropylethylamine and acyl chloride to obtain compounds III-3. Compounds III-3 can be treated with HBr/AcOH to obtain compounds of formula III-4.

General schemes of group A

Scheme 2: Synthesis mechanism for A7

Synthesis procedure A3

To a solution of compound A2 (2.64 g), diisopropylethylamine (3.07 g, 23.7 mmol) in DCM (40.0 ml) was added 3-nitrobenzoyl chloride A1 (2.20 g, crude) at 0°C. The reaction mixture was stirred at 10°C for 16 hours under N ₂ atmosphere. TLC showed that a new spot had formed. The reaction solution was washed with water (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound A3 (1.96 g) as an off-white powder.

Synthesis procedure A4

To a solution of compound A3 (1.76 g) in methanol (40.0 ml) was added Zn powder (3.10 g, 47.40 mmol) and NH ₄ Cl (2.54 g, 47.4 mmol). The reaction mixture was stirred at 10°C for 1 hour. TLC showed that the reaction was complete. The reaction mixture was poured into saturated aqueous NaHCO ₃ (20 ml) and extracted with ethyl acetate (10 ml x 2). The combined extract was washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give compound A4 (875 mg) as a brown tarry substance.

Synthesis procedure A6

To a solution of compound A4 (775 mg, 2.27 mmol) and diisopropylethylamine (601 mg, 4.65 mmol) in anhydrous THF (10 ml) was added a solution of compound A5 (500 mg, 2.72 mmol) in anhydrous THF (1, 0 ml) drop by drop at 15°C. After stirring at 15°C for 10 minutes, dimethylamine (2M in THF, 7.57 ml) was added. The reaction mixture was stirred at 15°C for 20 minutes. TLC showed that the reaction was complete. The reaction mixture was poured into water (10 ml) and then extracted with ethyl acetate (10 ml x 2). The organic extract was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product as a brown tarry substance. The crude product was purified using a Combi flash system to obtain compound A6 (337 mg) as a light brown tarry substance.

Synthesis procedure A7

To a solution of compound A6 (168 mg) in DCM (2 ml) was added trifluoroacetic acid (500 μl). The reaction solution was stirred at 10°C for 2 hours. TLC showed that the reaction was complete. The mixture was evaporated under reduced pressure. The residue was partitioned between DCM (10 ml) and saturated aqueous NaHCO ₃ (10 ml). The organic and aqueous layer were evaporated under reduced pressure to obtain 130 mg of crude compound A7 . The crude product was used directly in the next step without further purification.

Scheme 3: Mechanism of synthesis of A16 and A18

Synthesis procedure A10

To a solution of compound A8 (2.80 g, 12.5 mmol) in anhydrous DCM (100 ml) was added compound A9 (3.65 g, 18.8 mmol), Cu(OAc) ₂ (3.42 g, 18. 8 mmol) and TEA (3.81 g, 37.6 mmol, 5.22 ml). The reaction mixture was stirred at 15°C for 1 day. TLC showed that compound A13 was consumed. The reaction mixture was filtered. The filtrate was washed with water (20 ml) and evaporated under reduced pressure to obtain a light brown tarry substance. The crude tarry substance was purified using a Combi flash system to obtain compound A10 (629 mg) as a white powder.

Synthesis procedure A11

To a solution of compound A10 (625 mg, 1.68 mmol) in methanol (6 ml) was added NaOH (1 M, 3.36 ml). The reaction mixture was stirred at 15°C for 17 hours. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (5 ml) and neutralized with aqueous HCl (1 M, 3.40 ml), then extracted with DCM (10 ml x 2). The organic layer was washed with water (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain compound A11 (483 mg) as a white powder.

Synthesis procedure A12

To a solution of compound A11 (383 mg, 1.12 mmol), benzyl alcohol (969 mg, 8.96 mmol, 931.67 μl), TEA (453 mg, 4.48 mmol, 621 μl) in dioxane (10 ml) added diphenylphosphoryl azide (339 mg, 1.23 mmol, 267 μl). The reaction solution was refluxed for 2 hours. TLC showed that the reaction was complete. The reaction mixture was partitioned between water (30 ml) and DCM (30 ml). The organic extract was washed with water (10 ml×2), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain a residue. The crude product was purified using a Combi flash system to give compound A12 (1.20 g, crude) as a colorless oily substance. The crude product was used directly in the next step without further purification.

Synthesis procedure A13

To a solution of compound A12 (1.10 g, crude) in methanol (50 ml) was added Pd/C (100 mg, 50% moisture, 10% Pd). The reaction mixture was degassed under vacuum and purged with H ₂ 3 times, then stirred at 15°C for 16 hours under H ₂ (15 psi). TLC showed that the reaction was complete. The reaction mixture was filtered through a celite pad. The filtrate was evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound A13 (210 mg) as a colorless oily substance.

Synthesis procedure A15

To a solution of compound A13 (140 mg, 0.445 mmol), TEA (64 mg, 0.63 mmol) in DCM (2 ml) was added acrylic chloride A14 (61.0 mg, 0.674 mmol) dropwise at 20°C. The reaction solution was stirred at 20°C for 2 hours under N ₂ atmosphere. TLC showed that the reaction was complete. The reaction was quenched with water (5 ml) and then extracted with DCM (10 ml x 2). The combined extract was washed with water (5 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the crude product as a brown tarry substance. The crude product was purified using a Combi flash system to give compound A15 (131 mg) as a brown tarry substance.

Synthesis procedure A16

Compound A15 (130 mg) was treated in the same manner as A7 to obtain 90 mg of Compound A16 as a brown tarry substance.

Synthesis procedure A17

To a solution of compound A13 (210 mg, 0.668 mmol) and diisopropylethylamine (177 mg, 1.37 mmol) in anhydrous THF (5 ml) was added a solution of compound A5 (147 mg, 0.801 mmol) in anhydrous THF (1.0 ml) at drops at 15°C. After stirring at 15°C for 30 minutes, LCMS showed the desired product. The reaction mixture was poured into water (10 ml) and then extracted with DCM (10 ml x 2). The organic extract was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product as a brown tarry substance. The crude product was purified using a Combi flash system to obtain compound A17 (183 mg) as a light brown tarry substance.

Synthesis procedure A18

Compound A17 (180 mg) was treated in the same manner as A7 to obtain 133 mg of Compound A18 as a brown tarry substance.

Scheme 4: Synthesis route for A23

Synthesis procedure A21

To a solution of compound A20 (300 mg, 1.68 mmol) and compound A19 (506 mg, 2.02 mmol) in dioxane (5 ml) and H ₂ O (1 ml) was added Cs ₂ CO ₃ (547 mg, 1. 68 mmol), Pd(dppf)Cl ₂ (123 mg, 0.168 mmol) in an N ₂ atmosphere. The resulting mixture was heated at 100°C and stirred for 1.5 hours to obtain a black suspension. LCMS and TLC showed that the reaction was complete. The reaction was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give compound A21 (240 mg) as a yellow solid.

Synthesis procedure A22

Compound A21 (408 mg) was treated in the same manner as A6 to obtain 184 mg of Compound A22 as a yellow oily substance.

Synthesis procedure A23

Compound A22 (184 mg) was treated in the same manner as A7 to obtain 160 mg of Compound A23 as a yellow oily substance.

General schemes of group B

Scheme 5: General synthesis route for B4

Synthesis procedure B3

To a solution of compound B1 (2.48 g, 8.66 mmol), compound B2 (1.00 g, 7.87 mmol), pyridine-2-carboxylic acid (194 mg, 1.57 mmol) and K ₃ PO ₄ (3.34 g, 15.7 mmol) in DMSO (15 ml) was added CuI (150 mg, 0.787 mmol), the mixture was purged with N ₂ three times and stirred at 90°C for 17 hours to obtain a dark solution. LCMS indicated that the reaction was complete. TLC showed that the reaction was complete. The reaction mixture was poured into water (100 ml), extracted with ethyl acetate (100 ml x 2), the combined extracts were washed with brine (30 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give compound B3 (860 mg) as a light yellow oily substance.

Synthesis procedure B4

To a solution of compound B3 (860 mg, 2.59 mmol) in DCM (7 ml) was added TFA (3 ml), the reaction mixture was stirred at 25°C under N ₂ for 1 hour to obtain a brown solution. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure to obtain compound B4 (800 mg) as a brown tarry substance.

Scheme 6: General synthesis route for B7

Synthesis procedure B6

To a suspension of compound B5 (4.00 g, 25.2 mmol) and Cs ₂ CO ₃ (16.4 g, 50.5 mmol) in DMF (50 ml) was added 3-cyanophenol (3.16 g, 26.5 mmol), the mixture was stirred at 60°C for 17 hours to obtain a brown suspension. LCMS of the crude material (retention time: 1.384 min) indicated that the reaction was complete. The mixture was poured into water (400 ml), a lot of white solid was formed, it was filtered, and the filter cake was washed with water (30 ml x 3) to obtain the crude product. The crude product was purified using a Combi flash system to obtain 1.00 g of B6 as a yellow powder.

Synthesis procedure B7

To a solution of compound B6 (850 mg, 3.52 mmol) and Pd/C (170 mg, 10% Pd) in methanol (10 ml) was added NH ₃ .H ₂ O (1.83 g, 5.21 mmol), the mixture was purged with N ₂ three times and stirred at 20°C in a 15 psi H ₂ cylinder for 1 hour to obtain a brown slurry. LCMS of the crude product indicated that the reaction was complete. The mixture was filtered and the filtrate was evaporated under reduced pressure to obtain 700 mg of compound B7 as a yellow tarry substance.

Scheme 7: General synthesis mechanism for B11

Synthesis procedure B10

To a solution of NaH (1.73 g, 43.4 mmol) in DMF (100 ml) was added 7-nitro-2H-indazole B8 (5.19 g, 31.8 mmol) in several portions at 20°C, the resulting mixture was stirred for 1 hour at 20°C, then 2-fluorobenzonitrile B9 (3.50 g, 28.9 mmol) was added to the mixture, and the reaction mixture was stirred for another 12 hours at 130°C to obtain a black suspension. TLC showed that the reaction was complete. The reaction was quenched by adding H ₂ O (500 ml) and extracted with ethyl acetate (500 ml x 2). The combined organic layers were washed with brine (100 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified and powdered to give B10 (1.80 g) as a black solid.

Synthesis procedure B11

To a solution of compound B10 (200 mg, 0.8 mmol) in methanol (20 ml) and NH ₃ .H ₂ O (1.00 ml, 25%) was added Raney nickel (64.8 mg, 0.8 mmol) in atmosphere N ₂ . The suspension was degassed under vacuum and purged with H ₂ several times. The mixture was stirred under H ₂ (40 psi) at 20° C. for 2 hours to obtain a black slurry. TLC and LCMS showed that the reaction was complete. The reaction mixture was filtered through a celite pad and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give compound B11 (50 mg) as a yellow oily substance.

Scheme 8: General synthesis route for B17

Synthesis procedure B13

To a solution of compound B12 (1.50 g, 9.25 mmol) in methanol (50 ml) was added Zn (6.05 g, 92.5 mmol) and NH ₄ Cl (4.95 g, 92.5 mmol). The resulting mixture was stirred at 20°C for 12 hours to obtain a black suspension. TLC showed that the reaction was complete and one new spot had formed. The reaction mixture was filtered and evaporated under reduced pressure to leave a residue to give 1.80 g of compound B13 as a black solid, which was used in the next step without purification.

Synthesis procedure B14

To a solution of the crude product of compound B13 (1.80 g, 6.81 mmol) in methanol (50 ml) was added triethylamine (689 mg, 6.81 mmol) and Boc ₂ O (2.23 g, 10.2 mmol). The resulting mixture was stirred at 20°C for 12 hours to obtain a black solution. TLC showed that one new spot had formed. The reaction mixture was filtered under reduced pressure to obtain a residue. The residue was purified using a Combi flash system to give compound B14 (781 mg) as a white solid.

Synthesis procedure B16

To a mixture of compound B14 (810 mg, 3.23 mmol), compound B15 (500 mg, 2.15 mmol) in acetic acid (20 ml) was added Pd(OAc) ₂ (241 mg, 1.08 mmol), the mixture was stirred at 40-50°C under O ₂ atmosphere (15 psi) for 12 hours to obtain a black-brown suspension. LCMS (retention time = 1.436 minutes) indicated that the reaction was complete. Acetic acid was removed under reduced pressure, the residue was dissolved in DCM (150 ml) and washed with saturated aqueous NaHCO ₃ solution (100 ml x 3). The organic layer was dried over Na ₂ SO ₄ , filtered, and evaporated under reduced pressure to obtain a black-brown oil. The mixture was purified using a Combi flash system to obtain compound B16 (380 mg) as a yellow tarry substance.

Synthesis procedure B17

To a mixture of compound B16 (380 g, 0.869 mmol) in DCM (30 ml) was added trifluoroacetic acid (8 ml). The mixture was stirred at 15°C for 0.5 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was combined and evaporated under reduced pressure to obtain compound B17 (350 mg) as a yellow oily substance.

Scheme 9: General synthesis route for B23

Synthesis procedure B19

A solution of 2-chloroquinoline B18 (2.00 g, 12.2 mmol) in H ₂ SO ₄ (20 ml) was cooled to 0°C. HNO ₃ (3.55 g, 36.7 mmol) was added dropwise. The reaction solution was stirred at 25°C for 1 hour to obtain a black-brown solution. TLC showed that the reaction was complete. The reaction mixture was poured into water (50 ml), neutralized to pH = 7-8 with saturated Na ₂ CO ₃ . The resulting mixture was extracted with DCM (200 ml x 2). The combined organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified using a Combi flash system to give B19 (1.30 g) as a yellow solid.

Synthesis procedure B21

Cs ₂ CO _{3 (} 1.75 g, 5.36 mmol) and Pd(dppf)Cl ₂ (98.1 mg, 0.134 mmol) in an N ₂ atmosphere. The reaction mixture was heated to 100°C and stirred for 16 hours under N ₂ atmosphere to obtain a black mixture. TLC showed that the reaction was complete. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (200 ml x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound B21 (1.00 g) as a brown solid.

Synthesis procedure B22

Zn (863 mg, 13.2 mmol) was added to a solution of compound B21 (500 mg, 1.32 mmol) and NH ₄ Cl (706 mg, 13.2 mmol) in methanol (10 ml). The reaction mixture was stirred at 25°C for 16 hours to obtain a black-brown mixture. TLC showed that the reaction was complete. The reaction mixture was diluted with methanol (50 ml) and filtered. The filtrate was evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound B22 (500 mg) as a yellow solid.

Synthesis procedure B23

To a mixture of compound B22 (500 mg, 1.43 mmol) in DCM (7 ml) was added trifluoroacetic acid (3 ml). The reaction solution was stirred at 25°C for 1 hour to obtain a red solution. LCMS indicated that the reaction was complete. The reaction mixture was diluted with DCM (10 ml) and evaporated under reduced pressure to give compound B23 (300 mg) as a black-brown oil.

Scheme 10: General synthesis route for B31

Synthesis procedure B25

Isoquinoline-6-amine B24 (2.00 g, 13.87 mmol) was dissolved in pyridine (20 ml) and methylbenzenesulfonyl chloride (3.17 g, 16.64 mmol) was added. The reaction mixture was stirred at 20°C for 12 hours. LCMS indicated that the reaction was complete. Water (30 ml) was added to the reaction mixture with good stirring, the mixture was stirred at 20°C for 0.5 hour, and a pale yellow solid precipitated. The mixture was filtered, the solid was collected and washed with water (5 ml) to obtain compound B25 (2.2 g) as a yellow solid.

Synthesis procedure B26

Compound B25 (2.00 g, 6.70 mmol) was dissolved in CHCl ₃ (30.00 ml). Under ice-cooling (0°C), meta-chloroperoxybenzoic acid (1.71 g, 7.91 mmol) was added thereto, followed by stirring at 20°C for 12 hours. TLC showed that the reaction was complete. The solvent was evaporated and the resulting solid was washed with MTBE (50 ml). The filter cake was collected and dried under high vacuum to give B26 (1.96 g) as a light yellow solid.

Synthesis procedure B27

To a mixture of compound B26 (4.20 g, 13.4 mmol) in CHCl ₃ (120 ml) was added POCl ₃ (45.1 g, 293.9 mmol). The reaction mixture was heated to 61°C and stirred for 16 hours to obtain a black-brown solution. TLC showed that the reaction was complete. The reaction mixture was cooled to 20°C and evaporated under reduced pressure. The residue was poured into water (200 ml) and neutralized to pH = 8-9 with saturated Na ₂ CO ₃ . 300 ml of ethyl acetate was added and the mixture was filtered. The filtrate was collected, separated and the aqueous phase was extracted with ethyl acetate (200 ml x 2). The combined extracts were collected, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give compound B27 (4.00 g) as a yellow solid.

Synthesis procedure B28

A solution of compound B27 (4.00 g, 12.0 mmol) in H ₂ SO ₄ (50 ml) (90%) was stirred at 20°C for 16 hours to obtain a black-brown solution. LCMS indicated that the reaction was complete. The reaction solution was cooled to 0-10°C with ice water (100 ml), neutralized to pH = 7-8 with Na ₂ CO ₃ (solid) and extracted with ethyl acetate (300 ml x 2). The combined extracts were collected, dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give compound B28 (1.80 g) as a red solid.

Synthesis procedure B30

Cs 2 _{CO 3 ( 3} .65 g, 11.2 mmol) and Pd(dppf)Cl ₂ (205 mg, 0.280 mmol) in an N ₂ atmosphere. The reaction mixture was heated to 100°C and stirred for 4 hours under N ₂ atmosphere to obtain a black mixture. TLC showed that the reaction was complete. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (200 ml x 2). The combined extracts were dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound B30 (1.00 g) as a black-brown oily substance.

Synthesis procedure B31

Trifluoroacetic acid (6 mL) was slowly added to a solution of compound B30 (1.00 g, 2.86 mmol) in DCM (14 mL). The reaction solution was stirred at 25°C for 1 hour to obtain a red solution. LCMS indicated that the reaction was complete. The reaction solution was evaporated under reduced pressure to obtain compound B31 (1.00 g) as a black-brown oil, which was used in the next step without further purification.

Scheme 11: General synthesis route for B35

Synthesis procedure B33

To a solution of compound B19 (2.7 g, 12.9 mmol, 1 eq.) and compound 32 (3.15 g, 12.9 mmol, 1.0 eq.) in dioxane (50 ml) and H ₂ O ( 10 ml) added Na ₂ CO ₃ (2.74 g, 25.9 mmol, 2 eq.) and Pd(PPh ₃ ) ₄ (748 mg, 0.65 mmol, 0.005 eq.) under N ₂ atmosphere. The resulting mixture was heated at 80°C and stirred for 12 hours to obtain a yellow suspension. TLC showed that the reaction was complete. The reaction mixture was filtered to obtain a residue as a light yellow solid. The residue was then dissolved in DCM (200 ml) and H ₂ O (200 ml) and extracted with DCM (200 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give compound B33 (3.25 g) as a light yellow solid.

Synthesis procedure B34

To a solution of compound B33 (2.5 g, 8.64 mmol, 1 eq.) in DCM (100 ml) was added Pd/C (1.5 g, 1.75 mmol) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 15°C for 12 hours to obtain a black solution. LCMS indicated that the reaction was complete. The reaction mixture was filtered and evaporated under reduced pressure to give compound B34 (1.96 g) as a yellow solid.

Synthesis procedure B35

To a suspension of LiAlH ₄ (673 mg, 17.7 mmol, 2 eq.) in THF (20 ml) was added a solution of compound B34 (2.3 g, 8.87 mmol, 1 eq.) in THF (10 ml) at 0 °C. The reaction mixture was stirred at 15°C for 1 hour to obtain a red solution. LCMS indicated that the reaction was complete. The mixture was quenched with a saturated solution of NH ₄ Cl. The mixture was partitioned between ethyl acetate and H ₂ O. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine (200 mL), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give B35 (1.53 g, crude) as a brown solid. The crude product was used directly in the next step.

General Group D circuits

Scheme 12: General synthesis route for D3

Synthesis procedure D2

PPh ₃ (730 mg, 2.78 mmol) and diethyl azodicarboxylate (485 mg, 2.78 mmol). The resulting mixture was stirred at 20°C for 12 hours to obtain a yellow solution. LCMS and TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (30 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give D2 (587 mg) as a yellow oily substance.

Synthesis procedure D3

To a solution of compound D2 (587 mg, 1.86 mmol) in methanol (20 ml) and NH ₃ .H ₂ O (1 ml) (28%) was added Raney nickel (159 mg, 1.86 mmol) under N ₂ atmosphere . The suspension was degassed in vacuo and purged with H ₂ several times. The mixture was stirred under H ₂ (15 psi) at 20°C for 2 hours to obtain a black slurry. LCMS indicated that the reaction was complete. The reaction mixture was filtered through a celite pad and evaporated under reduced pressure to give compound D3 (600 mg) as a yellow oily substance.

Scheme 13: General synthesis route for D6

Synthesis procedure D5

To tert-butyl-4-hydroxypiperidine-1-carboxylate (4.82 g, 23.95 mmol) in DMF (50 ml) was added portionwise NaH (1.44 g, 35.92 mmol) at 0 °C. The reaction mixture was stirred at 20°C for 2 hours. Then, 2-fluorobenzonitrile D4 (2.90 g, 23.95 mmol) was added to the above mixture and the reaction mixture was heated to 50°C for 1 hour. TLC showed that the reaction was complete. Saturated NH ₄ Cl (100 ml) was carefully added dropwise to the reaction mixture at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (100 ml x 2). The combined extracts were washed with water (50 ml x 3), brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give compound D5 (9.10 g, crude) as a light yellow oil. .

Synthesis procedure D6

To a solution of Raney nickel (425 mg, 4.96 mmol) and compound D5 (3.00 g, 9.92 mmol) in methanol (90 ml) was added NH ₃ .H ₂ O (6 ml) under N ₂ atmosphere. The suspension was degassed in vacuo and purged with H ₂ three times. The mixture was stirred under H ₂ (15 psi) at 20°C for 4 hours. LCMS indicated that the reaction was complete. The reaction mixture was filtered, and the filtrate was evaporated to remove most of the methanol. The residue was diluted with DCM (100 ml), washed with brine (80 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give D6 (2.90 g) as a light yellow oil.

Scheme 14: General synthesis mechanism 2

The method for preparing compounds of formula IV-5 and IV-6 is shown in Scheme 14.

Route IV: Compound G24 can be treated with group E in the presence of diisopropylethylamine to give compounds IV-1. Compound IV-1 can be treated with m-CPBA to obtain compound IV-2. Compound IV-2 can be treated with Group F in the presence of diisopropylethylamine to give Compounds IV-3. Compound IV-3 can be treated with Pd/C and H ₂ or HCl to give Compound IV-4. Compound IV-4 can be treated with group C, as defined in claim 1, to produce compounds IV-5. Compounds IV-5 can be treated with an acid, such as HCl, to obtain compounds of formula IV-6.

General schemes of group E

Scheme 15: Synthesis route for E10

Synthesis procedure E2

To a solution of compound E1 (93 g, 476 mmol) in DMF (45 ml) was added 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (249 g, 1.43 mmol, 295 ml). The reaction mixture was stirred at 140°C for 3 hours to obtain a brown mixture. TLC showed the presence of a new spot. The mixture was cooled to room temperature and stirred at 0°C for 30 minutes. The solid precipitated. After filtration, the filter cake was washed with ethyl acetate/PE and dried under reduced pressure to obtain compound E2 (69 g) as a purple powder.

Synthesis procedure E3

A solution of E2 (63 g, 252 mmol), (2,4-dimethoxyphenyl)methanamine (63 g, 378 mmol, 57 ml) in toluene (150 ml) was stirred at 35°C for 2 hours to obtain a yellow mixture. The reaction mixture was then stirred at 65°C for 2 hours to obtain a yellow mixture. The reaction mixture was then stirred at 110°C for 3 hours to obtain a yellow mixture. TLC showed the presence of a new spot. The mixture was cooled to 20°C. A yellow solid precipitated. The mixture was filtered. The filter cake was washed twice with PE (50 ml) and dried under high vacuum to give E3 (50 g) as a yellow solid.

Synthesis procedure E4

A solution of E3 (55 g, 162 mmol) in TFA (330 ml) was stirred at 70°C for 16 hours to obtain a purple mixture. TLC showed the presence of a new spot. The reaction mixture was evaporated under reduced pressure to obtain a residue. PE (60 ml) was added to the residue and stirred at 25°C for 2 hours to obtain a purple mixture. After filtration, the filter cake was washed with PE (50 mL), dried under reduced pressure to give E4 (80 g, crude) as a purple solid.

Synthesis procedure E5

A solution of E4 (80 g, 421 mmol) in POCl ₃ (341 ml) was stirred at 100°C for 2 hours to obtain a brown mixture. TLC showed the presence of a new spot. The reaction mixture was evaporated under reduced pressure to obtain a residue. The residue was dissolved in DCM (1000 ml). The organic layer was washed with saturated NaHCO ₃ solution (1000 ml), a solid precipitated. After filtration, the filter cake was washed with DCM (300 ml × 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The residue was purified by column chromatography to give compound E5 (35 g) as a light yellow solid.

Synthesis procedure E7

To a solution of compound E6 (40 g, 183 mmol) in acetonitrile (400 ml) was added N-bromosuccinimide (35.9 g, 202 mmol), benzoyl peroxide (444 mg, 1.83 mmol). The reaction mixture was stirred at 90°C for 4 hours to obtain a brown mixture. LCMS showed the desired MS. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was washed with water (100 ml×4), brine (100 ml×3), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain E7 (57 g, crude) as a brown oil.

Synthesis procedure E8

A mixture of E7 (57 g, 192 mmol) and NaN ₃ (18.8 g, 290 mmol) in DMSO (290 ml) was stirred at 25°C for 16 hours to obtain a brown mixture. LCMS showed the desired MS. The reaction mixture was quenched with NaHCO ₃ (500 ml) and extracted with ethyl acetate (200 ml x 2). The organic layer was washed with water (300 ml×4), brine (300 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain E8 (42 g, crude) as a brown oil.

Synthesis procedure E9

To a solution of compound E8 (12 g, 46.3 mmol) in dioxane (60 ml) and H ₂ O (15 ml) was added E5 (9.66 g, 46.3 mmol), Cs ₂ CO ₃ (30.2 g , 92.6 mmol, 2 eq.) and Pd(dppf)Cl ₂ (1.69 g, 2.32 mmol, 0.05 eq.). The reaction mixture was stirred at 80°C under a protective atmosphere of N ₂ for 5 hours to obtain a black mixture. TLC showed the presence of a new spot. The reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (200 ml x 2). The organic layer was washed with water (100 ml×4), brine (100 ml×2), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by column chromatography to give compound E9 (8 g) as a brown solid.

Synthesis procedure E10

To a solution of compound E9 (8 g, 26.2 mmol, 1 eq.) in THF (80 ml)/H ₂ O (40 ml) was added PPh ₃ (10.3 g, 39.3 mmol, 1.5 eq. ). The reaction mixture was stirred at 60°C for 16 hours to obtain a brown mixture. TLC showed that the reaction was complete. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give compound E10 (7.32 g, crude) as a brown tarry substance.

Scheme 16: Synthesis route for E15

Synthesis procedure E12

To a mixture of E11 (2 g, 8.93 mmol) in pyridine (20 ml) was added Tf ₂ O (3.02 g, 10.71 mmol, 1.77 μl, 1.2 eq.) and at 0 ° C, the mixture was stirred at 0°C for 2 hours to obtain a brown mixture. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic layer was washed with water (20 ml×2), brine (30 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give E12 (2.2 g) as a white solid.

Synthesis procedure E13

Compound E13 (2.2 g) was treated in the same manner as B33 to obtain 1.3 g of Compound E13 as a yellow powder.

Synthesis procedure E14

To a mixture of E13 (600 mg, 1.77 mmol) and NH ₂ Boc (248 mg, 2.12 mmol) in dioxane (10 ml) was added Pd(OAc) ₂ (39.71 mg, 176.89 mmol) and xantphos (204 mg, 353.79 µmol) and Cs ₂ CO ₃ (1.15 g, 3.54 mmol), the mixture was stirred at 100°C for 16 hours to obtain a black mixture. TLC showed that the reagent was consumed. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic layer was washed with water (20 ml×2), brine (30 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to obtain compound E14 (190 mg) as a yellow solid.

Synthesis procedure E15

Compound E14 (400 mg) was treated in the same manner as B11 to obtain 385 mg of Compound E15 as a yellow tarry substance.

Scheme 17: Synthesis Path for E22

Synthesis procedure E16

Compound B12 (10.2 g) was treated in the same manner as B14 to obtain 15.2 g of compound E16 as a yellow powder.

Synthesis procedure E17

To a solution of compound E16 (7 g, 26.7 mmol) in THF (45 ml) was added lithium diisopropylamide (2 M, 20 ml) at -78°C under N ₂ atmosphere. The reaction mixture was stirred at -78°C for 30 minutes. Tributyl(chloro)stannane (10.4 g, 32 mmol, 1.2 eq.) was added to the reaction mixture at -78°C. The reaction mixture was stirred at -78°C for 30 minutes and the reaction mixture was stirred at 15°C for 17 hours to obtain a yellow mixture. TLC showed that the starting material was not completely consumed. A saturated solution of NH ₄ Cl (20 ml) was added to the reaction mixture. The mixture was partitioned between ethyl acetate (300 ml) and H ₂ O (300 ml). The organic extract was washed with saturated NH ₄ Cl solution (300 ml), brine (300 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a yellow resinous substance. The crude product was purified using a Combi flash system to give compound E17 (9.8 g) as a yellow oily substance.

Synthesis procedure E19

To a suspension of compound E18 (1 g, 5.10 mmol) in THF (10 ml) was added BH ₃ •THF (1 M, 15.3 ml) at 0° C. under N ₂ atmosphere. The reaction mixture was stirred at 15°C for 30 minutes to obtain a yellow mixture. LCMS showed that the starting material was not completely consumed. The reaction mixture was stirred at 15°C for 17 hours to obtain a yellow mixture. LCMS showed that the starting material was completely consumed. A small amount of the mixture was purified by preparative TLC to obtain a sample. The reaction was quenched with methanol (4 ml). The reaction mixture was evaporated under reduced pressure to give E19 (1.1 g, crude) as a yellow tarry substance.

Synthesis procedure E20

Compound E19 (1.1 g) was treated in the same manner as B14 to obtain 890 mg of Compound E20 as a colorless oily substance.

Synthesis procedure E21

Compounds E20 (800 mg) and E17 (1.91 g) were treated in the same manner as B33 to obtain 385 mg of compound E21 as a yellow oily substance.

Synthesis procedure E22

Compound E21 (600 mg) was treated in the same manner as A7 to obtain 450 mg of compound E22 as a yellow powder.

General Group F circuits

Scheme 18: Synthesis path for F5

Synthesis procedure F2

To a mixture of compound F1 (3 g, 16.20 mmol) and trimethylsilylformonitrile (1.61 g, 16.20 mmol, 2.03 ml) was added AlCl ₃ (60 mg, 449.97 μmol, 24.59 μl, 2. 78e-2 eq.), and the mixture was heated to 50°C for 20 hours. TLC showed that the reaction was complete. The reaction was quenched with water (10 ml) and then extracted with ethyl acetate (10 ml x 2). The combined organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated in vacuo to give compound F2 (4.6 g) as a yellow solid.

Synthesis procedure F3

To a solution of compound F2 (1 g, 3.52 mmol) in methanol (10 ml) was added K ₂ CO ₃ (52.48 mg, 379.71 μmol). The mixture was stirred at 20°C for 2 hours. TLC showed that the material had disappeared and one large new spot with greater polarity was detected. 8.75 ml of HCl (0.1 M) was added to the reaction mixture, then extracted with ethyl acetate (2×20 ml). The combined organic layer was dried over (Na ₂ SO ₄ ) and evaporated to dryness to give compound F3 (0.74 g) as a yellow oil.

Synthesis procedure F4

A mixture of compound F3 (2.42 g, 11.40 mmol), imidazole (993.59 mg, 14.59 mmol) and tert-butylchlorodimethylsilane (2.06 g, 13.68 mmol, 1.68 ml) in DMF (10 ml) was stirred at 20°C for 14 hours. TLC showed that the material was completely consumed and new spots had formed. The reaction mixture was diluted with water (50 ml) and then extracted with ethyl acetate 100 ml (50 ml x 2). The combined organic layers were washed with 100 ml of aqueous NaCl solution (50 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography eluting (PE:ethyl acetate = 5:1) to give compound F4 (2.44 g) as a colorless oil.

Synthesis procedure F5

To a solution of compound F4 (1 g, 3.06 mmol) in THF (12 ml) was added lithium aluminum hydride (200 mg, 5.27 mmol) at 0°C, which was stirred at 0°C for 0.5 hour to obtain white suspension. TLC showed that the material had disappeared. The reaction mixture was diluted with THF (20 ml) and then quenched with water (0.2 ml), 15% aqueous NaOH (0.2 ml) and water (0.6 ml) at 0°C. The mixture was then stirred at 0°C for 0.5 hours. The mixture was dried over anhydrous Na ₂ SO ₄ then filtered and the filter cake was washed with ethyl acetate (20 ml). The combined filtrate was evaporated under reduced pressure to give compound F5 (870 mg, mixture of 2 trans isomers) as a colorless oily substance.

Scheme 19: Synthesis path for F9

Synthesis procedure F7

To a mixture of F6 (1.7 g, 7.82 mmol), TEA (1.03 g, 10.2 mmol) in DCM (10 ml) was added tosyl chloride (1.57 g, 8.21 mmol, 1.05) at 0°C. The reaction mixture was stirred at 20°C for 17 hours to obtain a yellow solution. LCMS showed that the desired MS value was observed. The reaction mixture was evaporated under reduced pressure. The concentrate was diluted with ethyl acetate (150 ml) and the resulting solution was washed with aqueous HCl (100 ml, pH = 4), aqueous NaOH (1 N, 100 ml), brine (150 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give compound F7 (2.49 g) as a yellow oily substance.

Synthesis procedure F8

To a mixture of F7 (2.3 g, 6.19 mmol) in DMSO (20 ml) was added potassium cyanide (443 mg, 6.81 mmol, 291 μl) and KI (1.54 g, 9.29 mmol), mixture stirred at 80°C for 3 hours and at 100°C for 2 hours to obtain a black mixture. TLC showed that the reagent was consumed. The reaction mixture was quenched with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The organic layer was washed with water (50 ml×2), brine (30 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give F8 (1.19 g) as a yellow oily substance.

Synthesis procedure F9

Raney nickel (227 mg, 2.65 mmol) was added to a solution of F8 (600 mg, 2.65 mmol) in methanol (20 ml), the suspension was degassed under vacuum and purged with H ₂ several times, the mixture was stirred at 25 °C in an atmosphere H ₂ (15 psi) for 16 hours to produce a black mixture. TLC (PE/EA = 1/1) showed that the reaction was complete. The mixture was filtered and evaporated under reduced pressure to give F9 (530 mg, crude) as a yellow oil.

For group E, commercially available reagents such as benzylpiperidin-4-ylcarbamate, tert-butylpiperidin-4-ylcarbamate, tert-butylpiperazine-1-carboxylate, tert-butyl-2-(aminomethyl)morpholine-4-carboxylate, tert-butyl -2-(hydroxymethyl)morpholine-4-carboxylate, tert-butyl-4-aminopiperidine-1-carboxylate, 4-methoxypiperidine, piperidin-4-ylmethanamine, 4-methoxycyclohexane-1-amine, (tetrahydro-2H-pyran-4 -yl)methanamine, morpholine, azepan-4-ol, pyrrolidin-3-ol, 4-aminocyclohexan-1-ol, N-methylpiperidin-4-amine, (1R,4R)-4-(aminomethyl)cyclohexane-1- ol, (1S,3S)-3-aminocyclopentan-1-ol, piperidin-4-ol, 4-(aminomethyl)piperidin-2-one, piperidin-4-ylmethanol, 4-(trifluoromethoxy)piperidine, 4-ethoxypiperidine, 4-isopropoxypiperidine, 4-ethoxycyclohexane-1-amine, 4-methoxycyclohexane-1-amine, 4-isopropoxycyclohexane-1-amine and 3-aminopropan-1-ol.

Scheme 20: General synthesis route 3

The method for preparing compounds of formulas V-5 and V-6 is shown in Scheme 20.

Route V: Compound G3 can be treated with NaOEt to give compound I1. Compound I1 can be treated with POCl ₃ to obtain compound I2. Compound I2 can be treated with group E in the presence of diisopropylethylamine to give compounds V-1. Compound V-1 can be treated with Boc ₂ O to produce compounds V-2. Compound V-2 can be treated with Group F in the presence of tris(dibenzylideneacetone)dipalladium(0) to give compounds V-3. Compound V-3 can be treated with Pd/C and H ₂ or HCl to give Compound V-4. Compound V-4 can be treated with group C, as defined in claim 1, to produce compounds V-5. Compounds V-5 can be treated with an acid, such as HCl, to produce compounds of formula V-6.

Synthesis procedure I1

Na (790 mg, 34.3 mmol) was added to anhydrous EtOH (125 ml) and the mixture was stirred at 10°C for one hour. Compound G3 (3.50 g, 27.9 mmol) and diethyl propanedioate (5.42 g, 33.8 mmol) were added to this solution. The mixture was stirred at 78°C for 16 hours under N ₂ atmosphere to obtain a yellow solution. TLC showed that the reaction was complete. The mixture was evaporated under reduced pressure. The residue was dissolved in water (60 ml) and acidified to pH=3 with 3M HCl, then filtered to give compound I1 (3.70 g) as a white powder.

Synthesis procedure I2

To a mixture of compound I1 (1.30 g, 6.73 mmol) in POCl ₃ (20.6 g, 134 mmol) was added N,N-diethylaniline (672 mg, 4.51 mmol). The mixture was stirred at 100°C for 16 hours under N ₂ atmosphere. TLC showed the presence of a new spot. Most of the POCl ₃ was removed under reduced pressure. The mixture was then poured into H ₂ O (40 ml), extracted with DCM (50 ml x 3). The organic layer was washed with brine (50 ml x 2), dried over anhydrous Na ₂ SO ₄ , then filtered and evaporated under reduced pressure to give compound I2 (3.11 g, crude) as a yellow oil, for use without further purification at next stage.

Scheme 21: Mechanism of synthesis of compound 1 via Pathway I in the general mechanism of synthesis 1

Synthesis procedure G2

To a mixture of diisopropylamine (6.69 g, 66.2 mmol) in anhydrous THF (20 ml) was added n-BuLi (2.5 M, 27.7 ml) at 0°C and stirred at 0°C for 0. 5 hours, then the mixture was cooled to -70°C and G1 (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 hours, then the mixture was poured into a mixture of ethyl formate (4.90 g, 66.2 mmol) in THF (20 ml) at -70°C under N ₂ atmosphere and the resulting mixture was stirred at -70°C for 0.5 hour, then heated to 15°C and stirred at 15°C for 17 hours. TLC (silica gel, PE/ethyl acetate = 2/1) showed that the reaction was complete. The reaction mixture was poured into an aqueous solution of HCl (150 ml, 1M) at 0°C and stirred at 0°C for 0.5 hour, then the mixture was extracted with ethyl acetate (150 ml x 3). The organic layer was washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the filtrate was evaporated 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.

Synthesis procedure G3

To a solution of compound G2 (8.82 g, 67.5 mmol) and acetic acid (7.09 g, 118 mmol) in ethanol (5 ml) was added NH ₂ -NH ₂ .H ₂ O (4.39 g, 87 .7 mmol), the resulting mixture was stirred at 78°C for 17 hours to obtain a pale yellow solution. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure to obtain a residue, then the pH of the residue was adjusted to 9 with aqueous NaOH (1 M), diluted with water (50 ml) and extracted with ethyl acetate (100 ml x 3). The organic layer was washed with brine (150 ml), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was evaporated under reduced pressure to give compound G3 (10.0 g, crude) as a yellow tarry substance. The crude product was used directly in the next step without further purification.

Synthesis procedure G4

To a mixture of compound G3 (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 stirred at -70°C for 1 hour, a large amount of white solid formed. TLC showed that the reaction was complete. The mixture was then allowed to warm to -10°C and filtered, and the filter cake was washed with DCM (15 ml) to obtain 4.50 g of the desired compound as a white solid, the structure was confirmed by proton magnetic resonance. The filtrate was purified by silica gel column chromatography to give compound G4 (1.80 g) as a white solid.

Synthesis procedure G5

To a mixture of compound G4 (6.30 g, 24.6 mmol) in MeCN (50 ml) was added K ₂ CO ₃ (6.79 g, 49.2 mmol), the mixture was stirred at 80°C for 8 hours. LCMS of the crude product indicated that the reaction was complete. The mixture was cooled to room temperature, then acetic acid (15 ml) was added to the mixture and stirred at 15°C for 20 minutes, then the resulting mixture was evaporated under reduced pressure to obtain a residue, which was washed with water (50 ml x 3) to obtain the compound G5 (4.20 g) as a white solid.

Synthesis procedure G6

To a mixture of compound G5 (4.20 g, 20.0 mmol) in ethanol (40 ml) was added NaOH (2.00 g, 50.0 mmol) in H ₂ O (20 ml) at 15°C, then to the above iodomethane (2.84 g, 20.0 mmol) was added to the mixture and the resulting mixture was stirred at 15°C for 2 hours. LCMS of the crude product indicated that the reaction was complete. The mixture was evaporated under reduced pressure to leave a residue, which was treated with ice water (50 ml) and aqueous HCl (20 ml, 6 M) for 30 minutes to form a large white solid, which was filtered to give the crude product. The crude product was poured into acetonitrile (50 ml) to obtain a suspension, then the suspension was evaporated under reduced pressure to obtain compound G6 (3.60 g) as a white solid.

Synthesis procedure G7

To a mixture of compound G6 (1.00 g, 4.46 mmol) in DCM (30 ml) was added meta-chloroperoxybenzoic acid (3.07 g, 14.2 mmol) portionwise at 20°C. The reaction mixture was stirred at 20°C for 2 hours. LCMS indicated that the reaction was complete. The reaction mixture was diluted with a solution of a mixture of brine (20 ml) and NaOH/H ₂ O (3M, 10 ml). The aqueous layer was separated and the pH was adjusted to 1 with HCl (3M). A large amount of white powder precipitated. The mixture was then extracted with ethyl acetate (50 ml x 2). The organic layer was washed with brine (20 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give G7 (1.03 g) as a light brown tarry substance.

Synthesis procedure G9

To a solution of compound G7 (6.62 g, 25.83 mmol) in n-methyl-2-pyrrolidone (100 ml) was added compound G8 (18.15 g, 77.5 mmol). The reaction mixture was stirred at 140°C for 16 hours. TLC showed that the reaction was complete. The reaction mixture was partitioned between brine (500 ml) and ethyl acetate (400 ml). The organic layer was washed with water (100 ml×2), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain a residue. The residue was purified using a Combi flash system to give a brown tarry substance which was triturated with CH ₃ CN (50 ml) to give compound G9 (2.06 g) as an off-white powder.

Synthesis procedure G10

To a mixture of compound G9 (89 mg, 0.22 mmol) in POCl ₃ (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 evaporated under reduced pressure to obtain G10 (93 mg) as a brown tarry substance as a crude product. The crude product was used directly in the next step without further purification.

Synthesis procedure G11

To a solution of compound G10 (127 mg, 0.297 mmol), diisopropylethylamine (95.9 mg, 0.742 mmol) in DMF (2 ml) was added compound A7 (131 mg, 0.371 mmol). The reaction solution was stirred at 10°C for 1 hour. LCMS showed the desired MS value. The reaction mixture was partitioned between ethyl acetate (20 ml) and saturated aqueous NaHCO ₃ solution (20 ml). The organic layer was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound G11 (103 mg) as a brown tarry substance.

Compound synthesis procedure 1

To a solution of compound G11 (70 mg, 0.094 mmol) in AcOH (0.5 ml) was added HBr/AcOH (0.5 ml, purity 35%) at 15°C. This reaction solution was stirred at 15°C for 1 hour to obtain a light brown solution. LCMS indicated that the reaction was complete. The reaction mixture was diluted with 5 ml of MTBE to precipitate a gray powder, which was collected by filtration. The solid was dissolved in methanol (4 ml), then a drop of aqueous ammonia solution (28%) was added to make the solution alkaline. The crude product, dissolved in methanol, was purified by preparative HPLC. The eluent containing the desired product was evaporated under reduced pressure and the residue solution was lyophilized to obtain Compound 1 (9.9 mg) as a white powder.

Scheme 22: Mechanism for the synthesis of compound 9 via Pathway I in the overall synthesis mechanism 1

Synthesis procedure G12

To a solution of compound A23 (183 mg, 0.385 mmol) in CH ₃ CN (10 ml) was added diisopropylethylamine (226 mg, 1.75 mmol) and compound G10 (150 mg, 0.35 mmol). The resulting mixture was stirred at 20°C for 1 hour to obtain a white suspension. TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (10 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give compound G12 (75 mg) as an off-white solid.

Compound synthesis procedure 9

A solution of compound G12 (30 mg, 0.4 mmol) in HBr/acetic acid 35% (1 ml) was stirred at 20°C for 1 hour to obtain a yellow solution. TLC showed that the reaction was complete. MTBE (50 ml) was added to the reaction mixture and a large amount of solid precipitated, the mixture was filtered under reduced pressure to obtain an off-white solid as a filter cake. The filter cake was purified by preparative HPLC. Most of the solvent was evaporated from the residue and the residue was lyophilized to give compound 9 (7.8 mg) as a white powder.

Scheme 23: Mechanism for the synthesis of compound 16 via Pathway II in the general synthesis mechanism 1

Synthesis procedure G13

Diisopropylethylamine (27.1 mg, 0.2 mmol) was added to a solution of compound B11 (50 mg, 0.2 mmol) and compound G10 (90 mg, 0.2 mmol) in CH ₃ CN (5 ml). The resulting mixture was stirred at 0°C for 30 minutes to obtain a red solution. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure to obtain a residue. The residue was purified using a Combi flash system to give compound G13 (100 mg) as a yellowish solid.

Synthesis procedure G14

To a solution of compound G13 (100 mg, 0.158 mmol) in THF (5 ml) was added compound A5 (58.2 mg, 0.317 mmol) and diisopropylethylamine (82 mg, 0.634 mmol), the resulting mixture was stirred at 20°C for 1 hour to obtain a red solution. LCMS indicated that the reaction was complete. Dimethylamine (71.5 mg, 1.59 mmol) was added to the mixture, then stirred for an additional 3 hours at 20°C to obtain a red solution. TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using Combi flash to give 100 mg of material (crude), which was purified to give compound G14 (50 mg) as a yellow solid.

Compound synthesis procedure 16

A solution of compound G14 (50 mg, 67.4 μmol) in HBr/HOAc (35%) (1 ml) was stirred at 20°C for 30 minutes to obtain a red solution. LCMS indicated that the reaction was complete. MTBE (3 ml) was added to the reaction mixture and a yellow tarry substance precipitated. The yellow tarry substance was collected by filtration and washed with MTBE (3 ml x 2). The yellow tarry substance was dissolved in methanol (2 ml) and purified with a cation exchange resin eluting with 5% NH ₃ .H ₂ O/methanol, then lyophilized to give compound 16 (29.9 mg) as a yellow solid.

Scheme 24: Mechanism for the synthesis of compound 25 via Pathway II in the general synthesis mechanism 1

Synthesis procedure G15

To a solution of compound B17 (403 mg, 0.866 mmol) in MeCN (5 ml) was added diisopropylethylamine (976 μl), compound G10 (338 mg, 0.787 mmol). The mixture was stirred at 15°C for 0.5 hour to obtain a yellow mixture. TLC showed that the reaction was complete. The mixture was partitioned between DCM (50 ml x 2) and water (50 ml), the mixture was extracted with DCM (50 ml x 2), the combined extract was washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered, evaporated under reduced pressure with yielding a yellow oily substance, which was purified by the Combi flash system to obtain compound G15 (250 mg) as a brown oily substance.

Synthesis procedure G16

To a solution of compound G15 (250 mg, 0.397 mmol) in THF (5 ml) were added diisopropylethylamine (0.257 mg, 1.98 mmol) and compound A5 (218 mg, 1.19 mmol). The yellow mixture was stirred at 15°C for 1 hour. The color of the mixture changed to black. LCMS indicated that the reaction was complete. Dimethylamine (2 M, 992 μl) was added to the mixture and stirred at 15°C for 1 hour to obtain a black-brown mixture. LCMS indicated that the reaction was complete. The mixture was partitioned between DCM (50 ml) and water (30 ml). The aqueous solution was extracted with DCM (50 ml x 2), the combined extracted phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain a brown oil, which was purified by a Combi flash system to obtain compound G16 (250 mg) as a brown tarry substance.

Compound synthesis procedure 25

A mixture of compound G16 (250 mg, 0.337 mmol) in HBr/HOAc (3 ml) was stirred at 15°C for 0.5 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. MTBE (10 ml) was added to the reaction mixture to precipitate a yellow powder. The white powder was collected by filtration and washed with MTBE (5 ml × 2), basified with saturated Na ₂ CO ₃ solution to pH = 9-10 and extracted with DCM (50 ml × 2), the combined organic phase was washed with water (50 ml), dried over anhydrous Na ₂ SO ₄ was filtered and evaporated under reduced pressure to give a yellow oily substance, which was purified by preparative HPLC (0.1% TFA), made alkaline with saturated Na ₂ CO ₃ solution to pH = 9-10 and extracted with DCM (50 ml x 3 ), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain compound 25 (30 mg) as a white powder.

Scheme 25: Mechanism for the synthesis of compound 20 via Pathway II in the general synthesis mechanism 1

Synthesis procedure G17

To a solution of compound B23 (230 mg, 0.633 mmol) in CH ₃ CN (5 ml) was added diisopropylethylamine (818 mg, 6.33 mmol) and compound G10 (299 mg, 0.696 mmol) at 0-5°C. The reaction solution was stirred at 25°C for 1 hour to obtain a black-brown solution. LCMS showed the desired MS value. The reaction mixture was diluted with DCM (30 ml) and evaporated under reduced pressure. The residue was partitioned between water (50 ml) and DCM (100 ml). The separated organic layer was washed with water (80 ml), brine (80 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound G17 (150 mg) as a yellow oily substance.

Synthesis procedure G18

To a solution of compound G17 (200 mg, 0.312 mmol) in THF (5 ml) were added diisopropylethylamine (201 mg, 1.56 mmol) and compound A5 (172 mg, 0.935 mmol). The reaction solution was stirred at 25°C for 30 minutes to obtain a black-brown solution. Dimethylamine (2M, 1.56 µl) was then added and stirred for another 16 hours to obtain a black-brown solution. LCMS and TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure. The residue was partitioned between DCM (150 ml) and water (100 ml). The organic layer was washed with water (100 ml), brine (100 ml) and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound G18 (100 mg) as a yellow oily substance.

Compound synthesis procedure 20

A solution of compound G18 (150 mg, 0.199 mmol) in HBr/HOAc (2 mL, 35%) was stirred at 25°C for 0.5 hour to obtain a red solution. LCMS indicated that the reaction was complete. 10 ml of MTBE was added and the resulting white mixture was filtered. The filter cake was collected, washed with MTBE (20 ml), dissolved in methanol (3 ml) and basified with cation exchange resin to give compound 20 (46.6 mg) as a yellow powder.

Scheme 26: Mechanism of synthesis of compound 11 via Pathway II in the general mechanism of synthesis 1

Synthesis procedure G19

To a solution of compound B31 (400 mg, 0.933 mmol) in CH ₃ CN (10 ml) was added diisopropylethylamine (362 mg, 2.80 mmol) and compound G10 (500 mg, 1.38 mmol) at 0-10°C. The reaction solution was stirred at 25°C for 1 hour to obtain a brown solution. LCMS of the crude product indicated that the reaction was complete. TLC showed the formation of a new spot. The reaction solution was evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound F19 (380 mg) as a yellow tarry substance.

Synthesis procedure G20

To a solution of compound G19 (380 mg, 0.600 mmol) in THF (5 ml) was added a solution of compound A5 (330 mg, 1.80 mmol) in THF (2 ml) at 0-5°C in an ice bath. The reaction solution was stirred at a temperature of 0-25°C for 0.5 hours. Dimethylamine (2M, 3 µl, 10 eq) was added and stirred for another 2 hours to give a black-brown solution. LCMS of the crude product indicated that the reaction was complete. TLC showed that the reaction was complete. The reaction solution was evaporated under reduced pressure. The residue was dissolved in DCM (200 ml), washed with saturated NH ₄ Cl solution (100 ml), water (100 ml) and brine (100 ml), the organic layer was dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The residue was purified using a Combi flash system to give compound G20 (130 mg) as a yellow solid.

Compound synthesis procedure eleven

A solution of compound G20 (70 mg, 0.093 mmol) in HBr/HOAc (1 ml, 35%) was stirred at 25°C for 0.5 hour to obtain a yellow solution. LCMS showed the desired MS value. 10 ml of MTBE was added and the resulting mixture was filtered to obtain a white solid. The solid was dissolved in methanol (2 ml), purified with cation exchange resin and lyophilized to give a white powder, which was further purified by preparative HPLC. The fraction was evaporated under reduced pressure. The residue was neutralized to pH 7-8 with K ₂ CO ₃ (solid). The resulting white mixture was extracted with ethyl acetate (50 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , evaporated and lyophilized to give compound 11 (23.1 mg) as a white powder.

Scheme 27: Mechanism for the synthesis of compound 18 via Pathway III in the general synthesis mechanism 1

Synthesis procedure G21

Diisopropylethylamine (181 mg, 1.40 mmol) was added to a solution of compound D3 (300 mg, 0.7 mmol) and compound G10 (448 mg, 1.40 mmol) in CH ₃ CN (20 ml). The resulting mixture was stirred at 20°C for 1 hour to obtain a yellow solution. LCMS indicated that the reaction was complete. The reaction mixture was evaporated under reduced pressure to give a residue, TLC. The residue was purified using a Combi flash system to give compound G21 (240 mg) as a yellow oily substance.

Synthesis procedure G22

To a mixture of compound G21 (240 mg, 0.34 mmol) in DCM (7 ml) was added trifluoroacetic acid (4.62 g, 40.5 mmol). The resulting mixture was stirred at 20°C for 1 hour to obtain a yellow solution. TLC and LCMS showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure to obtain compound G22 (268 mg) as a yellow oily substance.

Synthesis procedure G23

To a solution of compound G22 (268 mg, 0.37 mmol) in THF (20 ml) was added diisopropylethylamine (143 mg) and compound A5 (67.6 mg, 0.37 mmol), the resulting mixture was stirred at 20°C for 1 hours. LCMS indicated that the reaction was complete. Dimethylamine (83.1 mg, 1.84 mmol) was then added to the mixture and stirred for an additional 2 hours to obtain a yellow suspension. TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml). The organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified using a Combi flash system to give compound G23 (74 mg) as a yellow oily substance.

Compound synthesis procedure 18

A solution of compound G23 (74.0 mg, 0.1 mmol) in HBr/HOAc 35% (1 ml) was stirred at 20°C for 1 hour to obtain a yellow solution. LCMS indicated that the reaction was complete. MTBE (3 ml) was added to the reaction mixture and a white tarry substance precipitated. The tarry solid was collected by filtration and washed with MTBE (3 ml x 2). The white tarry substance was dissolved in methanol (2 ml) and purified with cation exchange resin (PCX-SPE (deoxyguanidinoproclavamic acid solid phase extraction)) eluting with 5% NH ₃ .H ₂ O/methanol, the streams were evaporated and lyophilized to give compound 18 (42 .9 mg) in the form of a white powder.

Scheme 28: Mechanism of synthesis of compound 44 via Pathway IV in general synthesis mechanism 2

Synthesis procedure G24

To a mixture of compound G6 (1.00 g, 4.46 mmol) in POCl ₃ (14 ml) was added N,N-diethylaniline (2.00 g, 13.4 mmol) at 15°C, the mixture was stirred at 90°C within 3 hours. The mixture was evaporated under reduced pressure to give G24 (3.20 g, crude) as a brown tar, which was used in the next step without further purification.

Synthesis procedure G25

To a solution of E10 (7.32 g, 26.2 mmol) in MeCN (70 ml) was added diisopropylethylamine (6.77 g, 52.4 mmol, 9.13 ml), G24 (6.36 g, 26.2 mmol ). The reaction mixture was stirred at 25°C for 16 hours to obtain a brown mixture. TLC showed the presence of a new spot. The reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (100 ml x 2). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain a residue. The residue was purified by column chromatography to give G25 (11.3 g) as a yellow solid.

Synthesis procedure G26

To a mixture of compound G25 (11.3 g, 23.2 mmol) in DCM (110 ml) was added meta-chloroperbenzoic acid (10.0 g, 46.5 mmol, purity: 80%) at 0-10°C, mixture stirred at 0-10°C for 2 hours to obtain a yellow mixture. LCMS showed that the reaction was not complete. The mixture was stirred at 0-10°C for another 1 hour to obtain a yellow mixture. LCMS indicated that the desired product was observed. The mixture was partitioned between DCM (100 ml) and saturated aqueous Na ₂ SO ₃ (100 ml). The aqueous phase was extracted with DCM (100 ml x 2). The combined organic extract was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give G26 (6.6 g) as a yellow solid.

Synthesis procedure G27

Diisopropylethylamine (135 mg, 1.04 mmol) was added to a solution of 4-methoxycyclohexanamine (71.9 mg, 0.556 mmol) and G26 (180 mg, 0.348 mmol) in n-methyl-2-pyrrolidone (1 ml). The resulting mixture was heated at 110°C and stirred for 12 hours to obtain a brown solution. LCMS and TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (30 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1:1) to give compound G27 (105 mg) as an orange-yellow solid.

Synthesis procedure G28

Compound G27 (105 mg) was treated in the same manner as B7 to obtain 110 mg of Compound G28 as a yellow solid.

Compound synthesis procedure 44

To a solution of G28 (110 mg, 0.172 mmol) in n-methyl-2-pyrrolidone (2 ml) was added (E)-4-(dimethylamino)but-2-enoyl chloride (3 M, 172 μl) at 0°C to obtain the mixture was stirred at 15°C for 12 hours to obtain a yellow solution. LCMS showed that most of the starting material had been consumed. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified by preparative HPLC then evaporated to give compound 44 (21 mg) as a light yellow solid.

Scheme 29: Mechanism of synthesis of compound 79 via Path IV in general synthesis mechanism 2

Synthesis procedure G29

Diisopropylethylamine (149.83 mg, 1.16 mmol, 201.93 µl). The resulting mixture was heated at 110°C and stirred for 2 hours to obtain a yellow solution. LCMS and TLC showed that the reaction was complete. The reaction mixture was quenched by adding H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (30 ml x 3), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography to give compound G29 (285 mg) as a yellow solid.

Synthesis procedure G30

Compound G29 (285 mg) was treated in the same manner as B7 to obtain 258 mg of Compound G30 as a yellow solid.

Synthesis procedure G31

To a solution of 2-fluoroprop-2-enoic acid (16.38 mg, 181.90 µmol) in DMF (2 ml) added TEA (46.02 mg, 454.76 µmol, 63.30 µl) and HATU (1- [bis(dimethylamino)methylene]-1H-1,2.3-triazolo[4,5-b]pyridinium-3-oxide-hexafluorophosphate) (69.17 mg, 181.90 µmol), then compound G30 (90 mg, 151.59 µmol) and stirred at 15°C for 2 hours to obtain a brown solution. LCMS indicated that some of the starting material remained, the reaction mixture was stirred at 15°C for another 2 hours to obtain a brown solution. LCMS showed that the reaction was almost complete. The reaction mixture was poured into water (15 ml) and the yellow suspension was filtered. The filter cake was washed with PE (10 ml) and dried to give G31 (100 mg) as a yellow solid.

Compound synthesis procedure 79

A mixture of compound G31 (100 mg) in 4 M HCl/methanol (2 ml) was stirred at 15°C for 1 hour to obtain a yellow solution. LCMS and TLC showed that the reaction was successful. The solvent was removed under reduced pressure to obtain the crude product. It was purified by preparative HPLC, most of the solvent was removed under reduced pressure, and the remaining solvent was removed by lyophilization to give compound 79 (34.7 mg) as a yellow solid.

Scheme 30: Mechanism of synthesis of compound 58 via Pathway IV in general synthesis mechanism 2

Synthesis procedure G32

Diisopropylethylamine (249 mg, 1.93 mmol, 336 μl) and the mixture was stirred at 110°C for 16 hours to obtain a brown mixture. LCMS indicated that the reaction was complete. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic layer was washed with water (20 ml×2), brine (30 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give compound G32 (520 mg) as a red solid.

Synthesis procedure G33

Compound G32 (520 mg) was treated in the same manner as B7 to obtain 450 mg of Compound G33 as a yellow solid.

Synthesis procedure G34

To a solution of compound G33 (50 mg, 82 µmol, 1 equiv.) in THF (2 ml) was added a solution of compound A5 (330 mg, 164 µmol, 2 equiv.) in THF (2 ml) at 0-5 ° C in ice bath. The reaction solution was stirred at a temperature of 0-25°C for 1.5 hours. 2-(methylamino)acetamide (21 mg, 246 μmol, 3 eq.) and diisopropylethylamine (10 mg, 82 μmol, 14 μl, 1 eq.) were added and stirred for an additional 16 hours to obtain a black-brown solution. LCMS indicated that the desired product was observed. The reaction mixture was quenched with water (20 ml) and extracted with ethyl acetate (20 ml x 2). The organic layer was washed with water (20 ml×2), brine (30 ml×4), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC to give compound G34 (22 mg) as a white powder.

Compound synthesis procedure 58

Compound G34 (22 mg) was treated in the same manner as compound 79 to obtain 3 mg of compound 58 as a yellow solid.

Scheme 31: Mechanism for the synthesis of compound 81 via Pathway V in the overall synthesis mechanism 3

Synthesis procedure G35

To a solution of compound E10 (728 mg, 2.61 mmol) and compound I2 (500 mg, 2.17 mmol) in ethanol (10 ml) was added diisopropylethylamine (561 mg, 4.35 mmol, 0.757 ml, 2 eq.). The resulting mixture was stirred at 75°C for 12 hours to obtain a brown solution. TLC showed that the reaction was complete. The reaction mixture was evaporated under reduced pressure to obtain a residue. The reaction mixture was diluted with H ₂ O (50 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography to give compound G35 (948 mg) as a brown tarry substance.

Synthesis procedure G36

Compound G35 (948 mg) was treated in the same manner as B14 to obtain 930 mg of Compound G36 as a yellow solid.

Synthesis procedure G38

To a mixture of compound G36 (200 mg, 349 µmol) and compound G37 (90.19 mg, 698 µmol) in toluene (5 ml) was added Pd ₂ (dba) ₃ (31.9 mg, 34.9 µmol), t- BuONa (50.3 mg, 523 µmol, 1.5 eq.) and BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (21.7 mg, 34.9 µmol), and mixture stirred at 95°C for 4 hours to obtain a yellow mixture. LCMS showed that the reaction was not complete. The mixture was stirred at 95°C for 6 hours to obtain a red mixture. TLC showed that the reaction was complete. The mixture was partitioned between ethyl acetate (15 ml) and water (10 ml). The aqueous phase was extracted with ethyl acetate (10 ml x 2). The combined organic extract was washed with brine (130 ml), dried over Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system to give compound G38 (130 mg) as a yellow solid.

Synthesis procedure G39

Compound G38 (130 mg) was treated in the same manner as B7 to obtain 110 mg of Compound G39 as a yellow solid.

Synthesis procedure G40

Compound G39 (100 mg) was treated in the same manner as G31 to obtain 70 mg of compound G40 as a yellow solid.

Compound synthesis procedure 81

Compound G40 (70 mg) was treated in the same manner as compound 79 to obtain 18 mg of compound 81 as a yellow solid.

Exceptional synthesis mechanism

Scheme 32: Synthesis mechanism for compound 22

H2 synthesis procedure

To a mixture of compound H1 (214 mg, 1.75 mmol), diisopropylethylamine (1 ml) in MeCN (10 ml) was added compound G10 (500 mg, 1.17 mmol). The reaction solution was stirred at 20°C for 1 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. The reaction mixture was partitioned between DCM (100 ml) and water (80 ml). The aqueous phase was extracted with DCM (80 ml x 2). The combined extract was washed with brine (80 ml x 2), dried over anhydrous Na ₂ SO ₄ and filtered, then evaporated under reduced pressure to give the crude product as a yellow oily substance, which was purified by a Combi flash system to give compound H2 (500 g) in in the form of a yellow resinous substance.

Synthesis procedure H4

To a mixture of compound H2 (200 mg, 0.822 mmol) in DMF (5 ml) was added HATU (391 mg, 1.03 mmol), TEA (139 mg, 1.37 mmol) and stirred at 20°C for 30 minutes. Compound H3 (352 mg, 0.685 mmol) was then added to the mixture and stirred at 60°C under N ₂ for 5 hours to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was cooled to temperature and poured into water (50 ml). A yellow solid precipitated from the mixture. The mixture was filtered and the filter cake washed with water (50 ml) to obtain the crude product as a yellow powder, which was purified using a Combi flash system to obtain compound H4 (302 mg) as a yellow tarry substance.

Synthesis procedure H5

Compound H2 (300 mg) was treated in the same manner as A7 to obtain 290 mg of Compound H5 as a yellow tarry substance.

Synthesis procedure H6

Compound H5 (200 mg) was treated in the same manner as A6 to obtain 101 mg of Compound H6 as a yellow oily substance.

Compound synthesis procedure 22

A mixture of compound H6 (100 mg, 0.133 mmol) in HBr/HOAc (2 mL, 35%) was stirred at 20°C for 1 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. MTBE (10 ml) was added to the reaction mixture to precipitate a non-pure white powder. The white powder was collected by filtration and washed with MTBE (5 mL x 2), then purified by preparative HPLC (0.1% TFA), then basified _with cation exchange resin eluting with 5% _NH3.H2O /methanol to give compound 22 (15 mg) in the form of a white powder.

Scheme 33: Synthesis mechanism for compound 21

H8 synthesis procedure

To a mixture of compound H2 (207 mg, 0.972 mmol), compound H7 (500 mg, 0.972 mmol) in DCM (8 ml) was added AcOH (58.3 mg, 0.972 mmol). The mixture was stirred at 20°C for 1 hour, then NaBH(OAc) ₃ (309 mg, 1.46 mmol) was added to the mixture and stirred at 20°C for 24 hours. LCMS showed the desired MS value. The mixture was partitioned between DCM (50 ml) and saturated NaHCO ₃ solution (50 ml). The DCM phase was washed with NaHCO ₃ (50 ml x 2) and dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure to give a yellow oily substance, which was purified by the Combi flash system to obtain compound H8 (200 g) as a yellow oily substance .

Synthesis procedure H9

To a mixture of compound H8 (200 mg, 0.281 mmol) in DCM (5 ml) was added trifluoroacetic acid (1 ml). The mixture was stirred at 20°C for 2 hours to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was combined and evaporated under reduced pressure to give H9 (200 mg) as a yellow oily substance.

Synthesis procedure H10

To the compound solutionH9 (200 mg, 0.276 mmol) in THF (5 ml) added diisopropylethylamine (178 mg, 1.38 mmol), compoundA5 (152 mg, 0.827 mmol). The yellow mixture was stirred at 25°C for 1 hour, after which it turned black. LCMS indicated that the reaction was complete. Dimethylamine (2 M, 689 μL) was added to the mixture and stirred at 25°C for 1 hour to obtain a brown mixture. LCMS showed the desired MS value. The mixture was partitioned between DCM (50 ml) and water (30 ml). The aqueous phase was extracted with DCM (50 ml x 2). The combined extracted phase was washed with brine (30 ml), dried over anhydrous Na₂SO₄, filtered, evaporated under reduced pressure to obtain a brown oily substance, which was purified by a Combi flash system to obtain the compoundH10 (180 g) as a brown oily substance.

Compound synthesis procedure 21

A mixture of compound H10 (180 mg, 0.249 mmol) in HBr/HOAc (2.00 ml, purity: 35%) was stirred at 20°C for 1 hour to obtain a yellow mixture. TLC showed that the reaction was complete. MTBE (10 ml) was added to the reaction mixture to precipitate a non-pure white powder. The white powder was collected by filtration and washed with MTBE (5 mL x 2). The crude product was purified by preparative HPLC to give compound 21 (16.2 mg) as a white powder.

Scheme 34: Synthesis mechanism for compound 12

Synthesis procedure H12

( 4 -Methoxyphenyl)methanamine (475 mg, 3.46 mmol). The reaction mixture was stirred at 135°C for 24 hours under N ₂ atmosphere. The mixture was cooled to room temperature, water (50 ml) was added to the reaction mixture and extracted with MTBE (30 ml x 3), the combined organic phase was washed with water (20 ml) and brine (20 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to give H12 (910 g) as a red solid.

Synthesis procedure H13

To the compound solutionH12 (500 mg, 1.46 mmol) added Zn(CN) to DMA (5 ml)₂ (103 mg, 0.876 mmol), Pd₂(dba)₃ (134 mg, 0.146 mmol), DPPF (1,1'-bis(diphenylphosphino) ferrocene) (162 mg, 0.292 mmol) and Zn (15.28 mg, 0.234 mmol). The reaction mixture was stirred at a temperature of 150°C in a microwave oven for 0.5 hours in an atmosphere of N₂. LCMS indicated that the reaction was complete. The mixture was partitioned between water (30 ml) and ethyl acetate (30 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined extracts were washed with brine (50 ml), dried over anhydrous Na₂SO₄, filtered and evaporated under reduced pressure to obtain the compound, which was purified by a Combi flash system to obtain the compoundH13 (300 g) in the form of a red resinous substance.

Synthesis procedure H14

To a mixture of Raney nickel (100 mg) in MeOH (30 ml) was added compound H13 (500 mg, 1.73 mmol) and NH ₃ .H ₂ O (2.5 ml, 25%). The suspension was degassed under vacuum and purged with H ₂ several times, the mixture was stirred at 25° C. under an atmosphere of H ₂ (15 psi) for 3 hours to obtain a black mixture. TLC showed that the reaction was complete. The mixture was filtered and the filtrate was evaporated under reduced pressure to obtain H14 (400 mg) as a yellow tarry substance.

Synthesis procedure H15

To a solution of compound H14 (90.0 mg, 0.307 mmol), diisopropylethylamine (165 mg, 1.28 mmol) in acetonitrile (1 ml) was added compound G10 (110 mg, 256 mmol). The reaction solution was stirred at 25°C for 1 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was partitioned between DCM (30 ml) and water (20 ml). The aqueous phase was extracted with DCM (30 ml x 2). The combined extract was washed with brine (30 ml x 2), dried over anhydrous Na ₂ SO ₄ and filtered, then evaporated under reduced pressure to obtain the crude product as a yellow oily substance. The crude product was purified using a Combi flash system to obtain H15 (100 mg) as a yellow tarry substance.

Synthesis procedure H16

A mixture of compound H15 (100 mg, 0.146 mmol) in TFA (1 ml) was stirred at 25°C for 3 hours, LCMS showed that a large amount of starting material still remained; the mixture was heated to 60°C for 12 hours. LCMS showed the desired MS value, then the mixture was heated to 80°C for 14 hours to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was partitioned between DCM (50 ml) and saturated NaHCO ₃ solution (30 ml). The aqueous phase was extracted with DCM (50 ml x 2). The combined extract was washed with brine (30 ml x 2), dried over anhydrous Na ₂ SO ₄ and filtered, then evaporated under reduced pressure to obtain compound H16 (100 mg) as a yellow tarry substance.

Synthesis procedure H17

To a solution of H16 (100 mg, crude) and di-tert-butyl dicarbonate (55.6 mg, 0.255 mmol) in DCM (1 ml) was added diisopropylethylamine (32.9 g, 0.255 mmol). The resulting mixture was stirred at 25°C for 2 hours to obtain a colorless solution. LCMS indicated that the reaction was complete. The mixture was evaporated under reduced pressure to obtain compound H17 (102 mg) as a yellow tarry substance.

Synthesis procedure H18

To a mixture of compound H17 (102 mg) in THF (2 ml) were added diisopropylethylamine (248 mg, 1.92 mmol) and compound A5 (106 mg, 0.576 mmol), the mixture was stirred at 25°C for 1 hour. LCMS indicated that the reaction was complete. Dimethylamine (2 M, 383 μl) was added to the mixture. The mixture was stirred at 25°C for 30 hours to obtain a brown mixture. LCMS indicated that the reaction was complete. The mixture was partitioned between DCM (50 ml) and water (30 ml). The aqueous solution was extracted with DCM (50 ml x 2), the combined extracted phase was washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain a brown oil, which was purified by a Combi flash system to obtain compound H18 (80 mg) as a yellow oily substance.

Compound synthesis procedure 12

To a mixture of compound H18 (80 mg, 0.083 mmol) in DCM (2 ml) was added TFA (770 ml, 0.5 ml), the mixture was stirred at 25°C for 1 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was evaporated under reduced pressure to give a yellow oily substance, which was purified by preparative HPLC to give compound 12 (6.4 mg) as a white powder.

Scheme 35: Synthesis mechanism for compound 14

H20 synthesis procedure

To a solution of compound G7 (650 mg, 2.54 mmol) and diisopropylethylamine (1.64 g, 12.7 mmol) in acetonitrile (12 ml) was added compound H19 (488 mg, 3.80 mmol). The reaction mixture was stirred at 140°C for 28 hours under N ₂ atmosphere to obtain a brown solution. LCMS indicated that the reaction was complete. The reaction was carried out simultaneously in two vessels. The reaction mixture was combined and evaporated under reduced pressure to give the crude product as a brown tar, which was washed with methanol (15 ml) to give H20 (1.09 mg) as a yellow powder.

Synthesis procedure H21

To a mixture of compound H20 (400 mg, 1.31 mmol) in POCl ₃ (5 ml) was added N,N-diethylaniline (588 mg, 3.94 mmol). The mixture was stirred at 90°C for 1 hour to obtain a yellow mixture. The mixture was evaporated under reduced pressure to give H21 (420 mg) as a brown oil.

Compound synthesis procedure 14

To a mixture of compound H21 (300 mg, 0.929 mmol), diisopropylethylamine (2.40 g, 18.6 mmol) in CH ₃ CN (5 ml) was added compound A16 (533 mg, 1.39 mmol). The reaction solution was stirred at 25°C for 1 hour to obtain a yellow mixture. LCMS indicated that the reaction was complete. The mixture was poured and partitioned between DCM (80 ml) and water (50 ml), the aqueous phase was extracted with DCM (80 ml × 2), the combined extracted phase was washed with brine (80 ml × 2), dried over anhydrous Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain a yellow oily substance. The crude product was purified using a Combi flash system followed by preparative TLC. The product was lyophilized to give compound 14 (45.5 mg) as a yellow powder.

Scheme 36: Synthesis mechanism for compound 41

Synthesis procedure H23

Cs ₂ CO ₃ (630 mg, 1.93 mmol) was added to a solution of compound G26 (500 mg, 966.07 μmol) and compound H22 (271 mg, 1.93 mmol) in DMF (10 ml). The resulting mixture was heated at 30-40°C and stirred for 16 hours to obtain a yellow solution. LCMS indicated that the reaction was complete. The mixture was filtered and partitioned between ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml x 3). The organic layer was washed with saturated brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give the crude product as a yellow oil. The crude product was purified using a Combi flash system to give H23 (490 mg) as a yellow oily substance.

Synthesis procedure H24

Compound H23 (490 mg) was treated in the same manner as B7 to obtain 440 mg of compound H24 as a yellow powder.

Synthesis procedure H25

Compound H24 (390 mg) was treated in the same manner as E3 to obtain 310 mg of compound H25 as a yellow powder.

Compound synthesis procedure 41

Compound H25 (150 mg) was treated in the same manner as compound 44 to obtain 23 mg of compound 41 as a yellow powder.

Scheme 37: Synthesis mechanism for compound 41

Synthesis procedure H28

Diisopropyl azodicarboxylate ₍ 689 mg , 3 .41 mmol, 662 μ) at 0°C. The resulting mixture was stirred at 15°C for 24 hours to obtain a yellow solution. TLC showed that most of the starting material had been consumed. The reaction mixture was quenched by adding H ₂ O (30 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (10 ml x 2), dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography to give H28 (570 mg) as a yellow oil.

Synthesis procedure H29

To a mixture of compound G26 (1 g, 1.93 mmol) in dioxane (10 ml) and H ₂ O (10 ml) was added NaOH (309 mg, 7.73 mmol) and the mixture was stirred at 50°C for 12 hours with obtaining a yellow mixture. LCMS indicated that the desired product was observed. The mixture was evaporated under reduced pressure and adjusted to pH=3~4, the mixture was filtered and the white solid was collected to give H29 (620 mg) as a yellow solid.

Synthesis procedure H30

To a mixture of compound H29 (500 mg, 1.10 mmol) in toluene (10 ml) was added POBr ₃ (944 mg, 3.29 mmol, 334 μl) and N, N-diethylaniline (16.3 mg, 109 μmol, 17 .56 μl) at 15°C, the mixture was stirred at 100°C for 3 hours to obtain a yellow mixture. LCMS indicated that the desired product was observed. The mixture was evaporated under reduced pressure to obtain the crude product. The crude product was ground into a powder with (PE/EA = 3/1) at 15°C for 30 minutes to obtain compound H30 (330 mg) as a black-brown solid.

Synthesis procedure H31

Na ₂ CO ₃ ( 134 mg, _1.27 mmol, 2 eq.) and Pd(dppf)Cl ₂ (46.58 mg, 63.66 μmol) and the mixture was stirred at 80°C for 16 hours under N ₂ atmosphere to obtain a black mixture. LCMS indicated that the desired product was observed. The mixture was partitioned between ethyl acetate (15 ml) and water (10 ml). The aqueous phase was extracted with ethyl acetate (10 ml x 2). The combined organic extract was washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered, evaporated under reduced pressure to obtain the crude product. The crude product was purified using a Combi flash system (PE/EA=1/1) to obtain compound H31 (50 mg) as a red solid.

Synthesis procedure H32

Compound H31 (50 mg) was treated in the same manner as Compound B7 to obtain 43 mg of Compound H32 as a yellow powder.

Synthesis procedure H33

Compound H32 (11.5 mg) was treated in the same manner as Compound G31 to obtain 10 mg of Compound H33 as a yellow powder.

Compound synthesis procedure 87

Compound H32 (10 mg) was treated in the same manner as Compound A7 to obtain 3 mg of Compound 87 as a yellow powder.

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Table 1. Enzymatic activity of CDKs (1, 2, 5 and 7) and selectivity of CDK7

#cpds CDK1 CDK2 CDK5 CDK7 CDK1
/CDK7* CDK2/CDK7** CDK5/CDK7*** 1 C B B A B B C 2 B B B A B B C 3 B B A A C C C 5 C B B A B B C 6 C C B A A A C 7 C C C A A A B 8 C C B A A B B 10 C B B A B B C eleven C C C A A A A 12 C C B A A B C 14 C C B A A B B 15 C B B A A B B 16 C B B A B B C 18 C B B A A B B 19 B A A A C C C 20 C C B A B A B 21 C C B A A B B 22 C B B A A B C 23 C C B A B C C 24 B B B A B C C 25 B B A A B C C 26 C C C A A A A 27 C C C A B B B 28 C C C B B B B 29 C C C B B B B thirty C C C B B B B 31 C C C A A A A 32 C C C A A A A 33 C C C B B B B 34 C C C A A A A 35 C C C A B B B 36 C C C A A A A 37 C C C B B B B 38 C C C B B B B 39 C C C A A A B 40 C C C A A A B 41 C C C A B B B Activity range: A denoted. IC ₅₀ ≤ 100 nM, B symbol. 100 < IC ₅₀ ≤ 1,000 nM, C symbol. IC ₅₀ > 1,000nM
* CDK1/CDK7: Selectivity of CDK7 inhibition compared to CDK1 inhibition [times]
**CDK2/CDK7: Selectivity of CDK7 inhibition over CDK2 inhibition [times]
*** CDK5/CDK7: Selectivity of CDK7 inhibition compared to CDK5 inhibition [times]
Activity range: A denoted. [times] > 500, B symbol. 50 < [times] ≤ 500, C symbol [times] ≤ 50

Table 1 (continued)

#cpds CDK1 CDK2 CDK5 CDK7 CDK1/CDK7* CDK2/CDK7** CDK5/CDK7*** 42 C C C B B B B 43 C C C B B B B 44 C C C A A A A 45 C C C A A A A 46 C C C A A A A 47 C C C A A A B 48 C C C A A A A 49 C C C A A A A 50 C C C A A A A 51 C C C A A A A 52 C C C A A A A 53 C C C A A A A 54 C C C A A A A 55 C C C A A A B 56 C C C A A A A 57 C C C A A A A 58 C C C A A A A 59 C C C A A A A 60 C C C A A A A 61 C C C A A A A 62 C C C A A A A 63 C C C A A A A 64 C C C A A A A 65 C C C A A A A 66 C C C A A A A 67 C C C A A A A 68 C C C A A A A 69 C C C A B B B 70 C C C A A A A 71 C C C A B B B 72 C C C A A A A 73 C C C A A A B 74 C C B A B B B 75 C C C B B B B Activity range: A denoted. IC ₅₀ ≤ 100 nM, B symbol. 100 < IC ₅₀ ≤ 1,000 nM, C symbol. IC ₅₀ > 1,000nM
* CDK1/CDK7: Selectivity of CDK7 inhibition compared to CDK1 inhibition [times]
** CDK2/CDK7: Selectivity of CDK7 inhibition compared to CDK2 inhibition [times]
***CDK5/CDK7: Selectivity of CDK7 inhibition compared to CDK5 inhibition [times]
Activity range: A denoted. [times] > 500, B symbol. 50 < [times] ≤ 500, C symbol [times] ≤ 50

Table 1 (continued)

#cpds CDK1 CDK2 CDK5 CDK7 CDK1/CDK7* CDK2/CDK7** CDK5/CDK7*** 76 C C C A A A A 77 C C C A A A A 78 C C C A A A B 79 C C C A A A A 80 C C C A A A A 81 C C C B B B B 82 C C C A A A A 83 C C C A A A A 84 C C C B B B B 85 C C C B B B B 86 C C C C C C C 87 C C C A A A A 88 C C C B B B B Activity range: A denoted. IC ₅₀ ≤ 100 nM, B symbol. 100 < IC ₅₀ ≤ 1,000 nM, C symbol. IC ₅₀ > 1,000nM
* CDK1/CDK7: Selectivity of CDK7 inhibition compared to CDK1 inhibition [times]
**CDK2/CDK7: Selectivity of CDK7 inhibition over CDK2 inhibition [times]
*** CDK5/CDK7: Selectivity of CDK7 inhibition compared to CDK5 inhibition [times]
Activity range: A denoted. [times] > 500, B symbol. 50 < [times] ≤ 500, C symbol [times] ≤ 50

Table 2. H460 Cell Viability Assay

#cpds IC ₅₀ #cpds IC ₅₀ #cpds IC ₅₀ 1 B eleven A 21 B 2 A 12 A 22 B 3 A 13 A 23 B 5 A 14 A 24 B 6 A 15 A 25 A 7 A 16 A 26 A 8 A 18 A 27 A 9 B 19 B 10 A 20 A Activity range: A denotes IC ₅₀ ≤ 1 µM, B denotes 1 < IC ₅₀ ≤ 10 µM, C denotes IC ₅₀ ⋅10 µM

Table 3. MV4-11 Cell Viability Assay #cpds IC ₅₀ #cpds IC ₅₀ #cpds IC ₅₀ 3 A 42 A 62 A eleven A 43 A 63 A 20 A 44 A 64 A 25 A 45 A 65 A 26 A 46 A 66 A 27 A 47 A 67 A 28 A 48 A 68 A 29 A 49 A 69 A thirty A 50 A 70 B 31 A 51 A 71 A 32 A 52 A 72 A 33 A 53 A 73 A 34 A 54 A 74 A 35 A 55 A 75 A 36 A 56 A 76 A 37 A 57 A 77 A 38 A 58 A 78 A 39 A 59 A 79 A 40 A 60 A 41 A 61 A Activity range:
A denotes IC ₅₀ ≤ 1 µM, B denotes 1 < IC ₅₀ ≤ 10 µM, C denotes IC ₅₀ ⋅ 10 µM

Table 4. A2780 Viability Analysis

#cpds IC ₅₀ #cpds IC ₅₀ #cpds IC ₅₀ 3 A 41 A 60 A eleven A 42 A 61 A 20 A 43 A 62 A 25 A 44 A 63 B 26 A 45 A 64 A 27 A 46 A 65 A 28 A 47 A 66 A 29 A 48 A 67 A thirty A 49 A 68 A 31 A 50 A 69 A 32 A 51 A 70 B 33 A 52 A 71 A 34 A 53 A 72 A 35 A 54 A 73 B 36 A 55 A 74 A 37 A 56 A 75 A 38 A 57 A 76 A 39 A 58 B 77 B 40 A 59 A Activity range:
A denotes IC ₅₀ ≤ 1 µM, B denotes 1 < IC ₅₀ ≤ 10 µM, C denotes IC ₅₀ ⋅ 10 µM

Table 5. OVCAR-3 Viability Assay #cpds IC ₅₀ #cpds IC ₅₀ #cpds IC ₅₀ 3 A 41 A 60 A eleven A 42 A 61 A 20 A 43 A 62 A 25 A 44 A 63 B 26 A 45 A 64 A 27 A 46 A 65 A 28 A 47 A 66 A 29 A 48 A 67 A thirty A 49 A 68 A 31 A 50 A 69 A 32 A 51 A 70 B 33 A 52 A 71 A 34 A 53 A 72 A 35 A 54 A 73 B 36 A 55 A 74 A 37 A 56 A 75 A 38 A 57 A 76 A 39 A 58 B 77 B 40 A 59 A Activity range:
A denotes IC ₅₀ ≤ 1 µM, B denotes 1 < IC ₅₀ ≤ 10 µM, C denotes IC ₅₀ ⋅ 10 µM

Table 6. Summary of Compounds 1-88 with Respect to Their Structures and Relevant Characteristics

#cpds Structure Characteristics 1 White powder; ¹ H-NMR (DMSO-d6, 400 MHz): δ 10.28 (1H, brs), 10.25 (1H, brs), 8.86 (1H, brs), 8.13 (1H, s), 7.88 (1H, d, J= 8.0 Hz), 7.80 (1H, s), 7.72 (1H, s), 7.65 (1H, d, J=7.6 Hz), 7.60 (1H, d, J=7.6 Hz), 7.44 (1H, t, J= 8.0 Hz), 7.28 (1H, t, J=7.6 Hz), 7.12 (1H, d, J=7.2 Hz), 6.75 (1H, td, J=15.6, 6.0 Hz,), 6.28 (1H, d, J =15.6 Hz), 4.59 (2H, s), 4.42-4.54 (2H, m), 3.06 (2H, d, J=5.2 Hz), 2.85-2.98 (3H, m), 2.65-2.75 (1H, m) , 2.18 (6H, s), 1.64-1.76 (2H, m), 1.23 (6H, d, J=7.2 Hz), 1.03-1.15 (2H, m); LC/MS: 95.8%, MS (ESI): m/z 611.3[M+H] +. 2 White powder; ¹ H-NMR (DMSO-d6, 400 MHz): δ 10.12 (1H, brs), 8.85 (1H, brs), 7.70 (1H, s), 7.36-7.42 (2H, m), 7.24-7.36 (2H, m), 7.17 (1H, d, J=7.6 Hz), 7.07 (1H, s), 6.90 (1H, dd, J=8.0, 1.6 Hz), 6.63-6.74 (2H, m), 6.21 (1H, d , J=15.2 Hz), 4.55 (2H, s), 4.39-4.50 (2H, m), 2.99-3.08 (2H, m), 2.81-2.97 (3H, m), 2.66-2.77 (1H, m), 2.16 (6H, s), 1.61-1.76 (2H, m), 1.22 (6H, d, J=7.2 Hz), 0.99-1.13 (2H, m); LC/MS: 100%, MS (ESI): m/z 584.2[M + H] +. 3 White powder; ¹ H-NMR (DMSO- d ₆ , 400 MHz): δ 8.65 (1H, brs), 7.89 (1H, brs), 7.62 (1H, s), 7.48-7.59 (3H, m), 7.31-7.43 (2H , m), 7.16-7.22 (1H, m), 7.09-7.15 (1H, m), 6.95-7.06 (1H, m), 6.61 (1H, t, J =5.6 Hz), 6.56 (1H, s), 6.21 (1H, d, J =15.2 Hz), 4.83 (2H, d, J =5.2 Hz), 4.55-4.65 (2H, m), 3.10-3.20 (2H, m), 2.98-3.08 (1H, m) , 2.80-2.89 (3H, m), 2.30 (6H, s), 1.77-1.79 (2H, m), 1.28-1.32 (8H, m); LC/MS: 100%, MS (ESI): m/z 629.4[M + Na] ⁺ 4 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.56 (1H, s), 7.42-7.48 (2H, m), 7.26-7.32 (1H, m), 7.17-7.24 (1H, m), 7.14 (1H, brs), 7.07-7.12 (1H, m), 6.88-6.98 (2H, m), 6.60-6.70 (2H, m), 6.07 (1H, d, J=15.2 Hz), 4.77 (2H, d, J= 6.0 Hz), 4.68-4.76 (2H, m), 3.09 (2H, d, J=5.6 Hz), 2.96-3.04 (1H, m), 2.86-2.96 (3H, m), 2.26 (6H, s), 1.76-1.90 (2H, m), 1.23-1.34 (8H, m); LC/MS: 100%, MS (ESI): m/z 584.4[M + H] +. 5 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.79 (1H, brs), 7.60 (1H, s), 7.40-7.50 (1H, m), 7.26-7.33 (2H, m), 7.19 (1H, s) , 7.05-7.12 (2H, m), 6.93 (1H, d, J = 7.6 Hz), 6.75 (1H, d, J=7.6 Hz), 6.71 (1H, brs), 6.41 (1H, d, J=16.4 Hz), 6.24-6.34 (1H, m), 5.74 (1H, d, J=10.0 Hz), 4.62-4.75 (4H, m), 2.96-3.06 (1H, m), 2.83-2.95 (3H, m) , 1.80-1.84 (2H, m), 1.21-1.33 (8H, m); LC/MS: 100%, MS (ESI): m/z 527.3[M + H] +. 6 White powder; ¹ H-NMR (DMSO-d6, 400 MHz): δ 7.56 (1H, s), 7.33 (1H, d, J=8.0 Hz), 7.24-7.28 (1H, m), 6.92 (1H, d, J= 6.8 Hz), 6.80-6.88 (2H, m), 6.63 (1H, t, J=4.8 Hz), 6.53 (1H, d, J=16.0 Hz), 4.76-4.83 (2H, m), 4.63-4.70 ( 2H, m), 3.65-3.80 (3H, m), 3.53-3.56 (1H, m), 3.21-3.25 (2H, m), 3.09-3.14 (1H, m), 2.91-3.03 (3H, m), 2.35 (6H, s), 1.94-1.97 (2H, m), 1.86-1.90 (4H, m), 1.45-1.48 (2H, m), 1.27 (6H, d, J=7.2 Hz); LC/MS: 100%, MS (ESI): m/z 576.3[M + H]+. 7 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.49 (1H, s), 7.38-7.40 (2H, m), 7.14-7.22 (3H, m), 7.04-7.06 (2H, m), 6.87 (1H, d, J=8.0 Hz), 6.58-6.59 (1H, m), 6.53 (1H, t, J=4.8 Hz), 6.33-6.37 (1H, d, J=16.8 Hz), 6.12-6.14 (1H, m ), 5.69 (1H, d, J=10.8 Hz), 4.64-4.71 (4H, m), 2.82-2.95 (4H, m), 1.79-1.82 (2H, m), 1.19-1.27 (8H, m); LC/MS: 91.6%, MS (ESI): m/z 527.3[M + H]+. 8 White powder; ¹ H-NMR (DMSO-d6, 400 MHz): δ 10.26-10.27 (1H, s), 10.12-10.14 (1H, s), 8.85-8.69 (1H, brs), 8.21 (1H, s), 7.92 ( 1H, d, J=8.0 Hz), 7.72 (1H, s), 7.65-7.68 (1H, m), 7.37-7.49 (3H, m), 7.27-7.31 (1H, m), 7.19-7.23 (1H, m), 6.73-6.76 (1H, m), 6.28 (1H, d, J=15.6 Hz), 4.63 (2H, s), 4.42-4.47 (2H, m), 3.06 (2H, d, J=5.2 Hz ), 2.82-2.94 (3H, m), 2.70-2.77 (1H, m), 2.17 (6H, s), 1.64-1.69 (2H, m), 1.22 (6H, d, J=7.2 Hz), 1.02- 1.11 (2H, m); LC/MS: 100.0%, MS (ESI): m/z 611.3[M + H]+. 9 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 8.47-8.49 (2H, s), 7.97-7.99 (1H, m), 7.61-7.63 (1H, m), 7.55-7.58 (1H, m), 7.52 ( 1H, s), 7.38-7.49 (4H, m), 7.22-7.25 (1H, m), 7.04-7.11 (1H, m), 6.63-6.65 (1H, m), 6.35-6.40 (1H, m), 4.72-4.77 (1H, m), 4.78-4.55 (2H, m), 4.26-4.30 (1H, m), 3.19-3.21 (2H, m), 2.92-3.02 (2H, m), 2.76-2.83 (2H , m), 2.35 (6H, s), 1.79-7.82 (2H, m), 1.14-1.29 (8H, m); LC/MS: 95.3%, MS (ESI): m/z 619.4[M + H]+. 10 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, s), 7.44-7.53 (4H, m), 7.22-7.26 (1H, m), 7.08 (1H, t, J=7.6 Hz), 6.93 -7.00 (3H, m), 6.86 (1H, d, J=7.6 Hz), 6.71 (1H, t, J=6.2 Hz), 6.13 (1H, d, J=15.6 Hz), 4.79 (2H, d, J=6.4 Hz), 4.71-4.75 (2H, m), 3.12-3.15 (2H, m), 2.99-3.06 (1H, m), 2.89-2.96 (3H, m), 2.30 (6H, s), 1.86 -1.89 (2H, m), 1.24-1.33 (8H, m); LC/MS: 100.0%, MS (ESI): m/z 584.4[M + H]+. eleven White powder; ¹ H-NMR (DMSO-d6, 400 MHz): δ 10.51 (1H, brs), 8.44-8.50 (3H, m), 7.75 (1H, d, J=5.6 Hz), 7.64 (1H, s), 7.55 -7.60 (1H, m), 7.46-7.53 (3H, m), 7.42 (1H, t, J=8.0 Hz), 7.33 (1H, d, J=7.2 Hz), 6.78-6.85 (1H, m), 6.36 (1H, d, J=15.2 Hz), 4.25-4.43 (4H, m), 3.08 (2H, d, J=5.2 Hz), 2.72-2.86 (4H, m), 2.19 (6H, s), 1.60 -1.70 (2H, m), 1.19 (6H, d, J=7.2 Hz), 1.05-1.10 (2H, m); LC/MS: 98.9%, MS (ESI): m/z 619.4[M+H] +. 12 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 9.36 (1H, brs), 8.51 (1H, d, J=9.2 Hz), 8.14-8.17 (2H, m), 7.70 (1H, d, J=6.8 Hz ), 7.66 (1H, d, J=6.8 Hz), 7.60 (1H, s), 7.34-7.38 (1H, m), 7.02-7.11 (1H, m), 6.32 (1H, d, J=16.0 Hz) , 5.16 (2H, d, J=6.0 Hz), 4.78-4.84 (2H, m), 3.18 (2H, d, J=6.4 Hz), 2.94-3.03 (4H, m), 2.33 (6H, s), 1.92-1.97 (2H, m), 1.30-1.45 (2H, m), 1.25 (6H, d, J=6.8 Hz); LC/MS: 95.9%, MS (ESI): m/z 565.3[M + Na] +. 13 White powder; ¹ H-NMR(DMSO- d ₆ , 400 MHz): δ 9.93 (1H, brs), 8.89 (1H, brs), 7.81-7.83 (1H, m), 7.72 (1H, s), 7.23-7.31 (2H , m), 7.15 (1H, d, J= 8.0 Hz), 7.06 (1H, s), 6.86 (1H, dd, J= 7.6, 2.0 Hz), 6.69-6.75 (2H, m), 6.46 (1H, d, J= 15.6), 4.50-4.55 (4H, m), 3.03 (2H, d, J= 4.8 Hz) 2.84-2.93 (4H, m), 2.16 (6H, s), 1.75-1.80 (2H, m ), 1.18-1.23 (8H, m); LC/MS: 100%, MS (ESI): m/z 624.3[M+Na] ⁺ . 14 yellow powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.74 (1H, brs), 7.60 (1H, s), 7.41 (1H, d, J= 8.0 Hz), 7.23-7.31 (3H, m), 7.05-7.13 (2H, m), 6.93 (1H, dd, J= 8.4, 1.6 Hz), 6.75 (1H, dd, J= 8.4, 1.6 Hz), 6.69 (1H, t, J= 5.6 Hz), 6.42 (1H, dd, J= 16.8, 1.6 Hz), 6.21 - 6.31 (1H, m), 5.75 (1H, d, J= 10.4), 4.78-4.88 (2H, m), 4.68 (2H, d, J= 6.0 Hz) , 2.98-3.09 (1H, m), 2.72-2.85 (2H, m), 2.39-2.49 (1H, m), 2.31 (6H, s), 1.82-1.88 (2H, m), 1.34-1.47 (2H, m), 1.28 (6H, d, J= 6.8 Hz); LC/MS: 94.2%, MS (ESI): m/z 55.3[M + H] ⁺ . 15 yellow powder; ¹ H-NMR (CDCl3, 400 MHz): δ 8.18 (1H, s), 7.80 (1H, brs), 7.62 (1H, s), 7.27-7.32 (2H, m), 7.07-7.11 (2H, m) , 6.92-7.05 (2H, m), 6.69-6.74 (2H, m), 6.24 (1H, d, J= 15.2 Hz), 4.67-4.76 (4H, m), 3.20-3.21 (2H, m), 3.01 -3.04 (2H, m), 2.88-2.94 (2H, m), 2.33 (6H, s), 1.98-2.01 (2H, m), 1.36-1.45 (2H, m), 1.28 (6H, d, J= 6.8 Hz); LC/MS: 95.4%, MS (ESI): m/z 618.3[M+H] ⁺ . 16 yellow powder; ¹ H-NMR (CDCl3, 400 MHz): δ 9.22 (1H, brs), 8.59 (1H, t, J= 5.8 Hz), 8.42 (1H, d, J= 7.6 Hz), 8.19 (1H, s), 7.70 (1H, s), 7.66 (1H, d, J= 6.8 Hz), 7.40-7.47 (4H, m), 7.16-7.20 (1H, m), 7.04-7.08 (1H, m), 6.61 (1H, d, J= 15.2 Hz), 4.83-4.88 (2H, m), 4.58 (2H, d, J= 6.0 Hz), 3.38-3.40 (1H, m), 3.27 (2H, d, J= 6.4 Hz), 2.98-3.05 (3H, m), 2.56 (6H, s), 2.21-2.38 (2H, m), 1.65-1.68 (2H, m), 1.25-1.29 (8H, m); LC/MS: 95.6%, MS (ESI): m/z 608.3[M + H] ⁺ . 17 White powder; ¹ H-NMR (DMSO- d ₆ , 400 MHz): δ 11.13 (1H, brs), 10.76 (1H, brs), 9.08 (1H, brs), 8.24 (1H, d, J= 6.0 Hz), 8.00- 8.22 (3H, m), 7.79 (1H, s), 7.73 (1H, s), 7.43 (1H, d, J= 8.0 Hz), 7.33 (1H, d, J= 7.2 Hz), 7.23 (1H, s ), 7.05-7.15 (1H, m), 6.80-6.90 (1H, m), 6.73 (1H, d, J= 3.6 Hz), 6.56 (1H, d, J= 16.0 Hz), 4.55-4.70 (4H, m), 3.85-3.95 (2H, m), 2.85-3.00 (4H, m), 2.74 (6H, d, J= 3.6 Hz), 1.85-2.00 (2H, m), 1.30-1.50 (2H, m) , 1.22 (6H, d, J= 6.4 Hz); LC/MS: 100%, MS (ESI): m/z 607.3 [M+Na] ⁺ 18 Racemic mixture; White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.61 (1H, s), 7.24 (1H, t, J= 7.8 Hz), 6.88-6.96 (3H, m), 6.78-6.81 (1H, m), 6.60 -6.65 (1H, m), 6.40-6.45 (1H, m), 4.69-4.76 (4H, m), 4.48-4.51 (1H, m), 3.83-3.90 (1H, m), 3.43-3.72 (3H, m), 2.90-3.11 (6H, m), 2.27 (6H, d, J= 5.6 Hz), 1.99-2.08 (4H, m), 1.73-1.91 (4H, m), 1.25-1.37 (8H, m) ; LC/MS: 94.9%, MS (ESI): m/z 612.5[M + Na] ⁺ . 19 White powder; ¹ H-NMR (DMSO- d ₆ , 400 MHz): δ 8.72 (1H, s), 7.87 (1H, s), 7.58 (2H, s), 7.46-7.54 (2H, m), 7.33-7.40 (2H , m), 7.18-7.26 (2H, m), 6.90-7.01 (1H, m), 6.64 (1H, brs), 6.54 (1H, s), 6.13 (1H, d, J= 15.6 Hz), 4.82 ( 2H, s), 4.55-4.65 (2H, m), 3.11 (2H, d, J= 5.2 Hz), 2.98-3.05 (1H, m), 2.79-2.88 (3H, m), 2.28 (6H, s) , 1.70-1.80 (2H, m), 1.29 (8H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 629.2[M + Na] ⁺ 20 yellow powder; ¹ H-NMR (DMSO- d ₆ , 400 MHz): δ 10.08 (1H, brs), 8.89 (1H, t, J= 5.6 Hz), 8.69 (1H, d, J= 7.6 Hz), , 8.50 (1H , d, J= 8.4 Hz), 7.88 (1H, d, J= 8.4 Hz), 7.60-7.85 (7H, m), 7.43-7.49 (2H, m), 6.73-6.80 (1H, m), 6.50 ( 1H, d, J= 16.0 Hz), 5.04 (2H, d, J= 6.4 Hz), 4.30-4.33 (2H, m), 3.11-3.17 (1H, m), 3.00 (2H, d, J= 6.4 Hz ), 2.83-2.92 (1H, m), 2.62-2.67 (2H, m), 2.11 (6H, s), 1.71-1.75 (2H, m), 1.07-1.27 (8H, m); LC/MS: 100%, MS (ESI): m/z 619.4[M + H] ⁺ . 21 Racemic mixture; White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 7.60 (1H, s), 7.12 (1H, t, J= 7.2 Hz), 6.82-6.93 (1H, m), 6.64-6.69 (1H, m), 6.60 -6.63 (1H, m), 6.40-6.52 (3H, m), 4.70-4.80 (2H, m), 4.56-4.70 (2H, m), 3.37-3.83 (6H, m), 2.89-3.16 (6H, m), 2.25-2.31 (6H, m), 1.93-2.01 (3H, m), 1.59-1.76 (2H, m), 1.39-1.48 (2H, m), 1.23-1.33 (8H, m); LC/MS: 100%, MS (ESI): m/z 611.5[M + Na] ⁺ . 22 Racemic mixture; White powder; ¹ H-NMR (DMSO- d ₆ , 400 MHz): δ 7.89 (1H, brs), 7.59 (1H, s), 7.42-7.56 (2H, m), 7.21-7.26 (1H, m), 7.06 (1H , t, J= 6.0 Hz), 6.83-6.92 (1H, m), 6.65-6.75 (1H, m), 6.40 (1H, d, J= 15.6 Hz), 4.65-4.77 (4H, m), 3.86- 4.03 (1H, m), 3.75-3.85 (1H, m), 3.63 (1H, t, J= 5.6 Hz), 3.42-3.53 (1H, m), 3.18-3.36 (1H, m), 2.88-3.12 ( 6H, m), 2.32-2.46 (1H, m), 2.20-2.30 (7H, m), 1.83-1.92 (2H, m), 1.54-1.82 (2H, m), 1.19-1.40 (10H, m); LC/MS: 100%, MS (ESI): m/z 617.5[M + H] ⁺ . 23 White powder; ^1H NMR (DMSO- d ₆ , 400 MHz): δ 11.52 (1H, brs), 9.98 (1H, brs), 9.01 (1H, t, J= 5.4 Hz), 8.00 (1H, s), 7.91 (1H , s), 7.77 (1H, s), 7.73 (1H, d, J= 7.2 Hz), 7.39 (1H, t, J= 8.0 Hz), 7.31-7.34 (2H, m), 7.26 (1H, d, J= 8.0 Hz), 6.83 (1H, s), 6.67-6.73 (1H, m), 6.33 (1H, d, J= 15.2 Hz), 4.63-4.67 (4H, m), 3.13-3.19 (3H, m ), 2.86-2.94 (3H, m), 2.26 (6H, s), 1.85-1.91 (2H, m), 1.29-1.36 (2H, m), 1.23 (6H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 607.3[M + H] ⁺ . 24 brown powder;¹H-NMR (DMSO-d ₆, 400 MHz): δ 10.2 (1H, brs), 8.93-8.97 (1H, m), 8.71 (1H, s), 8.38 (1H, d,J=2.8 Hz), 7.77 (1H, s), 7.67 (1H, d,J=9.6 Hz), 7.56-7.72 (2H, m), 7.45-7.52 (2H, m), 7.39-7.44 (1H, m), 6.71-6.80 (1H, m), 6.38 (1H, d,J=15.2 Hz), 4.61 (2H, d,J=5.6 Hz), 4.39-4.50 (2H, m), 3.15-3.26 (2H, m), 2.85-2.93 (2H, m), 2.72-2.83(2H, m), 2.17-2.35 (6H, m), 1.81 -1.90 (2H, m), 1.14-1.34 (8H, m); LC/MS: 96.5%, MS (ESI): m/z = 608.3 [M+ H]⁺. 25 White powder; ¹ H-NMR (CDCl3, 400 MHz): δ 10.44 (1H, brs), 7.61 (1H, brs), 7.54-7.63 (3H, m), 7.48 (1H, d, J= 7.6 Hz), 7.32-7.41 (2H, m), 6.93-7.07 (2H, m), 6.79 (1H, d, J= 7.2 Hz), 6.57-6.68 (2H, m), 6.21 (1H, d, J= 14.8 Hz), 4.90 ( 2H, d, J= 5.6 Hz), 4.58-4.68 (2H, m), 3.12 (2H, d, J= 5.6 Hz), 3.98-3.06 (1H, m), 2.80-2.91 (3H, m), 2.29 (6H, s), 1.74-1.84 (2H, m), 1.29 (6H, d, J= 6.8 Hz), 1.20-1.26 (2H, m); LC/MS: 100%, MS (ESI): m/z 629.3[M + Na] ⁺ . 26 ( 3R , 4R ); pale yellow powder; ^1H NMR (400 MHz, DMSO _- d6 ): δ 10.91-11.17 (2H, m), 9.03 (1H, br s), 8.82 (1H, br s), 8.38-8.58 (3H, m), 7.79- 7.89 (1H, m), 7.70-7.77 (1H, m), 7.62-7.67 (1H, m), 7.50-7.57 (2H, m), 7.42-7.49 (1H, m), 7.37 (1H, br d, J= 7.2 Hz), 6.85-6.98 (1H, m), 6.63 (1H, d, J= 15.6 Hz), 5.67-5.96 (1H, m), 4.33-4.50 (2H, m), 3.96 (2H, d , J= 6.8 Hz), 3.42-3.57 (2H, m), 2.97-3.25 (3H, m), 2.81-2.90 (1H, m), 2.77 (6H, s), 2.58-2.69 (1H, m), 1.39-1.90 (3H, m), 1.19 (6H, br d, J= 6.4 Hz); LC/MS: 100%, MS (ESI): m/z 649.3[M + H] ⁺ 27 (1 R , 4 R ); yellow powder; ¹ H-NMR (400 MHz, CD ₃ OD): δ 8.67 (1H, s), 8.42 (1H, br d, J= 6.4 Hz), 8.24 (1H, br d, J= 6.4 Hz), 7.84-7.93 (2H, m), 7.78 (1H, d, J= 9.2 Hz), 7.68 (1H, br s), 7.49-7.62 (3H, m), 6.95-7.10 (1H, m), 6.72 (1 H, br d, J= 15.2 Hz), 4.70-5.10 (2H, m), 4.07 (2H, br d, J= 6.8 Hz) 3.47-3.65 (2H, m), 2.91-3.01 (6H, m), 2.77-2.87 (1H, m), 1.87-2.10 (3H, m), 1.65-1.72 (1H, m), 1.30-1.51 (4H, m), 1.12-1.23 (6H, m); LC/MS: 100%, MS (ESI): m/z 634.3[M+H] ⁺ . 28 yellow powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.42 (1H, s), 8.37 (1H, d, J= 6.0 Hz), 7.68-7.77 (2H, m), 7.61-7.67 (1H, m), 7.46-7.60 (4H, m), 7.40 (1H, d, J= 7.6 Hz), 6.92-7.02 (1H, m), 6.64 (1 H, d, J= 15.2 Hz), 5.01-5.04 (1H, m ), 4.39-4.43 (1H, m), 4.06 (2H, d, J= 6.4 Hz), 3.65 (2H, t, J= 6.0 Hz), 3.33-3.41 (2H, m), 2.97 (6H, s) , 2.82-2.91 (1H, m), 1.74-1.80 (2H, m), 1.15-1.25 (6H, m); LC/MS: 100%, MS (ESI): m/z 594.3[M+H] ⁺ . 29 yellow solid;¹H-NMR (400 MHz, CD₃OD): δ 8.66 (1H, s), 6.42-6.44 (1H, m), 8.21-8.23 (1H, m), 7.80-7.87 (3H, m), 7.59-7.71 (4H, m), 7.00-7.07 (1H, m), 6.74-6.78 (1H, d,J=15.6 Hz), 4.95-5.02 (1H, m), 4.71-4.81 (1H, m), 4.31-3.41 (2H, m), 4.08 (2H, d,J=7.2 Hz), 3.46-3.47 (2H, m), 3.08-3.13 (2H, m), 2.96-2.97 (6H, m), 1.85-1.97 (2H, m), 1.29-1.38 (2H, m), 1.16 -1.19 (6H, m); LC/MS: 100.0%, MS (ESI):634.3 m/z [(M+H)]⁺. thirty Racemic mixture; off-white powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.27-8.42 (2H, m) 7.25-7.75 (8H, m), 6.91-7.07 (1H, m), 6.33 (1H, d, J= 15.2 Hz) , 4.80-4.87 (1H, m), 4.60-4.67 (2H, m), 4.28-4.37 (1H, m), 3.47-3.56 (1H, m), 3.26 (2H, d, J= 6.4 Hz), 3.05 -3.13 (1H, m), 2.85-2.92 (1H, m), 2.45-2.54 (2H, m), 2.36 (6H, s), 2.01-2.11 (1H, m), 1.65-1.75 (2H, m) , 1.15-1.26 (6H, m); LC/MS: 95.9%, MS (ESI): m/z 324.2 [M/2+H] ⁺ . 31 light yellow powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.32 (1H, d, J= 6.0 Hz), 8.29 (1H, s), 7.63-7.68 (1H, m), 7.53-7.61 (2H, m), 7.49 (1H, t, J= 6.8 Hz), 7.36-7.40 (2H, m), 7.31-7.35 (2H, m), 6.91-7.00 (1H, m), 6.38-6.42 (1H, m), 4.34- 4.38 (1H, m), 4.13-4.25 (2H, m), 3.74-3.82 (1H, m), 3.49 (2H, d, J= 6.8 Hz), 2.98-3.13 (2H, m), 2.85 (1H, m), 2.53 (6H, s), 1.81 (2H, m), 1.23-1.45 (3H, m), 1.19 (6H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 620.2 [M + H] ⁺ . 32 (1S, 3S); light yellow solid;¹H-NMR (MeOD, 400 MHz): δ 8.69-8.71 (1H, m), 8.42-8.45 (1H, m), 8.25-8.27 (1H, m), 7.80-7.88 (3H, m), 7.58-7.72 (4H, m), 6.99-7.07 ( 1H, m), 6.73 (1H, d,J=15.2 Hz), 5.01-5.06 (1H, m), 4.91-4.94 (1H, m), 4.71-4.78 (1H, m), 4.39-4.44 (1H, m), 4.26-4.29 (1H, m), 4.07 (2H, d,J=7.2 Hz), 2.96 (6H, s), 2.84-2.88 (1H, m), 2.06-2.32 (2H, m), 1.95-1.99 (1H, m), 1.61-1.80 (3H, m), 1.18-1.21 (6H, m); LC/MS: 99.7%, MS (ESI):620.2 m/z [M+H]⁺. 33 (1 R, 4 R ); White powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.66 (1H, d, J= 2.0 Hz), 8.43 (1H, d, J= 6.8 Hz), 8.23 (1H, d, J= 6.8 Hz), 7.76 -7.88 (3H, m), 7.66-7.74 (1H, m), 7.55-7.63 (3H, m), 6.97-7.08 (1H, m), 6.71 (1H, d, J= 15.6 Hz), 4.89-4.90 (2H, m), 4.07 (2H, d, J= 6.4 Hz), 3.45-3.54 (1H, m), 3.17-3.26 (1H, m), 3.04 (1H, m), 2.96 (6H, s), 2.84 (1H, m), 1.88-2.05 (2H, m), 1.67-1.83 (2H, m), 1.36-1.49 (1H, m), 1.28-1.35 (1H, m), 1.14-1.21 (7H, m ), 0.84-1.11 (2H, m); LC/MS: 99.7%, MS (ESI): m/z 648.2 [M+H] ⁺ ; HPLC (254 nm): 100%. 34 yellow powder; ^1H NMR (400 MHz, CD ₃ OD): δ 8.67 (1H, s), 8.38-8.45 (1H, br s), 8.18-8.26 (1H, m), 7.78-7.88 (3H, m), 7.55- 7.73 (4H, m), 6.97-7.08 (1H, m), 6.74 (1H, d, J= 15.2 Hz), 4.95-5.03 (1H, m), 4.66-4.76 (1H, m), 4.48-4.59 ( 2H, m), 4.07 (2H, d, J= 6.8 Hz), 3.39-3.54 (1H, m), 3.03-3.24 (3H, m), 2.96 (6H, s), 2.76 (3H, s), 2.14 -2.31 (2H, m), 1.46-1.80 (2H, m), 1.19 (6H, d, J= 6.8 Hz); LC/MS: 99.7%, MS (ESI): m/z 633.3 [M+H] ⁺ 35 light yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.69 (1H, s), 8.44 (1H, d,J=6.4 Hz), 8.23 (1H, d,J=6.8 Hz), 7.81-7.87 (3H, m), 7.68-7.72 (2H, m), 7.59-7.60 (2H, m), 6.99-7.07 (1H, m), 6.73 (1H, d,J=15.2 Hz), 5.04-5.08 (1H, m), 4.70-4.74 (1H, m), 4.07 (2H, d,J=6.4 Hz), 3.41-3.44 (2H, m), 2.96 (6H, s), 2.82-2.86 (1H, m), 1.69-1.73 (2H, m), 1.28 (6H, s), 1.21 (6H, d ,J=6.8 Hz); LC/MS: 98.2%, MS (ESI):622.3 m/z [(M+H)]⁺. 36 White solid; ^1H NMR (400 MHz, DMSO _- d6 ): δ 11.24-11.45 (2H, m), 9.42-9.66 (1H, m), 8.61-8.66 (1H, m), 8.41-8.47 (1H, m), 8.18-8.23 (1H, m), 7.72-7.75 (2H, m), 7.67-7.69 (1H, m), 7.54-7.60 (1H, m), 7.41-7.52 (2H, m), 6.91-7.01 (1H , m), 6.65 (1H, m), 4.74-4.83 (1H, m), 4.50-4.61 (1H, m), 3.95-4.02 (2H, m), 2.72-2.81 (6H, m), 1.76- 1.91 (1H, m), 1.44-1.68 (5H, m), 1.21-1.38 (2H, m), 1.10-1.16 (6H, m); LC/MS: 100%, MS (ESI): m/z 634.3 [M+H] ⁺ . 37 Racemic mixture; off-white powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.64-8.70 (1H, m), 8.40-8.51 (1H, m), 8.17-8.28 (1H, m), 7.81-7.92 (3H, m), 7.68 -7.75 (2H, m), 7.58-7.66 (2H, m), 7.01-7.09 (1H, m), 6.77 (1H, d, J= 15.2 Hz), 5.11-5.20 (1H, m), 4.53-4.72 (2H, m), 4.09 (2H, d, J= 7.2 Hz), 3.38-3.86 (4H, m), 3.08-3.21 (1H, m), 2.93 (6H, s), 2.03-2.32 (2H, m ), 1.14-1.26 (6H, m); HPLC: 100%, MS (ESI): m/z 606.2 [M+H] ⁺ . 38 Racemic mixture; light yellow solid;¹H-NMR (MeOD, 400 MHz): δ 8.67 (1H, s), 8.41-8.43 (1H, m), 8.18-8.23 (1H, m), 7.80-7.87 (3H, m), 7.59-7.68 (4H, m), 6.99-7.07 (1H, m), 6.74 (1H, d,J=15.2 Hz), 4.95-4.99 (1H, m), 4.72-4.81 (1H, m), 4.07 (2H, d,J=7.2 Hz), 3.42-3.93 (4H, m), 3.09-3.14 (1H, m), 2.96 (6H, s), 2.07-2.22 (1H, m), 1.43-1.98 (5H, m), 1.16-1.19 (6H, m); LC/MS: 99.8%, MS (ESI):634.2 m/z [(M+H)]⁺ 39 Light yellow solid; ^1H NMR (400 MHz, CD ₃ OD): δ 8.68 (1H, s), 8.42 (1H, d, J= 6.0 Hz), 8.21 (1H, d, J= 6.4 Hz), 7.82-7.89 (3H, m), 7.65-7.75 (2H, m), 7.59-7.64 (2H, m), 7.00-7.11 (1H, m), 6.74 (1H, d, J= 15.6 Hz), 4.98-5.07 (1H, m) , 4.68-4.75 (1H, m), 4.54-4.62 (2H, m), 4.07 (2H, d, J= 6.8 Hz), 3.59-3.69 (1H, m), 3.08-3.28 (3H, m), 2.98 (6H, s), 2.94 (6H, s), 2.21-2.29 (2H, m), 1.72-1.87 (2H, m), 1.29-1.33 (2H, m), 1.19-1.24 (6H, m); LC/MS: 97.9%, MS (ESI): m/z 647.3 [M+H] ⁺ 40 yellow powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.58 (1H, s), 8.38 (1H, s), 8.10-8.19 (1H, m), 7.80-7.90 (2H, m), 7.66-7.74 (2H , m), 7.52-7.63 (3H, m), 6.02 (1H, s), 5.00-5.09 (1H, m), 4.65-4.72 (1H, m), 4.48-4.56 (2H, m), 3.46-3.59 (1H, m), 2.97-3.23 (3H, m), 2.33 (3H, s), 2.10-2.22 (2H, m), 2.01 (3H, s), 1.47-1.76 (2H, m), 1.21 (6H , d, J= 6.8 Hz); HPLC: 96.1%, MS (ESI): m/z 590.2[M+H] ⁺ 41 Yellow powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.51 (1H, s), 8.37 (1H, d, J= 2.8 Hz), 8.11 (1H, d, J= 6.8 Hz), 7.77-7.89 (4H, m), 7.62-7.71 (3H, m), 7.57 (1H, d, J= 6.8 Hz), 6.97-7.05 (1H, m), 6.58-6.63 (2H, m), 5.03-5.10 (1H, m) , 4.76-4.81 (1H, m), 4.74 (2H, s), 4.09 (2H, d, J= 7.2 Hz), 3.08-3.17 (1H, m), 2.99 (6H, s), 1.29-1.34 (6H , m); LC/MS: 99.2%, MS (ESI):617.2 m/z [M+H] ⁺ 42 off-white powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.65 (1H, d, J= 1.6 Hz), 8.41 (1H, d, J= 6.8 Hz), 8.21 (1H, d, J= 6.4 Hz), 7.77 -7.89 (3H, m), 7.55-7.73 (4H, m), 6.97-7.12 (1H, m), 6.75 (1 H, d, J= 15.2 Hz), 4.97-5.03 (1H, m), 4.69- 4.76 (1H, m), 4.07 (2H, d, J= 6.8 Hz), 3.66-3.85 (8H, m), 3.04-3.16 (1H, m), 2.96 (6 H, s), 1.16-1.21 (6H , m); HPLC: 99.4%, MS (ESI): m/z 606.2 [M+H] ⁺ 43 White powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.70 (1H, s), 8.46 (1H, d, J= 7.2 Hz), 8.22-8.28 (1H, m), 7.82-7.89 (3H, m), 7.57-7.76 (4H, m), 7.00-7.09 (1H, m), 6.71 (1H, d, J= 15.2 Hz), 4.96-5.02 (1H, m), 4.75-4.83 (1H, m), 4.08 ( 2H, d, J= 6.4 Hz), 3.84-4.01 (2H, m), 3.32-3.39 (2H, m), 3.23-3.28 (1H, m), 3.06-3.21 (1H, m), 2.98 (6H, s), 2.83-2.88 (1H, m), 1.73-1.80 (1H, m), 1.55-1.64 (2H, m), 1.25-1.32 (1H, m), 1.18-1.24 (6H, m); LC/MS: 100%, MS (ESI): m/z 634.2[M+H] ⁺ 44 Light yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.88-6.89 (1H, m), 8.41-8.43 (1H, m), 8.26-8.28 (1H, m), 7.78-7.88 (3H, m), 7.67-7.71 (1H, m), 7.55-7.60 ( 3H, m), 6.99-7.07 (1H, m), 6.71 (1H, d,J=15.2 Hz ), 4.95-4.99 (1H, m), 4.78-4.82 (1H, m), 4.07 (2H, d,J=7.2 Hz), 3.52-3.57 (1H, m), 3.40 (3H, s), 3.22-3.28 (1H, m), 2.96 (6H, s), 2.80-2.87 (1H, m), 2.03-2.17 (3H , m), 1.71-1.73 (1H, m), 1.27-1.48 (4H, m), 1.16-1.19 (6H, m); LC/MS: 100.0%, MS (ESI):648.3 m/z [(M+H)]⁺ 45 Light yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.68 (1H, s), 8.45 (1H, d,J=6.4 Hz), 8.23 (1H, d,J=6.8 Hz), 7.82-7.83 (3H, m), 7.68-7.72 (1H, m), 7.59-7.65 (3H, m), 6.99-7.05 (1H, m), 6.72 (1H, d,J=15.2 Hz), 5.04-5.08 (1H, m), 4.77-4.81 (1H, m), 4.07 (2H, d,J=6.8 Hz), 3.37-3.48 (3H, m), 3.18-3.27 (1H, m), 2.96-3.02 (8H, m), 2.83-2.88 (1H, m), 1.93-1.96 (m, 3H), 1.49 -1.55 (2H, m), 1.18-1.21 (6H, m); LC/MS: 100.0%, MS (ESI): 633.3 m/z [(M+H)]⁺ 46 off-white powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.59 (1 H, d, J= 2.0 Hz), 8.38 (1H, d, J= 6.4 Hz), 8.16 (1H, d, J= 6.4 Hz), 7.79-7.88 (2H, m), 7.66-7.78 (2H, m), 7.57-7.62 (2H, m), 7.53 (1H, s), 6.51-6.58 (2H, m), 5.94 (1H, dd, J = 8.0, 3.6 Hz), 4.98-5.09 (1H, m), 4.65-4.74 (1H, m), 4.49-4.57 (2H, m), 3.43-3.54 (1H, m), 2.95-3.21 (3H, m ), 2.04-2.21 (2H, m), 1.44-1.76 (2H, m), 1.20 (6H, d, J= 6.8 Hz); HPLC: 100%, MS (ESI): m/z 562.2[M+H] ⁺ . 47 Light yellow powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.43 (1H, s), 8.39 (1H, d, J= 6.4 Hz), 8.17 (1H, d, J= 6.4 Hz), 7.78-7.84 (2H, m), 7.62-7.71 (2H, m), 7.56-7.62 (2H, m), 7.55 (1H, s), 4.91-5.05 (1H, m), 4.63-4.71 (1H, m), 4.47-4.551 ( 2H, m), 3.43-3.56 (1H, m), 3.10-3.29 (2H, m), 3.00-3.08 (1H, m), 2.02-2.21 (5H, m), 1.63-1.76 (1H, m), 1.51-1.59 (1H, m), 1.21-1.27 (6H, m); LC/MS: 96.8%, MS (ESI): m/z 574.2 [M+H] ⁺ 48 Pale yellow powder;¹H NMR (CD₃OD, 400 MHz): δ 8.55 (1H, d,J=2.0 Hz), 8.37-8.42 (1H, m), 8.20 (1H, d,J=6.4 Hz), 7.77-7.92 (3H, m), 7.64-7.72 (1H, m), 7.54-7.62 (3H, m), 5.98 (1H, s), 5.71 (1H, d,J=1.2 Hz), 4.99-5.07 (1H, m), 4.67-4.73 (1H, m), 4.47-4.54 (1H, m), 3.44-3.56 (1H, m), 3.17-3.24 (1H, m), 3.03 -3.09 (1H, m), 2.08-2.21 (2H, m), 2.06 (3H, s), 1.64-1.78 (1H, m), 1.55-1.60 (1H, m), 1.16-1.21 (6H, m); LC/MS: 100%, MS (ESI): m/z 576.2 [M + H]⁺ 49 White powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.48 (1H, d, J= 1.6 Hz), 8.40 (1H, d, J= 6.8 Hz), 8.19 (1H, d, J= 6.8 Hz), 7.80 -7.89 (3H, m), 7.63-7.72 (2H, m), 7.55-7.62 (2H, m), 4.98-5.07 (1H, m), 4.68-4.75 (1H, m), 4.51-4.57 (2H, m), 3.46-3.52 (1H, m), 3.13-3.23 (2H, m), 3.04-3.09 (1H, m), 2.08-2.17 (2H, m), 1.74-1.87 (4H, m), 1.55- 1.72 (2H, m), 1.23-1.28 (6H, m); LC/MS: 99.8%, MS (ESI):601.2 m/z [M+H] ⁺ 50 Yellow powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.57 (1H, d, J= 2.0 Hz), 8.41 (1H, d, J= 6.4 Hz), 8.19 (1H, d, J= 6.8 Hz), 7.73 -7.88 (3H, m), 7.66-7.71 (1H, m), 7.56-7.62 (3H, m), 7.06-7.17 (1H, m), 6.25 (1H, dd, J= 14.8, 2.0 Hz), 4.99 -5.06 (1H, m), 4.66-4.73 (1H, m), 4.45-4.52 (2H, m), 3.47-3.58 (1H, m), 3.18-3.38 (2H, m, overlap with CD ₃ OD signal) , 3.0-3.09 (1H, m), 2.10-2.19 (2H, m), 1.98 (3H, dd, J= 6.8, 1.6 Hz), 1.65-1.80 (1H, m), 1.49-1.64 (1H, m) , 1.18 (6H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 576.3 [M + H] ⁺ 51 Racemic mixture; off-white powder; ^1H NMR (400 MHz, CD ₃ OD): δ 8.71 (1H, s), 8.48 (1H, d, J= 6.4 Hz), 8.27 (1H, d, J= 6.0 Hz), 7.81-7.92 (3H, m), 7.56-7.75 (4H, m), 7.00-7.13 (1H, m), 6.77 (1H, d, J= 15.2 Hz), 5.06-5.14 (1H, m), 4.72-4.79 (1H, m) , 4.06-4.21 (3H, m), 3.86-3.97 (2H, m), 3.43-3.59 (2H, m), 3.25-3.33 (3H, m), 3.14-3.26 (1H, m), 2.98 (6H, s), 2.83-2.94 (1H, m), 1.57-1.82 (2H, m), 1.21 (6H, d, J= 6.4 Hz); HPLC: 100%, MS (ESI): m/z 649.3[M+H] ⁺ 52 yellow powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.69 (1H, s), 8.47 (1H, s), 8.26 (1H, d, J= 5.2 Hz), 7.80-7.93 (3H, m), 7.56- 7.76 (4H, m), 7.02-7.14 (1H, m), 6.76 (1H, d, J= 14.8 Hz), 5.08-5.18 (1H, m), 4.69-4.78 (1H, m), 4.47-4.56 ( 2H, m), 4.03-4.08 (2H, m), 3.48-3.68 (5H, m), 2.94-3.18 (3H, m), 2.11-2.23 (2H, m), 2.00-2.07 (2H, m), 1.80-1.92 (4H, m), 1.51-1.67 (2H, m), 1.20 (6H, d, J= 6.0 Hz); HPLC: 97.1%, MS (ESI): m/z 659.3[M+H] ⁺ 53 yellow powder; ^1H NMR (400 MHz, CD ₃ OD): δ 8.69 (1H, s), 8.45 (1H, d, J= 5.2 Hz), 8.25 (1H, d, J= 6.4 Hz), 7.81-7.96 (3H, m), 7.59-7.76 (4H, m), 7.02-7.17 (1H, m), 6.79 (1H, d, J= 15.2 Hz), 5.01-5.08 (1H, m), 4.73-4.78 (1H, m) , 4.48-4.55 (2H, m), 4.05-4.21 (4H, m), 3.79-3.92 (2H, m), 3.48-3.63 (4H, m), 3.12-3.28 (4H, m), 2.11-2.27 ( 2H, m), 1.56-1.85 (2H, m), 1.20 (6H, d, J= 6.0 Hz); HPLC: 100%, MS (ESI): m/z 661.3[M+H] ⁺ 54 off-white powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.56 (1H, s), 8.31-8.36 (1H, m), 8.08-8.13 (1H, m), 7.77-7.90 (2H, m), 7.42-7.75 (5H, m), 7.06-7.13 (1H, m), 6.46 (1H, d, J= 15.2 Hz), 4.64-4.71 (1H, m), 4.52-4.58 (2H, m), 4.14-4.23 (2H , m), 3.44-3.53 (4H, m), 2.87-3.19 (3H, m), 2.04-2.13 (2H, m), 1.29-1.72 (3H, m), 1.20 (6H, d, J= 6.8 Hz ); LC/MS: 99.8%, MS (ESI):606.2 m/z [M+H]+ 55 yellow powder; ^1H NMR (400 MHz, DMSO _- d6 ): δ ppm 10.95 (1H, brs) 8.87 (1H, d, J= 4.8 Hz), 8.65-8.72 (1H, m), 8.64 (1H, s), 8.13 (2H, brs), 7.65-7.75 (2H, m), 7.39-7.57 (3H, m), 7.24-7.38 (3H, m), 6.82-6.95 (1H, m), 6.62 (1H, d, J= 14.8 Hz), 4.18-4.48 (4H, m), 3.76-3.88 (2H, m), 3.19-3.26 (1H, m), 2.83-2.94 (1H, m), 2.55-2.76 (9H, m), 1.86 (2H, m), 1.28-1.39 (2H, m), 1.20 (6H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 619.3 [M + H] ⁺ 56 yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.70-8.72 (1H, m), 8.29-8.33 (1H, m), 7.78 (1H, s), 7.61-7.72 (3H, m), 7.42-7.48 (2H, m), 7.32-7.34 (1H, m), 6.86-6.92 (1H, m), 6.72-6.75 (1H, m), 4.32-4.36 (2H, m), 4.03 (2H, d,J=7.2 Hz), 3.45-3.49 (1H, m), 3.02-3.15 (3H, m), 2.94 (6H, s), 2.61 (3H, s), 2.09-2.12 (2H, m), 1.55-1.61 (2H , m), 1.26 (6H, d,J=6.8 Hz); LC/MS: 100.0%, MS (ESI):633.3 m/z [(M+H)]⁺ 57 off-white powder;¹H NMR (400 MHz, CD₃OD): δ 8.63 (1H, s), 8.32-8.37 (1H, m), 8.14 (1H, d,J=6.4 Hz), 7.80-7.87 (2H, m), 7.72-7.76 (1H, m), 7.68 (1H, t,J=8.0 Hz ), 7.54-7.63 (2H, m), 7.48 (1H, s), 6.96-7.15 (1H, m), 6.72 (1H, d,J=15.20 Hz), 4.66-4.73 (2H, m), 4.53-4.59 (2H, m), 4.16 (2H, d,J=6.8 Hz), 3.69-3.74 (2H, m), 3.42-3.53 (1H, m), 2.93-3.25 (5H, m), 2.03-2.32 (6H, m), 1.43-1.69 (2H, m), 1.20 (6H, d,J=7.2 Hz); HPLC: 100%, MS (ESI): m/z 645.3[M+H]⁺ 58 yellow powder;¹H NMR (400 MHz, CD₃OD): δ 8.63 (1H, s), 8.37 (1H, d,J=6.4 Hz), 8.16 (1H, d,J=6.2 Hz), 7.73-7.88 (3H, m), 7.50-7.71 (4H, m), 6.95-7.08 (1H, m), 6.72 (1H, d,J=15.2 Hz), 4.95-5.03 (1H, m), 4.65-4.71 (1H, m), 4.46-4.54 (2H, m), 3.99-4.19 (4H, m), 3.42-3.50 (1H, m), 3.10 -3.17 (2H, m), 2.91-3.07 (4H, m), 2.05-2.13 (2H, m), 1.43-1.74 (2H, m), 1.16 (6H, d,J=6.8 Hz); HPLC: 100%, MS (ESI): m/z 662.3[M+H]⁺ 59 pale yellow powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.61 (1H, d, J= 1.6 Hz), 8.33 (1H, d, J= 6.8 Hz), 8.11 (1H, d, J= 6.4 Hz), 7.77 -7.85 (2H, m), 7.72-7.76 (1H, m), 7.64-7.70 (1H, m), 7.54-7.63 (2H, m), 7.48 (1H, s), 6.97-7.07 (1H, m) , 6.72 (1H, d, J= 15.2 Hz), 4.96-5.03 (2H, m), 4.67-4.74 (1H, m), 4.05-4.09 (2H, m), 3.91-4.00 (4H, m), 3.26 -3.32 (4H, m), 2.94-2.99 (7H, m), 1.20 (6H, d, J= 7.2 Hz); LC/MS: 100%, MS (ESI): m/z 605.6 [M+H] ⁺ 60 ( 3R , 4R ); off-white powder; ¹ H NMR (400 MHz, CD ₃ OD): δ 8.54 (1H, s), 8.33-8.37 (1H, m), 8.06-8.12 (1H, m), 7.67-7.78 (2H, m), 7.51-7.64 (3H, m), 7.44-7.50 (2H, m), 6.38-6.44 (2H, m), 5.80-5.86 (1H, m), 4.94-5.05 (2H, m), 4.52-4.72 (2H, m) , 3.49-3.75 (2H, m), 3.32-3.38 (1H, m), 2.64-2.95 (3H, m), 1.85-2.01 (1H, m), 1.71-1.79 (1H, m), 1.42-1.50 ( 1H, m), 1.09 (6H, d, J= 6.8 Hz); HPLC: 97.5%, MS (ESI): m/z 592.3[M+H] ⁺ 61 pale yellow powder; ^1H NMR (400 MHz, CD ₃ OD): δ 8.64 (1H, s), 8.37 (1H, d, J= 6.8 Hz), 8.16 (1H, d, J= 6.8 Hz), 7.76-7.86 (3H, m), 7.65-7.70 (1H, m), 7.54-7.64 (3H, m), 6.98-7.07 (1H, m), 6.72 (1H, d, J= 15.2 Hz), 4.95-5.01 (1H, m) , 4.81-4.87 (1H, m), 4.68-4.74 (1H, m), 4.07 (2H, d, J= 7.2 Hz), 3.85-3.99 (2H, m), 3.52-3.64 (3H, m), 3.40 (3H, s), 3.00-3.09 (1H, m), 2.96 (6H, s), 2.91 (1H, s), 1.83-2.05 (3H, m), 1.57-1.69 (2H, m), 1.15-1.20 (6H, m); LC/MS: 99.4%, MS (ESI): m/z 634.3 [M + H] ⁺ 62 Racemic mixture; yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.65-8.69 (1H, m), 8.43-8.47 (1H, m), 8.18-8.24 (1H, m), 7.78-7.88 (3H, m), 7.65-7.72 (2H, m), 7.57-7.61 ( 2H, m), 6.98-7.06 (1H, m), 6.73 (1H, d,J=15.2 Hz), 4.99-5.11 (2H, m), 4.70-4.81 (1H, m), 3.84-4.12 (5H, m), 3.38-3.65 (3H, m), 2.81-3.24 (9H, m), 1.16 -1.22 (6H, m); LC/MS: 100%, MS (ESI):657.2 m/z [M+Na]⁺ 63 yellow powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 8.63 (1H, s), 8.39-8.45 (1H, m), 8.11-8.17 (1H, m), 7.50-7.91 (7H, m), 6.96-7.13 (1H, m), 6.72 (1H, d, J= 15.4 Hz), 5.09-5.16 (1H, m), 3.97-4.16 (3H, m), 3.37-3.62 (3H, m), 3.12-3.27 (1H , m), 2.77-3.05 (8H, m), 2.24-2.31 (1H, m), 1.68-2.05 (3H, m), 1.12-1.29 (6H, m); LC/MS: 100%, MS (ESI): 619.3 m/z [M+H] ⁺ 64 (3R, 4R); yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.64-8.68 (1H, m), 8.51 (1H, dd,J=6.4, 3.2 Hz), 8.27-8.31 (1H, m), 7.81-7.92 (3H, m), 7.65-7.72 (2H, m), 7.57-7.62 (2H, m), 5.87 (1H, dd,J=46.0, 3.6 Hz), 5.46 (1H, dd,J=14.8, 3.6 Hz), 5.06-5.13 (1H, m), 4.65-4.75 (1H, m), 3.69-3.76 (1H, m), 3.54-3.62 (1H, m), 3.34-3.47 (3H, m) , 2.78-3.01 (3H, m), 1.98-2.05 (1H, m), 1.81-1.92 (1H, m), 1.53-1.65 (1H, m), 1.20 (6H, d,J=6.8 Hz); LC/MS: 99.4%, MS (ESI): 610.2 m/z [M+H]⁺ 65 (3R, 4R); yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.58-8.61 (1H, m), 8.44 (1H, dd,J=6.4, 2.4 Hz), 8.17-8.22 (1H, m), 7.79-7.91 (3H, m), 7.56-7.72 (4H, m), 6.92 (1H, d,J=2.0 Hz), 5.05-5.13 (1H, m), 4.68-4.75 (1H, m), 3.69-3.76 (1H, m), 3.37-3.59 (4H, m), 2.60-3.01 (7H, m), 1.96 -2.07 (3H, m), 1.79-1.88 (1H, m), 1.52-1.63 (1H, m), 1.18 (6H, d,J=6.8 Hz); LC/MS: 98.3%, MS (ESI): 632.2 m/z [M+H]⁺ 66 (3R, 4R); yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.52-8.59 (1H, m), 8.39-8.45 (1H, m), 8.04-8.13 (1H, m), 7.52-7.88 (7H, m), 5.94 (1H, s), 5.69 (1H, s) , 5.08-5.17 (1H, m), 4.62-4.73 (1H, m), 3.34-3.76 (5H, m), 2.76-3.05 (3H, m), 1.52-2.10 (6H, m), 1.20 (6H, d,J=6.8 Hz); LC/MS: 98.9%, MS (ESI): 606.2 m/z [M+H]⁺ 67 (3R, 4R); light yellow powder;¹H-NMR (CD₃OD, 400 MHz): δ 8.73 (1H, d,J=8.0 Hz), 8.32 (1H, d,J=8.8 Hz), 7.74 (1H, s), 7.59-7.69 (3H, m), 7.46-7.48 (2H, m), 7.35-7.37 (1H, m), 6.49-6.56 (1H, m), 6.32-6.36 (1H, m), 5.69-5.76 (1H, m), 4.91-4.95 (3H, m), 4.84-4.86 (1H, m), 3.60-3.66 (1H, m), 3.34-3.39 (1H, m) , 3.25-3.28 (1H, m), 2.84-2.94 (2H, m), 2.69-2.75 (1H, m), 2.57 (3H, s), 1.88-1.94 (1H, m), 1.73-1.77 (1H, m), 1.43-1.47 (1H, m), 1.26 (6H, d,J=6.8 Hz); LC/MS: 100.0%, MS (ESI):606.3 m/z [(M+H)]⁺ 68 (3R, 4R); yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.59-8.63 (1H, m), 8.42-8.47 (1H, m), 8.17-8.22 (1H, m), 7.55-7.73 (7H, m), 7.06-7.12 (1H, m), 6.22 (1H, d,J=15.2 Hz), 5.05-5.12 (1H, m), 4.64-4.75 (1H, m), 3.69-3.76 (1H, m), 3.30-3.58 (4H, m), 2.89-3.01 (1H, m), 2.75 -2.84 (2H, m), 1.95-2.04 (4H, m), 1.80-1.91 (1H, m), 1.52-1.63 (1H, m), 1.18 (6H, d,J=6.8 Hz); LC/MS: 100%, MS (ESI): 606.3 m/z [M+H]⁺ 69 Racemic mixture; yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.54-8.61 (1H, m), 8.42 (1H, d,J=6.8 Hz), 8.14-8.18 (1H, m), 7.55-7.87 (7H, m), 7.06-7.14 (1H, m), 6.22 (1H, d,J=15.2 Hz), 5.03-5.13 (1H, m), 4.67-4.72 (1H, m), 3.81-4.15 (3H, m), 3.34-3.61 (3H, m), 2.79-3.25 (3H, m), 1.97 (3H, d,J=6.8 Hz), 1.16-1.21 (6H, m); LC/MS: 100%, MS (ESI): 592.3 m/z [M+H]⁺ 70 Yellow powder;¹H-NMR (CD₃OD, 400 MHz): δ 8.54 (1H, d,J=7.6 Hz), 8.45 (1H, d,J=8.8 Hz), 7.65-7.77 (4H, m), 7.45-7.52 (2H, m), 7.35-7.37 (1H, m), 6.91-6.97 (1H, m), 6.22 (1H, d,J=14.8 Hz), 4.93-4.94 (2H, m), 3.64-3.65 (1H, m), 3.32-3.36 (2H, m), 3.26-3.28 (2H, m), 2.85-2.92 (2H, m), 2.74 -2.77 (1H, m), 2.62 (3H, s), 1.87-1.95 (3H, m), 1.70-1.77 (1H, m), 1.44-1.52 (1H, m), 1.25 (6H, d,J=6.8 Hz), 0.85-0.91 (1H, m); LC/MS: 98.5%, MS (ESI):620.2 m/z [(M+H)]⁺ 71 yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.57 (1H, d,J=2.0 Hz), 8.38 (1H, d,J=6.8 Hz), 8.16 (1H, d,J=6.8 Hz), 7.79-7.86 (2H, m), 7.66-7.74 (2H, m), 7.57-7.62 (3H, m), 7.07-7.14 (1H, m), 6.25 (1H, dd,J=15.2, 1.6 Hz), 5.01-5.05 (1H, m), 4.68-4.72 (1H, m), 4.01-4.05 (4H, m), 3.33-3.36 (4H, m), 3.00-3.07 (1H, m) , 1.98 (3H, dd,J=6.8, 1.6 Hz), 1.20 (6H, dd,J=6.8, 1.6 Hz); LC/MS: 100.0%, MS (ESI):562.2 m/z [(M+H)]⁺ 72 (3R, 4R); yellow powder;¹H-NMR (CD₃OD, 400 MHz): δ 8.46-8.52 (1H, m), 8.36-8.38 (1H, m), 8.05-8.08 (1H, m), 7.78-7.87 (2H, m), 7.65-7.69 (2H, m), 7.49-7.55 ( 3H, m), 7.05-7.12 (1H, m), 6.24 (1H, dd,J=15.2, 1.2 Hz), 4.99-5.03 (1H, m), 4.65-4.72 (1H, m), 3.67-3.73 (1H, m), 3.38-3.48 (4H, m), 2.98-3.05 (1H, m) , 2.81-2.91 (2H, m), 2.4-2.09 (1H, m), 1.97 (3H, dd,J=6.8, 1.2 Hz), 1.81-1.86 (1H, m), 1.62-1.68 (1H, m), 1.17-1.22 (6H, m); LC/MS: 99.4%, MS (ESI):605.3 m/z [(M+H)]⁺ 73 ( 3R , 4R ); off-white powder; ^1H NMR (CD ₃ OD, 400 MHz): δ 7.85 (1H, s), 7.36-7.45 (3H, m), 7.34 (1H, d, J= 8.0 Hz), 7.19 (1H, d, J= 7.6 Hz), 6.97-7.05 (1H, m), 6.60-6.74 (1H, m), 6.17 (1H, d, J= 15.2 Hz), 4.93-4.97 (2H, m), 3.55-3.61 (1H, m) , 3.45-3.54 (1H, m), 3.35-3.43 (1H, m), 3.23-3.27 (1H, m), 3.03-3.09 (1H, m), 2.94-3.01 (1H, m), 2.57-2.68 ( 2H, m), 2.54 (3H, s), 1.88 (3H, d, J= 6.4 Hz), 1.64-1.84 (2H, m), 1.34-1.45 (1H, m), 1.30 (6H, d, J= 6.8 Hz); LC/MS: 100%, MS (ESI): m/z 608.3 [M + H] ⁺ 74 ( 3R , 4R ); White powder; ¹ H NMR (CD ₃ OD, 400 MHz): δ 7.93 (1H, s), 7.68-7.84 (2H, m), 7.59 (2H, m), 7.36 (1H, d, J= 7.2 Hz), 7.23- 7.30 (1H, m), 6.89-7.04 (2H, m), 6.77-6.83 (1H, m), 6.48-6.56 (1H, m), 6.18 (1H, d, J= 14.8 Hz), 4.51-4.69 ( 2H, m), 3.60-3.69 (2H, m), 3.41-3.52 (1H, m), 3.13-3.19 (1H, m), 2.70-3.02 (4H, m), 1.89-1.99 (4H, m), 1.74-1.82 (1H, m), 1.41-1.57 (1H, m), 1.20-1.34 (6H, m); LC/MS: 99.9%, MS (ESI):594.2 m/z [M+H] ⁺ 75 White powder; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.33-8.57 (3H, m), 7.53-7.65 (4H, m), 7.34-7.48 (4H, m), 6.95-7.12 (2H, m), 6.29- 6.52 (1H, m), 4.69-4.88 (1H, m), 4.38-4.59 (3H, m), 4.17-4.36 (1H, m), 3.54-3.73 (1H, m), 3.25-3.40 (2H, m ), 2.83-3.05 (3H, m), 2.48 (6H, s), 1.85-2.0 (2H, m), 1.46 (9H, s), 1.24-1.26 (8H, m); LC/MS: 100%, MS (ESI): m/z 719.3 [M + H] ⁺ 76 (3R, 4R); Yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.66-8.70 (1H, m), 8.45 (1H, dd,J=6.8, 2.4 Hz), 8.19-8.24 (1H, m), 7.80-7.88 (3H, m), 7.64-7.71 (2H, m), 7.56-7.61 (2H, m), 7.01-7.08 (1H, m) , 6.70 (1H, d,J=15.2 Hz), 5.02-5.07 (1H, m), 4.69-4.79 (1H, m), 4.02 (2H, d,J=7.2 Hz), 3.70-3.76 (1H, m), 3.53-3.60 (3H, m), 3.31-3.46 (3H, m), 2.76-3.07 (5H, m), 1.96-2.03 (3H, m), 1.78 -1.91 (4H, m), 1.51-1.62 (2H, m), 1.19 (6H, d,J=7.2 Hz); LC/MS: 100%, MS (ESI): 689.3 m/z [M+H]⁺. 77 Mixture of 2 trans isomers; yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.55-8.62 (1H, m), 8.41-8.46 (1H, m), 8.15-8.19 (1H, m), 7.56-7.87 (7H, m), 7.06-7.18 (1H, m), 6.21 (1H, d,J=16.0 Hz), 5.09-5.21 (1H, m), 4.67-4.82 (2H, m), 4.26-4.35 (1H, m), 3.41-3.62 (3H, m), 3.12-3.21 (2H, m), 2.80 -2.86 (1H, m), 2.38-2.59 (1H, m), 1.97 (3H, dd,J=7.2, 1.6 Hz), 1.18 (6H, d,J=6.8 Hz). LC/MS: 100%, MS (ESI): 592.2 m/z [M+H]⁺. 78 ( 3R , 4R ); gray powder; ^1H NMR (MeOD, 400 MHz): δ ppm 7.85 (1H, s), 7.34-7.48 (4H, m), 7.18 (1H, d, J =7.6 Hz), 7.03-7.10 (1H, m), 6.49 (1H, s), 5.34-5.52 (1H, m), 5.21 (1H, dd, J =15.2, 3.2 Hz), 4.92-4.95 (2H, m), 3.50-3.62 (2H, m), 3.37-3.45 (1H, m), 3.20-3.27 (1H, m), 2.93-3.05 (2H, m), 2.50-2.61 (5H, m), 1.67-1.83 (2 H, m), 1.33-1.42 (1H, m ), 1.30 (6H, d, J =6.8 Hz); LC/MS: 100%, MS (ESI): m/z 612.3 [M + H]+ 79 Yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.56 (1H, d,J=2.0 Hz), 8.36 (1H, d,J=6.4 Hz), 8.15 (1H, d,J=6.8 Hz), 7.76-7.83 (3H, m), 7.61-7.67 (1H, m), 7.53-7.60 (2H, m), 7.44 (1H, s), 5.85 (1H, dd,J=46.0, 3.6 Hz), 5.44 (1H, dd,J=15.2, 3.6 Hz), 5.00 (1H, d,J=15.6 Hz), 4.63 (1H, d,J=15.6 Hz), 3.89-4.00 (4H, m), 3.21-3.29 (4H, m, blocked by water signal), 2.87-2.95 (1H, m), 1.15-1.21 (6H, m); LC/MS: 100%, MS (ESI): 566.2 m/z [M+H]⁺ 80 Racemic mixture; Yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.62-8.65 (1H, m), 8.44-8.49 (1H, m), 8.20-8.24 (1H, m), 7.79-7.90 (3H, m), 7.65-7.71 (2H, m), 7.54-7.61 ( 2H, m), 5.85 (1H, dd,J=46.4, 3.6 Hz), 5.44 (1H, dd,J=14.8, 3.6 Hz), 5.03-5.13 (1H, m), 4.65-4.76 (1H, m), 3.81-4.12 (3H, m), 3.32-3.61 (3H, m), 2.78-3.21 (4H, m) , 1.16-1.21 (6H, m); LC/MS: 99.3%, MS (ESI): 596.2 m/z [M+H]⁺ 81 off-white powder; ^1H NMR (400 MHz, CD ₃ OD): δ 8.56 (1H, s), 8.44 (1H, d, J= 6.8 Hz), 8.24 (1H, d, J= 6.4 Hz), 7.92-8.00 (1H, m), 7.81-7.91 (2H, m), 7.73 (1H, t, J= 7.2 Hz), 7.62 (1H, d, J= 7.6 Hz), 7.52-7.56 (1H, m), 7.46 (1H, s ), 5.85 (1H, dd, J= 46.4, 4.0 Hz), 5.48 (1H, dd, J= 15.2, 4.0 Hz), 4.90-5.02 (2H, m), 4.73-4.83 (1H, m), 3.41 ( 3H, s), 3.23-3.32 (2H, m), 2.85-2.94 (1H, m), 1.99-2.24 (3H, m), 1.65-1.76 (1H, m), 1.30-1.55 (4H, m), 1.15-1.24 (6H, m); HPLC: 98.5% MS (ESI): m/z 608.2[M+H] ⁺ 82 (3R, 4R); light yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.52-8.60 (1H, m), 8.44 (1H,J=6.8 Hz), 8.22-8.26 (1H, m), 7.81-7.92 (3H, m), 7.67-7.72 (1H, m), 7.56-7.63 (2H, m), 7.48 (1H, s), 5.87 (1H , dd,J=46.0, 2.8 Hz), 5.46 (1H, dd,J=15.2, 4.0 Hz), 5.07-5.12 (1H, m), 4.73-4.79 (1H, m), 3.69-3.75 (1H, m), 3.37-3.56 (4H, m), 2.99-3.12 (1H, m) , 2.81-2.97 (1H, m), 2.06-2.12 (1H, m), 1.82-1.89 (1H, m), 1.64-1.73 (1H, m), 1.17-1.24 (6H, m); LC/MS: 99.7%; MS (ERI): 609.2m/z [(M+H)]⁺ 83 Mixture of 2 trans isomers; Yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.60-8.67 (1H, m), 8.48-8.52 (1H, m), 8.24-8.28 (1H, m), 7.81-7.93 (3H, m), 7.56-7.73 (4H, m), 5.85 (1H, dd,J=46.0, 3.6 Hz), 5.44 (1H, dd,J=14.8, 3.6 Hz), 5.09-5.22 (1H, m), 4.67-4.77 (1H, m), 4.36-4.35 (1H, m), 3.46-3.62 (3H, m), 3.10-3.21 (2H, m) , 2.81-2.88 (1H, m), 2.41-2.62 (1H, m), 1.16-1.22 (6H, m); LC/MS: 100%, MS (ESI): 596.2 m/z [M+H]⁺ 84 Yellow solid;¹H-NMR (CD₃OD, 400 MHz): δ 8.63 (1H, s), 8.43 (1H, d,J=6.8 Hz), 8.29 (1H, d,J=6.8 Hz), 7.82-7.92 (3H, m), 7.65-7.71 (1H, m), 7.57-7.62 (2H, m), 7.54 (1H, s), 5.85 (1H, dd,J=46.4, 3.6 Hz), 5.45 (1H, dd,J=14.8, 3.6 Hz), 4.92-4.99 (1H, m), 4.72-4.80 (1H, m), 3.51-3.58 (1H, m), 3.39 (3H, s), 3.22-3.31 (1H, m, overlapped by signal CD₃OD), 2.76-2.83 (1H, m), 2.01-2.18 (3H, m), 1.69-1.73 (1H, m), 1.27-1.46 (4H, m), 1.15-1.21 (6H, m); LC/MS: 100%, MS (ESI): 609.2 m/z [M+H]⁺ 85 White powder; H NMR (CDCl ₃ , 400 MHz): δ 8.54 (1H, d, J= 5.6 Hz), 8.30 (1H, s), 8.04 (1H, brs), 7.59 (1H, d, J= 8.8 Hz), 7.55 (2H, d, J= 6.0 Hz), 7.44 (1H, s), 7.30-7.42 (3H, m), 7.25 (1H, d, J= 8.8 Hz), 6.92-6.96 (1H, m), 5.85 ( 1H, dd, J= 47.6, 3.6 Hz), 5.26 (1H, dd, J= 14.8, 3.6 Hz), 4.76-4.85 (1H, m), 4.12-4.31 (3H, m), 3.42-3.53 (3H, m), 3.09-3.18 (2H, m), 2.83-2.96 (1H, m), 1.80-1.87 (2H, m), 1.43-1.51 (2H, m, blocked by water signal), 1.15-1.21 (9H, m ); LC/MS: 98.8%, MS (ESI): m/z 609.3 [M+H] ⁺ 86 Off-white powder; ^1H NMR ( _CDCl3 , 400 MHz): δ 8.62 (1H, d, J= 6.0 Hz), 8.41 (1H, s), 8.06-8.15 (1H, m), 7.61-7.75 (3H, m), 7.31 -7.57 (5H, m), 7.02-7.23 (1H, m), 5.95 (1H, dd, J= 47.6, 3.2 Hz), 5.37 (1H, dd, J= 14.8, 3.2 Hz), 4.85-4.96 (1H , m), 4.46-4.54 (1H, m), 4.07-4.36 (2H, m), 3.47-3.60 (2H, m), 29.5-3.04 (1H, m), 1.92-2.05 (2H, m), 1.68 -1.80 (2H, m), 1.27 (6H, d, J= 6.8 Hz); LC/MS: 97.3%, MS (ESI):649.1 m/z [M+H] + 87 Racemic mixture; off-white powder; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.39 (1H, s), 7.97 (1H, d, J= 6.4 Hz), 7.83-7.92 (2H, m), 7.73-7.80 (4H, m), 7.61 -7.72 (3H, m), 7.56 (1H, d, J= 7.6 Hz), 7.44 (1H, t, J= 8.0 Hz), 7.12-7.16 (1H, m), 5.85 (1H, dd, J= 40.0 , 4.0 Hz), 5.79 (1H, dd, J= 14.8, 3.6 Hz), 5.35-5.38 (1H, m), 5.03-5.07 (1H, m), 3.64-3.69 (1H, m), 3.18- 3.27 ( 2H, m), 3.11-3.17 (1H, m), 2.41-2.48 (2H, m), 2.02-2.08 (1H, m), 1.58-1.64 (1H, m), 1.28-1.34 (6H, m); HPLC: 96.9% MS (ESI): m/z 643.2[M+H] ⁺ 88 Yellow powder; ^1H NMR ( _CDCl3 , 400 MHz): δ 8.47 (1H, d, J= 6.0 Hz), 8.28 (1H, d, J= 1.2 Hz), 8.04-8.08 (1H, m), 7.59 (1H, d , J= 9.2 Hz), 7.52-7.57 (2H, m), 7.35-7.46 (3H, m), 7.26-7.34 (2H, m), 5.85 (1H, dd, J= 47.6, 3.6 Hz), 5.27 ( 1H, dd, J= 15.2, 3.6 Hz), 4.78-4.85 (1H, m), 4.08-4.24 (3H, m), 3.32-3.39 (4H, m), 3.19-3.30 (2H, m), 2.85- 2.96 (1H, m), 1.79-1.84 (2H, m), 1.45-1.58 (2H, m, overlapped by the water signal), 1.17 (6H, d, J= 6.8 Hz); LC/MS: 98%, MS (ESI): m/z 595.2 [M + H] ⁺

Claims (15)

1. A compound having a structure selected from structures 11, 26, 27, 31, 32, 34-36, 39-41, 44-73, 76-80, 82, 83 and 87 as defined in the table: 2. Pharmaceutical composition for the prevention and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases, containing a compound according to claim 1 as an active substance having inhibitory activity against cyclin-dependent kinase ( CDK), together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. 3. Use of a compound according to claim 1 as a pharmaceutically active agent which has inhibitory activity against cyclin-dependent kinase 7 (CDK7). 4. Use of a compound according to claim 1 for the prevention and/or treatment of a disease associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest due to abnormal activity and/or overexpression of one or more cyclin-dependent kinases (CDKs), in in particular, cyclin-dependent kinase 7 (CDK7), where the disease is selected from proliferative diseases, infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases and inflammatory diseases. 5. Use according to claim 4, wherein the proliferative disease is cancer, preferably a cancer selected from the group consisting of or consisting of the following diseases: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurilemmoma, amplular colon carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, bladder cancer, bronchial carcinoma, estrogen-dependent and estrogen-independent breast cancer, Burkitt's lymphoma, body cancer, tumor of unknown primary site, carcinoma (CUP syndrome), colorectal cancer, small intestinal cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial types of cancer, Ewing tumors, gastrointestinal tract tumors, stomach cancer, gallbladder cancer, gallbladder carcinomas, uterine cancer, cervical cancer, glioblastomas, gynecological tumors, ear, nose and throat tumors, hematological tumor, hairy cell leukemia, urethral cancer, skin cancer, testicular cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumor, carcinoids, Kaposi's sarcoma, cancer larynx, germinal cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer of the mouth and lips), central nervous system cancer , liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymphomas, stomach cancer, malignant melanoma, malignant neoplasm, malignant neoplasms of the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's lymphoma / non-Hodgkin lymphoma, fungoid granuloma, nasal cancer, neuroma, neuroblastoma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer glands, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, T-cell lymphoma, thymoma, tubal carcinoma, eye tumors, urethral cancer, urological tumors, urothelial carcinoma, vulvar cancer, warts, tumors soft tissue, soft tissue sarcoma, nephroblastoma, cervical carcinoma, tongue cancer, invasive ductal carcinoma of the breast, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small cell lung carcinoma, non-small cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma , mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astropytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumors, uterine sarcoma, salivary gland cancers, anal gland adenocarcinomas, mastocytomas, renal pelvis tumor, ureter tumor, hereditary papillary renal cancers, sporadic papillary renal cancers, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, subpharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer, squamous cell carcinoma, melanoma oral cavity, AIDS-associated lymphoma, cutaneous T-cell lymphoma, central nervous system lymphoma, malignant fibrous histiocytoma, lymph node sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma , and feline mammary carcinoma. 6. Use according to claim 4, wherein the infectious disease, including opportunistic diseases, is a disease selected from the group consisting of or consisting of the following diseases: AIDS, adenoviral infection, alveolar hydatid echinococcosis (AHD), amoebiasis, angiostrongyliasis, anisakiasis , anthrax, babesiosis, balantidiasis, Baylisascaris nematode infection, bilharzia (schistosomiasis), blastocytosis, Lyme borreliosis, botulism, Brainerd's diarrhea, brucellosis, bovine spongiform encephalopathy (BSE), candidiasis, capillariasis, chronic fatigue syndrome (CFS), disease Chagas, chicken pox, chlamydia pneumoniae infection, cholera, chronic fatigue syndrome, Creutzfeldt-Jakob disease (CJD), clonorchiasis, cutaneous larva migrans (CLM), coccidiridomycosis, conjunctivitis, coxsackie infection (Cox A16), cryptococcal disease, cryptosporidiosis, Western fever Nila, cyclosporiasis, neurocysticercosis, cytomegalovirus infection, dengue fever, Dipylidium caninum infection, Ebola hemorrhagic fever (EHF), alveolar echinococcosis (AE), encephalitis, intestinal amoeba infection, Entamoeba dispar infection, Entamoeba hartmanni infection, Entamoeba polecki infection, enterobiasis, enterovirus infection (polio/non-polio), Epstein-Barr virus infection, E. coli infection, food infection, foot and mouth disease, fungal dermatitis, fungal infections, gastroenteritis, group A streptococcal disease, group B streptococcal disease, Hansen's disease (leprosy), hantavirus pulmonary syndrome, lice (pediculosis), Helicobacter pylori infection, hematological disease, Hendra virus infection, hepatitis (HCV, HBV), herpes zoster (shingles), HIV, human ehrlichiosis, parainfluenza virus infection, influenza, isosporiasis, Lassa fever, leishmaniasis, visceral leishmaniasis (VL), malaria, Marburg hemorrhagic fever, measles, meningitis, Mycobacterium avium complex (MAC) infection, infection with the amoeba Naegleria Fowler, nosocomial infection, infection with non-pathogenic intestinal amoebae, onchocerciasis, opisthorchiasis, papillomavirus infection, parvovirus infection, plague, Pneumocystis pneumonia (RSV), polyomavirus infection, Q fever, rabies, respiratory syncytial virus infection, rheumatic arthritis, Rift Valley fever, rotavirus infection, roundworm infection, salmonellosis, scabies, shigelliosis, shingles, encephalitis lethargica, smallpox, streptococcal infection , tapeworm infection, tetanus, toxic shock syndrome, tuberculosis, duodenitis, parahemolytic vibrio infection, vibrio common purulent infection, viral hemorrhagic fever, warts, waterborne infections, varicella zoster virus infection, whooping cough and amaryllium fever. 7. Use according to claim 4, in which the immunological disease and/or autoimmune disease is a disease selected from the group including or consisting of the following diseases: asthma, diabetes, rheumatic diseases, rejection of transplanted organs and tissues, rhinitis, chronic obstructive lung diseases, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis/eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, manifestations of allergic diseases, primary immunodeficiencies, antibody deficiency conditions, cell-mediated immunodeficiencies, severe combined immunodeficiency, DiGeorge syndrome, IgE hyperproduction syndrome (HIES), Wiskott-Aldrich syndrome (WAS), ataxia-telangiectasia, immune-mediated cancers, leukocyte defects, autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) , multiple sclerosis (MS), immune-mediated diabetes 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 thyroiditis, dermatomyositis, Goodpasture's syndrome (GPS), myasthenia gravis (MG), sympathetic ophthalmia, phacogenic uveitis, chronic aggressive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia and Werlhof's disease. 8. Use according to claim 4, wherein the inflammatory disease is caused, induced, initiated and/or enhanced by bacteria, viruses, prions, parasites, fungi and/or caused by irritant, traumatic, metabolic, allergic, autoimmune or idiopathic agents. 9. Use according to claim 4 or 8, wherein the inflammatory disease is selected from the group consisting of or 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 skin diseases, inflammatory disease uveitis and inflammatory diseases of the larynx. 10. Application according to paragraphs. 4, 8 or 9, wherein the inflammatory disease is selected from the following diseases: 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 diseases of uveitis, inflammatory diseases of the larynx, wherein said inflammatory diseases are preferably selected from the group consisting of abscess, Acanthamoeba infection, juvenile acne, actinomycosis, acute inflammatory dermatoses, acute laryngeal infections in adults, acute multifocal placoid pigment epitheliopathy, acute (thermal) trauma, acute retinal necrosis, acute suppurative otitis media, algae diseases, allergic contact dermatitis, amyloidosis, angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, pseudorabies, autoantibodies in vasculitis, bacterial diseases, bacterial laryngitis, bacterial meningitis, Behçet's disease (BD) , shotgun choroidopathy, Gilchrist blastomycosis, Born's disease, brucellosis, bullous myringitis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in immature animals, canine hemorrhagic fever, canine herpes virus encephalomyelitis, chronic cholesteatoma, granulomatous diseases (CGD) , chronic inflammatory dermatoses, chronic recurrent encephalomyelitis, chronic suppurative otitis media, ocular cicatricial pemphigoid (OCP), common upper respiratory tract infection, granuloma, Crohn's disease, cryptococcal disease, dermatomyositis, diphtheria, discoid lupus erythematosus (DLE), drug-induced vasculitis, drug-induced drug reaction or hypersensitivity, encephalitic zoonosis, eosinophilic meningoencephalitis, erythema multiforme (EM), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalitis, feline spongiform encephalopathy, fibromyalgia, Fuchs' heterochromic uveitis, gastroesophageal (larynopharyngeal) reflux disease giant cell arteritis, glanders, glaucomatocyclic crisis, gonorrheal granular myringitis, granulomatous meningoencephalitis (GME), herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune and idiopathic disorders, infections of an immunodeficient host, infectious canine hepatitis, inhalational laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki syndrome, La Crosse viral encephalitis, laryngeal abscess, laryngotracheobronchitis, leishmaniasis, phacogenic uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lymphoma, meningitis, greyhound meningoencephalitis, others, th meningitis/meningoencephalitis , microscopic polyangiitis, multifocal choroiditis, multifocal encephalomyelitis caused by canine distemper in mature animals, multiple sclerosis, muscle tension dysphonia (MTD), mycotic (fungal) diseases, mycotic diseases of the central nervous system, necrotizing encephalitis, neosporosis, encephalitis of old dogs, onchocerciasis, parasitic encephalomyelitis, parasitic infections, parsplanitis, parvovirus encephalitis, childhood laryngitis, pollutant and inhalant allergies, polymyositis, post-vaccination canine distemper encephalitis, prion protein-induced diseases, protothecosis, protozoal encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug encephalitis, oh lesion, radiation laryngitis, radiation necrosis, relapsing polychondritis, Reiter's syndrome, retinal pigmentary degeneration, retinoblastoma, rheumatoid arthritis, rickettsial diseases, Rocky Mountain spotted fever, salmon poisoning disease (SPD), sarcocystosis, sarcoidosis, schistosomatosis, scleroderma, rhinoscleroma, creeping choroiditis, idiopathic cerebellitis, Sjögren's syndrome, spasmodic croup, spirochetal (syphilis) diseases, spongiotic dermatitis, sporotrichosis, steroid-responsive meningitis-arteritis, Stevens-Johnson syndrome (SJS, erythema multiforme), epiglottitis, sympathetic ophthalmia, syngamosis, syphilis, systemic vasculitis for sarcoidosis, Takayasu syndrome, tendinitis (tendonitis), thromboangiitis obliterans (Buerger's disease), canine tick-borne viral encephalitis, toxic epidermal necrolysis (TEN), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, allergic rash (urticaria), vasculitis, vasculitis and malignant neoplasms, vasculitis and rheumatoid arthritis, vasculitis in idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal and parasitic infections, viral diseases, viral laryngitis, vitiligo, voice abuse, vocal cord hemorrhage, Vogt-Koyanagi-Harada (VKH) syndrome, Wegener's granulomatosis and Whipple's disease.