HK1171742A - Tricyclic pyrazol amine derivatives - Google Patents

Description

Tricyclic pyrazolylamine derivatives

Technical Field

The present invention relates to compounds of formula (I) and related structural formulae, their use as pharmaceuticals and their use in the treatment of autoimmune, inflammatory, multiple sclerosis and other diseases such as cancer.

Background

Phosphoinositide 3-kinase (PI3K) has important signal transduction roles in cell proliferation, cell survival, angiogenesis, membrane trafficking, glucose transport, neurite outgrowth, membrane shrinkage, peroxide production, actin reorganization and chemotaxis (Cantley, 2000, Science, 296, 1655) -1657).

The term PI3K refers to a mammalian lipid kinase family consisting of 8 identified PI3Ks, which can be divided into three subfamilies according to their structure and substrate specificity.

Class I PI3K includes two subclasses: class IA and class IB.

Class IA contains an 85KDa regulatory unit (responsible for the interaction between Src homology domain 2(SH2) and other proteins interacting with phosphotyrosine residues) and a 110KDa catalytic subunit that generates second messenger signals downstream of tyrosine kinases to control cell metabolism, growth, proliferation, differentiation, motility and survival. There are three catalytic forms (p100 α, p110 β, p110 δ) and five regulatory isoforms (p85 α, p85 β, p55 γ, p55 α and p50 α) of this class.

Class IB is activated by the G protein β γ subunit of the G protein heterodimer. The only characteristic member of class IB is PI3K γ (consisting of the p110 γ catalytic subunit complexed with the regulatory protein p101 of 101-KDa).

Class IA PI3K includes the α, β and δ isoforms, about 170KDa, characterized by the presence of the C2 domain at the C-terminus.

Class III PI3K includes phosphoinositide (phosphatidylinositol) -specific kinase-3.

The evolutionarily conserved isoforms P110 α and β are widely expressed, whereas δ and γ are more specifically expressed in the hematopoietic cell system, smooth muscle cells, muscle cells and endothelial cells (vanhaesbroeck et al, 2001, annu. rev. biochem., 70, 535-602). Their expression is regulated in an inducible manner, depending on the cell type, tissue type, stimulus and disease state.

PI3K is an enzyme involved in phospholipid signaling, activated in response to various extracellular signals, such as growth factors, mitogens, integrins (inter-cellular interactions), hormones, cytokines, viruses, and neurotransmitters; it is also subject to intracellular cross-regulation by other signal transduction molecules, such as small gtpases, kinases or phosphatases (i.e. cross-talk, where such initial signals activate several parallel pathways and in a second step transmit signals to PI3Ks by intracellular signal transduction).

Inositol phosphates (PtdIns) are the basic building blocks that make up inositol lipids in eukaryotic cells, and contain D-myo-inositol-1-phosphate (Ins1P) linked to diglycerides through a phosphate group. The cephalinositols of PtdIns have five free hydroxyl groups, three of which are found to be phosphorylated in the cell in different combinations. PtdIns and their phosphorylated products are collectively referred to as inositol phospholipids or inositol Phosphates (PI). Eight PI species have been demonstrated to be present in eukaryotic cells (Vanhaaesebroeck et al, 2001, supra). All PIs are present on the cell membrane and are substrates for kinases, phosphatases and lipases.

In vitro, PI3K enables three different substrates inositol phosphate (PtdIns), inositol phosphate-4-phosphate (PI (4) P) and inositol phosphate-4, 5-diphosphate (PI (4,5) P)₂) Phosphorylation of the 3 hydroxyl group of the mesoinositol ring produces three lipid products, inositol phosphate-3-monophosphate (PI (3) P), phosphatidyl-3, 4-diphosphate (PI (3,4) P), respectively₂) And phosphatidyl-3, 4, 5-triphosphate (PI (3,4,5) P₃)。

A preferred substrate for class I PI3K enzymes is PI (4,5) P₂. Class II PIKs have a stronger preference for the substrate PtdIns than the substrates PI (4) P and PI (4,5) P₂. Class III PI3K may be responsible for the production of most intracellular PI (3) P by using only PtdIns as a substrate in vivo (Vanhaesebroec et al, 2001, supra).

The phosphoinositide intracellular signal transduction pathway begins with the binding of a signal transduction molecule (extracellular ligand, stimulatory factor, receptor dimerization, transcriptional activation by a heterologous receptor such as a tyrosine kinase receptor) to a G protein-coupled transmembrane receptor integrated in the membrane of the fine stroma, resulting in the activation of PI3 Ks.

PI3K, once activated, binds the membrane phospholipid PI (4,5) P₂Conversion to PI (3,4,5) P₃Further transformation by 5' -phosphoinositide-specific phosphatasesInto another phosphorylated form of phosphoinositide, the enzymatic activity of PI3K can thus directly or indirectly lead to the production of two isoforms of 3' -phosphoinositide which act as second messengers for intracellular signal transduction (Toker et al, 2002, Cell Mol Life Sci.59(5) 761-79).

The phosphorylated products of PtdIns are involved as second messengers in various signal transduction pathways, including those necessary for cell proliferation, cell differentiation, cell growth, cell size, cell survival, apoptosis, cell adhesion, cell motility, cell migration, chemotaxis, invasion, cytoskeletal remodeling, cell deformation, vesicle trafficking, and metabolic pathways, among which function (Stein, 2000, mol. med. today 6(9) 347-57). Chemotaxis refers to the movement of cells along a gradient of chemical inducer concentration. Chemical inducers, also known as chemokines, are involved in a number of important diseases, such as inflammatory/autoimmune diseases, neurodegeneration, neovascularization, invasion/metastasis and wound healing (Wyman et al, 2000, immunological Today 21(6)260-4 and Gerard et al, 2001, natimmunological.2 (2) 108-15).

Thus, activation of PI3 kinase is thought to be involved in a number of cellular responses including cell growth, differentiation and apoptosis (Parker et al, 1995, Current Biology, 5,577-99; Yao et al, 1995, Science, 267, 2003-05).

Recent biochemical studies have shown that class I PI3Ks (e.g. the class IB PI3K γ isoform) are bispecific kinases, i.e. they exhibit lipid kinase activity (phosphorylation of phosphoinositides) and protein kinase activity, as they are able to induce phosphorylation of other proteins as substrates, including autophosphorylation as an intracellular regulatory mechanism.

PI3Ks appears to be involved in many aspects of leukocyte activation. P 85-associated PI3 kinase activity has been shown to be physiologically associated with the cytoplasmic domain of the costimulatory factor CD28, critical for T cell activation in antigen response. These effects are associated with increased transcription of many genes including interleukin-2, an important T cell growth factor (Fraser et al, 1991, Science, 251,313-16). No longer interacting with PI3 kinase after mutation in CD28 would result in failure to induce IL-2 production, suggesting that PI3 kinase plays an important role in T cell activation.

PI3K plays important roles in cellular activities, including inhibition of apoptosis, actin skeletal reorganization, cardiomyocyte growth, activation of glycogen synthase by insulin, tumor necrosis factor alpha-mediated neutrophil priming, peroxide production, and leukocyte migration and adhesion to endothelial cells.

In recent years, it has been reported that PI3K γ can transduce inflammatory signals through various g (i) protein-coupled receptors (lafpargue et al, 2002, Immunity 16(3)441-51) and plays a key role, for example, in mast cell function, activation of leukocytes, immune responses including cytokines, chemokines, adenosine, antibodies, integrins, cohesion factors, growth factors, viruses or hormones (Lawlor et al, 2001, j.cell. sci., 114(Pt 16) 2903-10).

Two compounds, LY294002 and whatmannin (wortmannin) (see below), have been widely used as PI 3-kinase inhibitors. These two compounds are non-specific inhibitors of PI3K, as they are unable to distinguish between the four members of the class I PI3 kinase.

IC of Woltmann's IC for various class I PI 3-kinases₅₀Is 1-10 nM; IC of LY294002 on any class I PI 3-kinase₅₀About 15-20 μ M (Fruman et al, 1998, Ann. Rev. biochem., 67, 481-507), IC for CK2 protein kinase₅₀5-10mM, and has certain inhibitory activity on phosphatase.

Wotmannin is a fungal metabolite that irreversibly inhibits the activity of the PI3K enzyme by covalently binding to the catalytic domain of the enzyme. Inhibition of PI3K activity by whatmannin abrogates subsequent cellular response to extracellular factors (Thelen et al, 1994, proc.natl.acad.sci.usa, 91,4960-64). Experiments with whatmannin have shown that PI3K is active in cells of the hematopoietic lineage, especially neutrophils, monocytes and other types of leukocytes, and is involved in many non-memory immune responses associated with acute and chronic inflammation.

Based on the studies on Woltmann, it was demonstrated that the function of PI 3-kinase is also essential for certain aspects of leukocyte signal transduction via G-protein coupled receptors (Thelen et al, 1994, supra). In addition, ortermanning and LY294002 have been shown to block neutrophil migration and peroxide release.

Some of the results show that inhibitors of PI3K (such as LY294002) can increase the antitumor activity of certain cytotoxic Drugs (such as taxol) in vivo (Grant, 2003, Current Drugs, 6(10), 946-948).

However, since these compounds do not distinguish between the various PI3K isoforms, it is not clear which PI3K isoform or isoforms are involved in these phenomena. Specific inhibitors of each member of the enzyme family provide valuable tools for interpreting the function of each enzyme, and varying the degree of selectivity for PI3K may be of great interest depending on the disease application.

p110 δ is mainly expressed in hematopoietic cells such as leukocytes. To evaluate the role of the delta isoform of the p110 catalytic subunit of PI3K, PI3K delta deficient mice were recently studied (journal et al, 2002, Molecular and cellular biology, 22(4), 8580-. These experiments indicate that PI3K δ -deficient animals are viable, that PI3K δ deficiency results in loss of function of the B-cell antigen-specific receptor complex, and that signaling through the cytokine receptor complex is not affected (journal et al, 2002, supra).

It has also been shown that inactivation of the p110 δ isoform of PI3K of mast cells can lead to defective stem cell factor-mediated proliferation, adhesion and migration in vitro and impaired antigen IgE-induced degranulation and cytokine release. Inactivation of p110 δ protects mice from allergic anaphylaxis, suggesting that p110 δ is a target for therapeutic intervention in allergy and mast cell-related pathologies (ali. et al., 2004, Nature, 431, 1007-1010).

Mast cells appear as the only immune cells capable of participating in various inflammatory diseases of the nervous system (e.g., multiple sclerosis), the skin, joints, and the cardiopulmonary, intestinal, and urinary tract systems (theoidentities et al, 2004, j. of neuro-imaging, 146, 1-12).

The PI3K pathway is highly correlated with certain widely spread diseases, making the need for developing PIK enzyme inhibitors (including selective inhibitors) even more urgent so that the function of each isozyme can be better characterized. .

In recent years, the following compounds have been developed as PI3K inhibitors: thiazole derivatives (WO 2005/021519; and WO 04/078754), thiazolidine derivatives (WO 2004/007491 and WO2004/056820), and quinazolinone derivatives (WO 03/035075).

Dihydrochromene pyrazole derivatives have been disclosed (WO2009/010824, WO2007/075772, and WO 2008/035356). The present invention provides novel tricyclic pyrazole derivatives and their use as Pi3K modulators.

Disclosure of Invention

One aspect of the present invention provides a compound represented by the general formula (I).

Another aspect of the present invention provides compounds of general formula (I) suitable for the treatment and/or prevention of diseases associated with phosphoinositide-3-kinase (PI3K), such as PI3K α, PI3K γ, PI3K δ or PI3K β.

Another aspect of the present invention provides a triclocarban (triclosan) compound capable of modulating, particularly inhibiting, the activity or function of phosphoinositide-3-kinase (PI3Ks) in a disease state in a mammal, particularly a human.

Another aspect of the invention provides a method for the treatment and/or prevention of a disease selected from the group consisting of autoimmune, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial and viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, transplant rejection, lung injury, respiratory diseases and ischemic conditions.

Another aspect of the invention provides compounds of formula (I) which are more selective for PI3K δ than other isoforms.

Another aspect of the invention provides a kit or kit of parts comprising at least one compound of formula (I), preferably in combination with an immunomodulator.

Preferably, the kit consists of the following individual packages:

(a) an effective amount of a compound of formula (I) and/or pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios, and

(b) an effective amount of another pharmaceutically active ingredient.

Another aspect of the present invention provides a method for synthesizing compounds represented by general formulae (I) and (I).

Detailed Description

The present invention provides compounds of the general formula (I):

in the formula (I), the compound is shown in the specification,

X₁represents a nitrogen atom or CR³，

X₂，X₅Each independently being a nitrogen or carbon atom,

u represents optionally having1. An aromatic 6-membered ring of 2 or 3 nitrogen atoms, comprising X₅Inside; or an unsaturated or aromatic 5-membered ring having 1 to 3 heteroatoms selected from N, S or O, including X₅The meaning of (a) is given,

z represents an unsaturated or aromatic 5-membered heterocyclic ring having 2 nitrogen atoms, including X₅The meaning of (a) is given,

t represents S, SO or SO₂，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，-NR⁶COAr，NR⁶COHet，COHet，-NR⁶SO₂R⁶，CO₂R⁶Comprising CO₂Y，

R²Represents H, Ar, Het, A, Cyc,

R³the structural formula (I) represents a group of H, Y,

R⁴represents H, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂Or if X₁Is CR³And also means Hal, in the name of Hal,

R⁵represents H, Y or Ar when R⁵When is Y and R is 2, two R⁵Groups may be linked together to provide a morpholino group in the bridge system with the two R ⁵The groups are connected with each other,

R⁶is H, A, Cyc or Ar.

u is 0, 1, 2, 3, or 4, preferably 0 or 1,

r is a number of 0, 1 or 2,

g is a number of 1 or 2,

ar represents a total of 6 to 14Monocyclic or fused bicyclic unsaturated or aromatic carbocyclic ring of carbon atoms, said carbocyclic ring being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which finally contains SO₂Or a CO group, said heterocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)₁-_qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_{2- m}(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

Het²to represent

Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_{1- q}A_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y，CO₂H or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein₂The radicals being optionally substituted by O, NR⁶，CO，CONR⁶，NR⁶CO, OCO, and/or substituted by a-CH = CH-or-C ≡ C-group, or represents cycloalkyl or cycloalkylalkylene having 3 to 7 ring carbon atoms;

Y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

In one embodiment, U is an aromatic 6-membered ring, optionally having 1 or 2 nitrogen atoms, including X⁵Within the meaning of (a) or (b),

in another embodiment, X⁵Is a carbon atom, and is a hydrogen atom,

in another embodiment, X²Is a carbon atom, and is a hydrogen atom,

in another embodiment, X²And X⁵Are all carbon atoms, U is an aromatic 6-membered ring optionally having 1 or 2 nitrogen atoms, and Z is an unsaturated or aromatic 5-membered heterocyclic ring having 2 nitrogen atoms.

In another embodiment, X¹Is CR³Wherein R is³As aboveAnd (4) defining.

In another embodiment, T is SO₂。

In another embodiment, X₂And X₅Are all carbon atoms, U is an aromatic 6-membered ring optionally having 1 nitrogen atom, Z is an unsaturated or aromatic 5-membered heterocyclic ring having 2 nitrogen atoms, T is SO₂And X₁Is CR³Wherein R is³As defined above.

In a more specific embodiment, the following moiety in formula (I):

Selected from the group consisting of:

in the formula, R¹，R²，R³，R⁴And T is as defined above, or a salt thereof,

and, U¹，U²，U³And U is⁴Represents CR¹Or U is¹，U²，U³And U⁴One or two of which are independently N, the remainder being CR¹Or U is¹And U⁴One of them is S, U²-U³Together form a group CR¹The balance being CR¹Or U is¹And U⁴One of them is S, U²-U³Together form a group CR¹The remainder being N, or the above moieties represent the following groups:

in the formula of U¹Represents N, U²-U³Together form a group CR¹，U⁴Is CR¹，X⁵Is N, and Z, X¹，X²，R²And T is as defined above.

In one embodiment, R²Is Ar.

In another embodiment, R²Is Het or Cyc.

In another embodiment, R²Containing 1 or 2 chiral centers.

In a preferred embodiment, the invention provides a compound of formula (Ia),

in the formula, X₁，X₂，X₅，R⁴，T，R¹Z, U, r and U are as defined above, and

m represents a saturated or unsaturated 4, 5,6, 7 or 8 membered ring optionally containing 1 to 3 heteroatoms selected from N, S and O,

the symbol indicates a chiral center,

R^Mdenotes Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²；or-(CHY)_n-Het²；

t is 0, 1, 2, 3 or 4, preferably 0 or 1.

In a more specific embodiment, the present invention provides compounds represented by the general formula (I):

in the formula of U¹，U²，U³And U is⁴As defined above, and

R²represents H, Ar, Het, A, Cyc,

R⁴Represents H, Hal, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂，

R³The structural formula (I) represents a group of H, Y,

R⁵represents H, Y or Ar when R⁵When is Y and R is 2, two R⁵Groups may be linked together to provide a morpholino group for the bridging system,

R¹denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，-NR⁶COAr，NR⁶COHet，COHet，-NR⁶SO₂R⁶，CO₂R⁶Comprising CO₂Y，

T represents S, SO or SO₂.

r represents a number of 0, 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²(ii) a Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which heterocycle is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_{1- q}A_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein ₂The radicals being optionally substituted by O, NR⁶，CONR⁶-and/or substituted by a-CH = CH-or-C ≡ C-group, or represents a cycloalkyl or cycloalkylalkylene group having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

R⁶is H, A, Cyc or Ar,

hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4.

In another embodiment, the present invention provides a compound of formula (I), wherein U¹，U²，U³And U is⁴Represents CR¹，R¹2 or 3 of the radicals being H, preferably 3R¹The group is H.

In another embodiment, the present invention provides a compound of formula (I), wherein U¹，U²，U³And U is⁴Represents CH.

In another embodiment, the present invention provides a compound of formula (I), wherein U¹And U⁴One of them is S, U²-U³Together form a group CR¹The balance being CR¹。

In another embodiment, the present invention provides a compound of formula (I) or (I), wherein

R²Represents H, Ar, Het, A, Cyc,

R³，R⁴each independently represents H, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，

R⁵Represents a group of H, Y or Ar,

U¹，U²，U³and U is⁴Represents CR¹Or U is¹，U²，U³And U⁴One or two of which are independently N, the remainder being CR¹，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，

T represents S, -SO or-SO₂，

r represents a number of 0, 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF ₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²(ii) a Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a radical having 1, 2, 3 or 4N, O and/or S atomsMonocyclic or bicyclic saturated, unsaturated or aromatic heterocycle which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²(ii) a Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

cyc denotes a saturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_{1- q}A_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²(ii) a Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein₂The radicals being optionally substituted by O, NR⁶，CONR⁶And/or is replaced by a-CH = CH-or-C ≡ C-group, or represents a cycloalkyl or cycloalkylalkylene group having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

R⁶is H, A, Cyc or Ar.

Hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

Substituents present more than once in compounds of formula (I) and related formulae (e.g. R)⁵) They are meant to be independent of each other.

In another embodiment, the invention relates to a compound of formula (A1),

in the formula, R¹，R²，R⁵R and T are as defined above,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

In a second embodiment, the present invention relates to a compound of formula (A2)

In the formula, R¹，R²，R⁵And r is as defined above, and r is,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

In another embodiment, the invention relates to a compound of formula (A3),

in which Q is Ar, Cyc, alkyl having 1 to 8 carbon atoms, or Het, and R¹，R³，R⁴And T is as defined above,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

In another embodiment, the invention relates to a compound of formula (A4),

In the formula, R¹，R³，R⁴，R⁵T and R are as defined above, and R^7aAnd R^7bEach independently selected from H, Y, A, Hal, NO₂，CN，OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOA，-NHSO₂A，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOA，N(H)_1-qA_qSO₂-N(H)_{2- m}(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios.

In another embodiment, the invention relates to a compound of formula (A5),

in the formula, R¹，R²，R³，R⁴，R⁵T and r are as defined above, and W is H, Y, Q, - (CH)₂)_pQ，-(CH₂)_pN(R⁶)₂，-(CH₂)_pOR⁶，

And p is 1, 2 or 3, and Q is Ar, Cyc, or Het.

In another preferred embodiment, the present invention provides a compound represented by the general formula (A6) or (A7),

and mixtures of compounds (A6) and (A7) in various ratios,

in the formula, R¹，R³，R⁴，R⁵T, g, and r are as defined above, and

R¹⁰represents a perfluoroalkyl group, A, COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²；

R⁶Y, A, m, n, Het and Het²As defined above.

Preferably, R¹⁰Represents A, Het²，-(CH₂)_n-Het²Or- (CHY)_n-Het²。

Preferably, R¹⁰Denotes branched OR unbranched alkyl having 1 to 6 carbon atoms in which one OR more, preferably 1 to 3, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶-CN substitution, R⁶Is a branched or straight chain alkyl group having 1 to 6 carbon atoms.

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers, including mixtures thereof in various ratios.

The following compound B1, having accession number 931355-99-6, was purchased from ChemDiv corporation. The compound is not used in pharmacology or medicine.

In a preferred embodiment, compound B1 is excluded from the compounds of the present invention.

In this context, Me means methyl and Et means ethyl.

The general formulae (I), (I) and related formulae also include mixtures of compounds of the general formulae (I), (I) and related formulae, for example mixtures of two diastereomers or enantiomers, in a ratio of 1: 1,1: 2,1: 3,1: 4,1: 5,1: 10,1: 100 or 1: 1000.

"alkyl" means a carbon chain containing 1,2, 3, 4, 5,6, 7, 8, 9, 10, 11 or 12 carbon atoms. Alkyl particularly preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1,2-, 1,3-, 2,2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1,2, 2-trimethylpropyl, more preferably trifluoromethyl, tert-butyl, isobutyl, tert-butyl, pentyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, Pentafluoroethyl or 1,1, 1-trifluoroethyl.

"cycloalkylalkylene" means a carbon chain having 1 to 6 carbon atoms in which 1 hydrogen atom is replaced by a cycloalkyl group. Cycloalkylalkylene preferably denotes cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, or cycloheptylmethylene.

"perfluoroalkyl" means having 1 to 8, preferably 1 to 6An alkyl chain of carbon atoms in which all hydrogen atoms are replaced by fluorine atoms. Perfluoroalkyl preferably represents CF₃。

Hal preferably represents F, Cl or Br.

"amino" represents the group-NR 'R' ', wherein R', R '' are each hydrogen, Y, Ar, Het, Cyc or A. R' and R "together with the nitrogen atom to which they are attached may optionally form a Het group. R' and R "together with the nitrogen atom to which they are attached preferably form a 5-membered unsaturated or aromatic heterocyclic ring having 1, 2, 3, 4 heteroatoms selected from N, O and S.

Ar preferably represents a monocyclic or bicyclic aromatic carbocyclic ring having 6 to 14 carbon atoms, which is unsubstituted or substituted by F, Cl, Br, CF₃，OCF₃，NO₂，CN，A，OR⁶，N(H)_2-m(A)_m，-CON(R⁶)₂，COHet，-NHCOA，CO₂A，-SO₂A，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)SO₂A is mono-, di-or tri-substituted,

more specifically, Ar is

Wherein R is^aAnd R^bEach independently of the other represents H, Hal, NO₂，A，CN,N(R⁶)₂，-NR⁶COA，-NR⁶CO₂A，-OR⁶，-CO₂A，-CON(R⁶)₂，-COHet，-SO₂N(H)_2-m(A)_m，-NHSO₂A，-(CH₂)_n-N(R⁶)SO₂A，–SO₂A，-SO₂Het, Ar, or Cyc,

R⁶a, Ar, Het, Cyc and m are as defined above.

Examples of preferred Ar groups are selected from the following groups:

het preferably represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1 or 2 heteroatoms selected from N, O and S, which heterocycle is unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, Hal, CF₃，OCF₃，NO₂，CN，OR⁶，N(R⁶)₂，CON(R⁶)₂，-CO₂A，-SO₂A，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)₂Mono-, di-or tri-substituted.

In one embodiment, Het is preferably a groupWherein h is 0, 1 or 2, preferably 1, optionally substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_{2- m}(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²；-(CHY)_n-Het²And (4) substitution.

More preferably, Het represents one of the following groups:

wherein R is^aAnd R^bAs defined above.

Preferably, R^aAnd R^bEach independently represents one of the following groups:

Y，H，Hal，NO₂，CN，-(CH₂)_n-NH-SO₂Y，-O(CH₂)_n-N(H)_2-m(Y)_m，-NH(CH₂)_n-N(H)_2-m(Y)_m，-NH(CH₂)_n-OH，-NH(CH₂)_n-OY，-O-(CH₂)_n-OH，-O-(CH₂)_n-OY，OH，OY，-(CH₂)_n-OY，-(CH₂)_n-OH，-(CH₂)_n-N(H)_2-m(Y)_m，-NHCOY，-NHCO₂Y，-CF₃，Het²，-(CH₂)_n-Het²；-(CHY)_n-Het²；

wherein Y, m, and n are as defined above.

Group- (CH)₂)_n-Het²Preferably representsWherein n is as defined above. Preferably, n is 2.

Y preferably represents a branched or straight chain alkyl group having 1 to 6 carbon atoms.

T preferably represents SO or SO₂。

Cyc preferably denotes a saturated carbocyclic ring having 1 to 8 carbon atoms, which is unsubstituted or substituted by alkyl having 1 to 8 carbon atoms, Hal, CF₃，OCF₃，NO₂CN, perfluoroalkyl, OH, NH₂，COH，CO₂H，CONH₂，-(CH₂)_n-OR⁶Mono-, di-or tri-substituted, and R⁶And n is as defined above.

Most preferably, Cyc represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

R³And R⁴Preferably represents H or Y.

Most preferably, R³And R⁴Both represent H.

Or, R³Is also represented by (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂。

If X is₁Is a nitrogen atom, R⁴Preferably Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂。

R¹Preferably represents H, OR⁶，Hal，CN,NO₂，-(CH₂)_n-N(R⁶)₂，-O(CH₂)_n-N(R⁶)₂，-NR⁶-(CH₂)_n-N(R⁶)₂，-NR⁶-(CH₂)_n-OR⁶，-NR⁶-CO₂R⁶，-NR⁶-COR⁶。

Preferably, R¹Is H or Hal.

R²Preferably selected from H, straight or branched C₁-C₆-alkyl or one of the following:

in another embodiment, R²Represents one of the following groups:

in another preferred embodiment, R²Represents one of the followingGroup (b):

in another preferred embodiment, R²Represents one of the following groups:

preferably, R⁶Represents H or A.

More preferably, the group A represents a branched OR unbranched alkyl group having 1 to 8 carbon atoms, in which one OR more, preferably 1 to 3, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y or N (R)⁶)₂A substitution, and one or more, preferably 1 to 3, non-adjacent CH(s) therein₂The radicals being optionally substituted by O, NR⁶，CONR⁶-and/or substituted by a-CH = CH-or-C ≡ C-group, or represents a cycloalkyl or cycloalkylalkylene group having 3 to 7 ring carbon atoms.

In a preferred embodiment, the present invention provides compounds of formula (I), wherein R⁵Is H.

In another preferred embodiment, the present invention provides a compound of formula (I), wherein U¹，U²，U³And U ⁴One of them is N and the others are CR¹，R¹As defined above.

In another preferred embodiment, the present invention provides compounds of formula (I), wherein R²Represents H, Y, Ar, Het or Cyc, R³And R⁴Are all H.

In another preferred embodiment, the present invention provides compounds of formula (I), wherein R²Represents H, Y, Ar, Het or Cyc, R³And R⁴Are both H, T is SO₂。

In another preferred embodiment, the present invention provides compounds of formula (I), wherein R²Represents H, Y, Ar, Het or Cyc, R³And R⁴Are both H, T is SO₂And U is₁，U₂，U₃And U₄Is CR¹。

Most preferably, the present invention provides compounds of formula (I), (I) and related formulae selected from the group consisting of. In the tables, when a structure contains one or more stereocenters, the corresponding structure is represented in any absolute configuration. These structures also include structures with opposite stereochemistry and the corresponding racemates:

synthesis of Compounds of the invention

The following abbreviations have the following definitions, respectively:

aq. (of water), h (hr), g (g), L (L), mg (mg), MHz (megahertz), μ M (micromolar), min (min) mM (millimeter), mmol (millimole), mM (millimole), m.p. (melting point), eq (equivalent), mL (mL), μ L (microliter), ACN (acetonitrile), BOC (tert-butoxycarbonyl), CBZ (benzoxy formate), CDCl (CDCl) ₃(deuterated chloroform), CD₃OD (diazomethanol), CH₃CN (acetonitrile), cHex (cyclohexane), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMA (dimethylacetamide), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), DMSO-d₆(deuterated dimethyl sulfoxide), EDC (1- (3-dimethyl-amino-propyl) -3-ethylcarbodiimide), ESI (electrospray ionization), EtOAc (ethyl acetate), Et₂O (diethyl ether), EtOH (ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU (dimethylamino- ([1, 2, 3)]Triazolo [4,5-b]Pyridin-3-yloxy) -methylene]Dimethylammonium hexafluorophosphate), HPLC (high Performance liquid chromatography), i-PrOH (isopropanol), K2CO₃(Potassium carbonate), LC (liquid chromatography), MeCN (acetonitrile), MeOH (methanol), MgSO₄(magnesium sulfate), MS (Mass Spectrometry), MTBE (methyl Tert-butyl Ether), Mtr (4-methoxy-2, 3, 6-trimethylbenzenesulfonyl), MW (microwave), NaHCO₃(sodium bicarbonate), NaBH₄(sodium borohydride), NMM (N-methylmorpholine), NMR (nuclear magnetic resonance), POA (phenoxyacetate), PyBOP (benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate), RT (room temperature), RT (retention time), SPE (solid phase extraction), T3P (propanephosphoric anhydride), tBu (tert-butyl), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), TLC (thin layer chromatography), UV (ultraviolet).

The general methods and procedures described in the following examples can be used for the preparation of compounds of general formula (I) and related formulae of the present invention.

The compounds according to formula (I) can be synthesized starting from readily available starting materials by the following general methods and procedures. It is noted that while only typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise indicated. In general, the compounds of formula (I) can be obtained by a variety of synthetic methods using liquid and/or solid phase chemistry protocols. Examples of synthetic routes to prepare compounds of formula (I) are described below. Optimum reaction conditions may vary with the particular reactants or solvents, but such conditions may be determined by one skilled in the art using routine optimization procedures.

In the following, all substituents, e.g. Q, R¹，R²，R³，R⁴，R⁵，R⁶，T，U₁，U₂，U₃，U₄A, Het, Ar, m, n, r and p have the meanings indicated in the formulae (I) and (I), unless stated otherwise.

According to R¹，R²，R³，R⁴，R⁵，U₁，U₂，U₃And U₄According to the properties of (1), different synthetic strategies can be selected for synthesizing the compound of the general formula (I). In general, the synthetic route of any single compound of formula (I) or (I ×) depends on the specific substituents per molecule and the ease with which the necessary intermediates are obtained, and these factors are evaluated by a person skilled in the art. For all protection and deprotection methods, see "protecting groups" edited by Philip j. kocienski, Georg Thieme verie veriag Stuttgart press, new york, 1994, and "protecting groups in organic synthesis" edited by Theodora w.greene and Peter g.m.wuts, wiley interscience press, 3 rd edition, 1999.

Compounds according to general formula (I) can be prepared according to the synthetic route described in general scheme a:

scheme A:

wherein R is⁵，g，R⁴，R²，R¹，T，U，Z，X₁，X₂，X₅U and r are as defined above and V represents H or Y.

As a representative example, compounds of formula (I) may be prepared by reference to synthetic pathway 5, described in general scheme 1. According to a preferred synthesis route, the compounds of the general formula (I) can be prepared starting from the corresponding derivatives of the general formula (Ib) by reaction with R³-X (and may also be R)⁴-X), wherein X is a leaving group, such as halogen or sulfonyl, R³And R⁴As defined above, by performing one or two alkylation reactions. Preferred reaction conditions are to treat the compound of formula (Ib) with a base (e.g. NaH) followed by an alkyl or benzyl halide in a suitable solvent (e.g. THF) at room temperature.

Scheme 1

The compounds of the formula (Ib) can be prepared from the corresponding compounds of the formula (IIb) (where R is²As defined above, V represents H or Y as defined above) may be prepared by directly reacting a compound of formula (IIb) wherein V represents Y with an amine, or by hydrolyzing the ester (IIb) to an acid wherein V represents Y, and coupling with an amine. Starting from an acid (IIb) wherein V represents Y, the compounds of formula (Ib) can be obtained using the conventional conditions for amide formation from carboxylic acids and amines in coupling reagents such as DCC, DIC, EDC, HATU, or the conventional conditions for acid chloride or activated ester formation. Preferably, the compound of formula (IIb) is treated with a 50% solution of propanephosphoric anhydride in ethyl acetate, and morpholine derivative (D) (wherein R is ⁵And r is as defined above) in the presence of a base (e.g. triethylamine) in a suitable solvent (e.g. THF) at room temperature. Another advantageWith the condition that AlCl is used₃Or AlMe₃The amine derivative D is pretreated and the compound of formula (IIb) wherein Y is an alkyl group is added in a suitable solvent such as DCM or THF at a temperature of 0 ℃ to 50 ℃.

The corresponding carboxylic acids can be obtained by hydrolysis of the corresponding esters with reagents such as, but not limited to, LiOH, NaOH or KOH in solvents such as water, ethanol, THF, dioxane or mixtures thereof.

Compounds of the general formula (IIa) and R can be used²-X (wherein X is halogen or sulfonyl) to produce a compound of formula (IIb). Preferred conditions are treatment of the compound of formula (IIa) with an alkyl halide in the presence of a base (e.g. potassium carbonate) in a suitable solvent (e.g. acetonitrile) at a temperature in the range between room temperature and 60 ℃.

Another route for the synthesis of compounds of formula (Ib) is to use compounds of formula (Ia) with R²-X (wherein X is halogen or sulfonyl) is subjected to an alkylation reaction. Preferred conditions are treatment of the compound of formula (Ia) with an alkyl halide in the presence of a base (e.g. potassium carbonate) in a suitable solvent (e.g. acetonitrile) at a temperature in the range between room temperature and 60 ℃.

The compounds of the formula (Ia) can be derived from the corresponding derivatives of the formula (IIa) (where R is²And V is as defined above) by directly reacting the compound of formula (IIa) with a morpholine derivative D, or by hydrolyzing the ester (IIb) to the acid (wherein V represents H) and coupling with a morpholine derivative D. Starting from an acid (IIb) wherein V represents H, the compounds of formula (Ia) can be obtained using the conventional conditions for amide formation from carboxylic acids and amines in coupling reagents such as DCC, DIC, EDC, HATU, or the conventional conditions for acid chloride or activated ester formation. Preferably, the compound of formula (IIb) is treated with a 50% solution of propanephosphoric anhydride in ethyl acetate, and morpholine derivative D (wherein R is⁵And r is as defined above) in a suitable solvent (e.g. THF). Another preferred condition is the use of AlCl₃Or AlMe₃Pretreating the amine derivative D and adding a compound of formula (IIb) whereinV is alkyl).

The corresponding carboxylic acids can be obtained by hydrolysis of the esters with reagents such as, but not limited to, LiOH, NaOH or KOH in solvents such as water, ethanol, THF, dioxane or mixtures thereof.

The compounds of the general formula (IIa) and (IIb) can also be prepared by cyclisation of a compound of the general formula (III) with hydrazine, a substituted hydrazine, a protected hydrazine, for example with a PG group ²As defined above (scheme 2). The hydrazine derivative VII may or may not be protected with a protecting group such as Boc group. Preferred conditions are reflux treatment of the compound of formula (III) with a hydrazine derivative in the presence of an acid (e.g. acetic acid) in a suitable solvent (e.g. methanol or ethanol). Another preferred condition is the reflux treatment of the compound of formula (III) with the derivative using Boc-in an acid (e.g. hydrochloric acid) in a suitable solvent (e.g. ethanol).

The compounds of formula (III) can be prepared by reacting a compound of formula (IV) with V-OCOCO-X (wherein V and X are as defined above) in the presence of a base. The base is preferably a metal alkoxide. Preferred conditions are treatment of the compound of formula (IV) with butyllithium and V-OCOCO-X in succession in a suitable solvent, such as THF, MTBE or toluene, at a temperature ranging from-78 ℃ to room temperature. Preferably, V-OCOCO-X is diethyl oxalate. Other preferred conditions are treatment of compound (IV) with sodium ethoxide followed by diethyl oxalate in a suitable solvent (such as toluene or MTBE) at a temperature in the range of 0 ℃ to room temperature.

The compounds of the formulae (I), (Ia), (Ib), (IIa) and (IIb) can be converted into further compounds of the formulae (I), (Ia), (Ib), (IIa) and (IIb) by the methods described in the examples below or by suitable interconversion techniques which are known to the person skilled in the art.

By oxidation, the compounds of the general formulae (I), (Ia), (Ib), (IIa) and (IIb), in which T is S, can be converted into the corresponding compounds of the general formulae (I), (Ia), (Ib), (IIa) and (IIb), in which T is SO or SO, respectively₂). Preferred conditions are use in a suitable solvent such as acetic acid at 100 ℃The compounds of the formulae (I), (Ia), (Ib), (IIa) and (IIb) were treated with a solution of 30% hydrogen peroxide in water.

Scheme 2

A compound of the formula (IV) wherein U₁，U₂，U₃And U₄As defined above (e.g. U)₁，U₂，U₃And U₄Represents CR¹) They can be purchased commercially or they can be prepared by performing a Friedel-Craft reaction on compounds of formula (V) (scheme 3). Preferred conditions are treatment of the compound of formula (V) with oxalyl chloride and tin (IV) chloride in a suitable solvent, such as dichloromethane, at a temperature in the range of 0 ℃ to room temperature. Other preferred conditions are the treatment of compound (V) with polyphosphoric acid at 80 ℃ to 120 ℃.

A compound of the general formula (IV) wherein U₁Represents N, U₂，U₃And U₄Represents CR¹Commercially available or available in accordance with Journal of Heterocyclic Chemistry, 37(2), 379-; 2000, by the procedure described in.

A compound of the general formula (IV) wherein U₃Represents N, U ₁，U₂And U₄Represents CR¹4-chloronicotinic acid can be used as a starting material according to Journal of Heterocyclic Chemistry, 37(2), 379-382; 2000, by the procedure described in.

A compound of the general formula (IV) wherein U₁Denotes S, U₂-U₃And U₄Represents CR¹A 5-membered ring, commercially available or as described in Tetrahedron, 54(21), 5599-; 1998.

A compound of the general formula (IV) wherein U₄Denotes S, U₂-U₃And U₁Represents CR¹A 5-membered ring, commercially available, or 3-bromothiophene according to Tetrahedron, 54(21), 5599-; 1998.

A compound of the general formula (IV) wherein U₄Represents N, U₁Represents S, and U₂-U₃Represents CR¹Forming a 5-membered ring, commercially available, or as tert-butyl (5-bromo-1, 3-thiazol-2-yl) carbamate according to Tetrahedron, 54(21), 5599-propan 5606; 1998.

Scheme 3

A compound of the formula (V) wherein U₁，U₂，U₃And U₄As defined above, can be prepared by alkylation of a compound of formula (VI). Preferably provided that G is used in the presence of a base such as potassium carbonate in a suitable solvent such as dimethyl formamide at 60 ℃ ⁴-CH₂CH₂CO-G³(wherein G is⁴Is halogen, G³Is OH or OY, Y being as defined above) to the compound of formula (VI).

The preparation of the compounds of formula (VII) can be seen in scheme 4. A compound represented by the general formula (VIIa) or (VIIb) (wherein R is²Is Ar or Het, PG represents a protective group including, but not limited to, a carbamate group or an alkyl group) with R²-X (wherein R²Is aryl or heteroaryl and X is halogen or a sulfonate group). According to Journal of Organic Chemistry, 74(12), 4542-4546; the procedure described in 2009 uses a metal as catalyst for the coupling reaction. Preferred conditions are copper iodide and Cs₂CO₃The compound of formula (IX) is treated with an aryl halide, preferably an iodine derivative, in the presence of a suitable solvent, such as DMSO, at 50 ℃ to 100 ℃.

A compound of the formula (VIIa) (wherein G¹CHG²Represents R²) Can be prepared from compounds of formula (VIII) by reduction (scheme 4B). Preferred conditions are treatment of the compound of formula (VIII) with sodium cyanoborohydride in a suitable solvent, such as a mixture of acetic acid and water, at a temperature in the range of 0 ℃ to room temperature.

Compounds of the general formulae (VIIc) and (VIId) (wherein G¹CHG²Represents R²) Can be prepared by reduction of a compound of formula (VIII) with hydrogen in the presence of a suitable catalyst or ligand/catalyst. The formation of compound (VIIc) or the formation of compound (VIId) is facilitated by the appropriate choice of ligand and/or catalyst and/or protecting group. Achiral conditions are used to obtain the compound of formula (VIIa). To carry out the chiral reduction, preference is given to treating the compound of the formula (VIII) with rhodium (I) bis (cycloocta-1, 5-diene) tetrahydroborate and one of the enantiomers of the Josiphos ligand at room temperature under 30 bar of hydrogen in a suitable solvent such as methanol.

A compound of the formula (VII) (wherein G¹And G²Each independently is H or A, or G¹And G²Together represent Cyc) can be represented by the general formula G¹COG²The compounds shown are reacted with hydrazine derivatives (IX) to prepare (scheme 4B). Preferred conditions are treatment of derivative G with Boc-hydrazine in a suitable solvent (e.g. toluene) at 60 deg.C¹COG². Asymmetric reduction of compound VIII gives enantiomers VIIc and VIId. The reaction can be carried out using known asymmetric reactions or asymmetric reactions as described in detail in the experimental section below.

Scheme 4

Scheme 4B

A compound (R) represented by the general formula (A)⁵，R²，R⁴T and U¹，U²，U³U⁴As defined above) can be seen in scheme 5. A compound represented by the general formula (A) (wherein R⁴As defined above) derivatives which can be represented by the general formula (Ic) with the general formula R⁴-X (wherein X is a halogen or a sulfonate group) or subjecting a compound represented by the general formula (Xb) to intramolecular cyclization. Preferred alkylation conditions are treatment of the compound of formula (Ic) with sodium hydride in a suitable solvent such as THF at 0 deg.C to 50 deg.C to add further alkyl halide. Preferred intramolecular cyclization conditions are in a suitable solvent (e.g., toluene) at 80 ℃ to 100 ℃ with a palladium source (e.g., palladium acetate), a ligand (e.g., triphenylphosphine), and a base (e.g., Cs) ₂CO₃) The compound of the general formula (Xb) is processed.

The compounds of formula (Ic) can be subjected to a cyclization reaction based on palladium catalysis as described above from derivatives of formula (Xa) or when R is⁴Is an alkyl ether protecting group (e.g., MOM group) by dealkylation according to formula (A). The preferred conditions for cleavage of the MOM protecting group are treatment of the compound of formula (Ic) with sodium hydride in a suitable solvent (e.g. THF) at 0 ℃ to 50 ℃ and addition of an alkyl halide. Preferred intramolecular cyclization conditions are treatment of the compound of formula (a) with a suitable acid such as hydrochloric acid in a suitable solvent such as dioxane at 100 ℃.

The compound represented by the general formula (Xb) may be a derivative represented by the general formula (Xa) or an alkyl derivative R⁴-X (wherein X is halogen or sulfonate group, R⁴As defined above) reaction. Preferred alkylation conditions are treatment of the compound of formula (Ic) with sodium hydride in a suitable solvent such as THF at 0 deg.C to 50 deg.C to add further alkyl halide.

A compound of the formula (Xa) (wherein T is SO)₂) Derivatives of formula (XI) with sulphurAcyl chloride is reacted. Preferred conditions are treatment of the compound of formula (XI) with sulphuryl chloride in the presence of a base (pyridine or TEA) in a suitable solvent such as DCM at room temperature.

The compound represented by the general formula (XI) can be produced by subjecting a compound represented by the general formula (XII) to a reduction reaction. Preferred conditions are to treat the compound of formula (XII) with Pd/C10% in a suitable solvent (e.g. AcOEt) at 1 atmosphere of hydrogen and room temperature.

The compound shown in the general formula (XII) can be prepared from a derivative shown in the general formula (XIII) and a general formula R²-Y (wherein Y is a boronic acid or boronic ester group) is subjected to a coupling reaction. Preferred alkylation conditions are treatment of a compound of formula (XIII) with an aromatic boronic acid in the presence of a base such as TEA and copper acetate in a suitable solvent such as DCM at a temperature in the range of 0 ℃ to room temperature.

Compounds of formula (XIII) can be prepared from the corresponding derivatives of formula (XIV) with reference to the conditions described in scheme 1, wherein V is as defined above.

Scheme 5

A compound represented by the general formula (B) (wherein R⁵，R²T and U²，U³As defined above) can be seen in scheme 6. The compounds of formula (B) can be prepared from the corresponding derivatives of formula (IIc) wherein V is as defined above, according to the conditions described in scheme 1.

The compound represented by the general formula (IIc) can be produced by subjecting a derivative represented by the general formula (XV) to intramolecular cyclization reaction. Preferred intramolecular cyclization conditions are treatment of compounds of formula (XV) with CuI in the presence or absence of a ligand (e.g. N, N-dimethylamino acetic acid) in a suitable solvent (e.g. DMSO) at 100 ℃ to 180 ℃.

The compound represented by the general formula (XV) can be converted into a compound represented by the general formula ECompound (wherein T is a sulfuric acid group, U₂And U₃Represents CR¹) Nucleophilic substitution of a compound of formula (XVIc). Preferably in the presence of a base (e.g. K)₂CO₃) Treating a compound of formula (XVIc) with a thiol derivative E, wherein X is a bromine atom, R is a bromine atom, in the presence of a suitable solvent (e.g. ACN) at a temperature in the range of room temperature to 90 ℃²Represents aryl or heteroaryl and V represents ethyl.

The compound represented by the general formula (XVIc) can be produced by halogenating a derivative represented by the general formula (XVIb). Preferably in a suitable solvent (e.g. Et)₂O) treating the compound of formula (XVIb) with a brominating agent such as triphosphor bromide at a temperature in the range of 0 ℃ to room temperature.

The compound represented by the general formula (XVIb) can be produced by reduction of the derivative represented by the general formula (XVIa). Preferred conditions are treatment of the compound of formula (XVIa) with a reducing agent, such as sodium borohydride, in a suitable solvent, such as a mixture of THF and EtOH, at a temperature in the range of 0 ℃ to room temperature.

The compound represented by the general formula (XVIa) can be prepared by Vilsmeier-Haack reaction of a derivative represented by the general formula (XVII). Preferred conditions are treatment of the compound of formula (XVII) with tribromooxyphosphorus in a suitable solvent, such as DCM, at a temperature in the range of 50 ℃ to 100 ℃.

The compounds of formula (XVII) may be purchased commercially or prepared according to the procedures described in Synthesis (2003), (15), 2353-2357.

Scheme 6

A compound represented by the general formula (C) (wherein R⁵，R²T and U¹，U²，U³U⁴As defined above) can be seen in scheme 7. The compounds of the formula (C) can be prepared from the corresponding compounds of the formula (IId)Wherein V is as defined above, according to the conditions described in scheme 1.

The compound represented by the general formula (IId) may be a compound represented by the general formula (IIe) with R²-X (wherein X is halogen or sulfonate group) is reacted. Preferred conditions are treatment of the compound of formula (IIe) with an alkyl halide in the presence of CuI and PdAc in a suitable solvent such as DMF at 100 ℃ to 150 ℃.

The compounds of the formula (IIe) can be prepared by cyclisation of a compound of the formula (XVIII) with a compound F, wherein V is as defined above. Preferred conditions are treatment of the compound of formula (XVIII) with a base (such as sodium tert-butoxide and diethyl chlorophosphate) in a suitable solvent (such as DMF) at a temperature in the range of 0 ℃ to room temperature followed by addition of ethyl cyanoacetate.

Compounds of formula (XVIII), wherein T, U1U2, U3 and U4 are as defined above, are commercially available or may be prepared according to the procedures described in Medicinal Chemistry (2010), 53(17), 6386-6397.

Scheme 7

Compounds of formula (I) can be prepared according to the procedures described in schemes 1 to 8, wherein Compound D is

Replacement by compound D:

wherein g is as defined above.

In one embodiment, the present invention provides a method for the oxidation of a compound of formula (I) or (I), wherein T is S, to a compound of formula (I) or (I), wherein T is SO₂). The oxidation step uses a common oxidant, including mCPBA, H₂O₂Or KMNO₄。

The compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) can be converted into further compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) by the methods described in the examples below or by suitable interconversion techniques known to the person skilled in the art.

By means of oxidation, the compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) in which T is S can be converted into the corresponding compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) in which T is SO or SO ₂). Preferred conditions are treatment of the compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) with a 30% hydrogen peroxide solution in water at 100 ℃ in a suitable solvent such as acetic acid, or treatment of the compounds of the formulae (I), (Ia), (Ib), (Ic), (IIa), (IIb), (IIc), (IId), (IIe), (A), (B) and (C) with 3-chloroperoxybenzoic acid in a suitable solvent such as DCM at temperatures ranging from room temperature to 50 ℃.

Compounds of the general formulae (VI), E, F, (IX), XIV), (XVII), (XVIII) and general formula G³-CH₂CH₂CO-G⁴，V-OCOCO-X，H₂N-NH-R²，R²-X, morpholine derivatives D, R³-X and R⁴The reagents represented by-X may be purchased commercially or prepared by methods described in the examples below or by conventional methods well known to those skilled in the art。

If the general synthetic methods described above are not suitable for obtaining compounds of formula (I) and/or intermediates required for the synthesis of compounds of formula (I), appropriate preparative methods known to those of ordinary skill in the art should be used.

The compounds of the invention associated with the solvent molecule may be isolated by crystallization from evaporation of a suitable solvent or by evaporation of a suitable solvent.

The pharmaceutically acceptable anionic salts of compounds of formula (I), (I) and related formulae containing a base centre can be prepared by conventional methods. For example, a solution of the free base can be treated with a suitable acid (either neat or dissolved in a suitable solvent) and the resulting salt isolated by filtration or evaporation of the reaction solvent in vacuo.

The compounds of general formula (I), (I) and related formulae can also be obtained by liberating the compounds of general formula (I), (I) and related formulae from a functional derivative thereof by action with a solvolytic or hydrogenolysis agent.

Preferred starting materials for the solvolysis or hydrogenolysis are compounds corresponding to the general formulae (I), (I) and related formulae but containing the corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups. Preference is given to those compounds which carry an amino-protecting group other than a H atom attached to a N atom, in particular those which carry an R-N group other than a HN group, where R represents an amino-protecting group, and/or may be those which carry a hydroxyl-protecting group other than a hydroxyl H atom, for example according to the general formulae (I), (I) and related formulae, but carrying a-COOR group, where R means a hydroxyl-protecting group other than a-COOH group.

It is also possible for a large number of-identical or different-protected amino and/or hydroxyl groups to be present in the molecule of the starting materials. If the protecting groups present are different from one another, they can in most cases be removed by selective cleavage.

The term "amino protecting group" is a generic term referring to a group that is suitable for protecting (preventing) an amino group from chemical reaction, but which is readily removed after the chemical reaction to be performed elsewhere in the molecule is complete. These groups typically represent unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), neither their type nor their size is of major importance, but preference is given to those having from 1 to 20, in particular from 1 to 8, carbon atoms.

The term "acyl" is to be understood in the broadest sense relevant to the present process. It includes acyl groups derived from aliphatic, arylaliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl groups such as benzoyl and tolyl; aralkoxyalkanoyl, such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("benzyloxycarbonyl"), 4-methoxybenzyloxycarbonyl, and FMOC; and arylsulfonyl groups such as Mtr. Preferred amino protecting groups are BOC and Mtr, and also CBZ, Fmoc, benzyl and acetyl.

The term "hydroxy-protecting group" is also a generic term referring to a group suitable for protecting a hydroxy group from chemical reactions that can be readily removed after the chemical reactions that are to be performed elsewhere in the molecule have been completed. Typical representatives of these radicals are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl radicals, and also alkyl radicals. The type and size of the hydroxyl-protecting groups are not so critical, since they are removed after the desired chemical reaction or reaction sequence, preference being given to groups having from 1 to 20, in particular from 1 to 10, carbon atoms. Examples of hydroxy-protecting groups are, in particular, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred.

The compounds of the general formula (I), (I) and related formulae are liberated from their functional derivatives-depending on the protective group used-for example using strong acids, preferably TFA or perchloric acid, also strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid or sulfonic acids, such as benzenesulfonic acid or p-toluenesulfonic acid. The presence of additional inert solvents is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as THF or dioxane, amides such as DMF, halogenated hydrocarbons such as DCM, and also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the above solvents are also suitable. TFA is preferably used in excess, without further addition of solvent, and perchloric acid is preferably prepared by reacting acetic acid with 70% perchloric acid in a 9: the general formula of the formula 1 is used. The temperature of the cleavage reaction is preferably controlled between 0 and about 50 deg.C, preferably between 15 and 30 deg.C (room temperature).

For example, the BOC, OBut and Mtr groups are preferably cleaved using TFA in DCM or about 3-5N HCl in dioxane at 15-30 deg.C, while the FMOC group can be cleaved using about 5-50% dimethylamine, diethylamine or piperidine in DMF at 15-30 deg.C.

Protecting groups which can be removed by hydrogenolysis (e.g., CBZ, benzyl or the release of amidino groups by decomposition of oxadiazole derivatives) can be cleaved by reaction with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst, such as palladium, preferably immobilized on a support such as carbon). Suitable solvents here are indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at a temperature of between about 0 and 100 ℃ and a pressure of between about 1 and 200 bar, preferably between 20-30 ℃ and 1-10 bar. Hydrogenolysis of the CBZ group is easily successful, for example, with 5 to 10% Pd/C in methanol, or with ammonium formate (instead of hydrogen) on Pd/C, methanol/DMF at 20-30 ℃.

The esters can be hydrolyzed, e.g. using Cl, H₂SO₄Or using LiOH, NaOH or KOH in water, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100 ℃And (4) reacting at a certain degree.

The free amino group may be further acylated with an acid chloride or anhydride, or alkylated with an unsubstituted or substituted alkyl halide in a conventional manner, advantageously in an inert solvent such as dichloromethane or THF, and/or in the presence of a base such as triethylamine and pyridine, at a temperature between-60 ℃ and +30 ℃.

The general formula (I) and related structural formulas also include optically active forms (stereoisomers), enantiomeric monomers, racemates, diastereoisomers, and hydrates and solvates of these compounds.

The term "solvate of a compound" is used to indicate an adduct of such a compound with an inert solvent molecule formed by the attractive forces of each other. Solvates are, for example, mono-or dihydrate or alcoholates.

The term "hydrate of the compound" is used to denote an adduct of the compound of formula (I) with 1, 2, 3 or 4 water molecules. Preferably, the hydrate is a monohydrate or a dihydrate.

Changes may be made to these methods during use which are self-explanatory but are not described in further detail herein.

If desired, the starting materials can be generated in situ, so that no separation from the reaction mixture is necessary, but a further conversion to the compounds of the general formula (I) is immediately possible.

The starting materials required for the preparation of the compounds of the general formula (I) and the related formulae are generally known. If they are novel compounds, they can be prepared by known methods.

The chemical reaction is preferably carried out in an inert solvent.

Examples of suitable inert solvents include hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, isopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or a mixed solvent of the above solvents.

Another aspect of the invention relates to mixtures of a plurality of compounds of formula (I), (I) and related formulae, preferably mixtures of 2 to 10 compounds, more preferably mixtures of 2 or 3 compounds. In another aspect, the invention also includes isomers, stereoisomers, diastereomers, enantiomers, and geometric isomers of (I) or (I). The invention also includes mixtures of isomers such as stereoisomers, diastereomers, enantiomers and geometric isomers represented by (I), (I) and related structural formulae.

In a further aspect of the invention there are provided pharmaceutically acceptable derivatives, solvates, tautomers, salts and stereoisomers of the compounds of formula (I), (I) and related formulae.

The invention therefore relates in particular to the use of compounds corresponding to the general formulae (I), (I) and related formulae as defined above as medicaments.

The invention therefore relates in particular to the use of compounds of the general formula (I), (I) and related formulae according to the above definition for the preparation of pharmaceutical preparations for the prophylaxis and/or treatment of inflammatory or autoimmune diseases, multiple sclerosis, cancer and related diseases.

The invention also includes metabolites of the compounds of formula (I).

The compounds of the general formula (I), (I) and related formulae may be used in non-salt final form. In another aspect, the invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be prepared by reaction with various organic and inorganic acids or bases using methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula (I), (I) and related formulae are prepared mainly by conventional methods. For compounds of general formula (I), (I) and related formulae which contain an acidic centre such as a carboxyl group, a suitable salt thereof may be obtained by reaction with a suitable base to give the corresponding base addition salt. Examples of such bases are alkali metal hydroxides including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as sodium or potassium methoxide and sodium or potassium propoxide; alkali hydrides such as sodium hydride or potassium hydride; and various organic bases such as piperidine, diethanolamine and N-methylglutamine, benzathine, choline, diethanolamine, ethylenediamine, meglumine, benzphetamine, diethylamine, piperazine and tromethamine. Also included are aluminum salts of compounds of formula (I), (I) and related formulae. For compounds of formula (I), (I) and related formulae which contain a basic center, these compounds can be reacted with pharmaceutically acceptable organic or inorganic acids, such as hydrogen halides, e.g. hydrogen chloride, hydrogen bromide or hydrogen iodide, to form acid addition salts; other mineral acids and their corresponding salts, such as sulfates, nitrates or phosphates, etc., and alkyl or monoaryl sulfonates, such as ethanesulfonate, p-toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts, such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates, etc. Pharmaceutically acceptable acid addition salts of compounds of formula (I), (I) and related formulae therefore include: acetate, adipate, alginate, arginine, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, hydrobromide, butyrate, camphorate, camphorsulfonate, caprylate, hydrochloride, chlorobenzoate, citrate, cyclopentylpropionate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethylsulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate, gluconic acid, glutamate, glycerophosphate, hemisuccinate, monosulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, hydrogen sulfonate, hydrogen sulfite, hydrogen carbonate, hydrogen, Malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, hydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, but these examples do not represent a limitation of the salts. The two types of salts can be preferably formed or interconverted using ion exchange resin techniques.

Further, the alkali salts of the compounds represented by the general formulae (I), (I;) and related structural formulae include aluminum salts, ammonium salts, calcium salts, copper salts, iron (III) salts, iron (II) salts, lithium salts, magnesium salts, manganese (III) salts, manganese (II) salts, potassium salts, sodium salts, and zinc salts, but these examples do not represent a limitation to the present invention. Among the above salts, ammonium salts are preferred; alkali metal sodium and potassium salts and alkaline earth metal calcium and magnesium salts. The salts of the compounds of formula (I) may also be derived from pharmaceutically acceptable non-toxic organic bases including primary, secondary and tertiary amines, substituted amines, also including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethyl-amino-ethanol, 2-dimethyl-amino-ethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glutamine, glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine (N-methyl-D-glucamine), morpholine, piperazine, piperidine, polyurethane resins, procaine, Purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (tromethamine), but these examples are not meant to be limiting to the present disclosure.

Furthermore, the compounds of the invention of the general formulae (I), (I) and related formulae which contain basic nitrogen-containing groups can be quaternized, the reagents used can be (C)₁-C₄) Alkyl halides, such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl sulfate, diethyl ester, and diamyl ester; (C)₁₀-C₁₈) Alkyl halides such as chlorides, bromides and iodides of decane, dodecane, lauryl, myristyl and stearyl; and aryl- (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Water-soluble and oil-soluble compounds of the general formula (I) can be prepared using these salts.

Among the above pharmaceutically acceptable salts, acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, glutamate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine are preferred, but these examples are not limiting to the present invention.

As mentioned above, pharmaceutically acceptable base addition salts of the compounds of the general formulae (I), (I) and related formulae are formed by reaction with metals or amines, such as alkali metals, alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glutamine and procaine.

If the compounds of formula (I), (I) and related formulae contain more than one group which can form pharmaceutically acceptable salts, the compounds of formula (I), (I) and related formulae also include double salt structures. Typical double salt forms include, for example, ditartrate, diacetate, difumarate, diglucamine, diphosphate, disodium and trihydrochloride, but these examples are not limiting to the invention.

In connection with the above, it will be seen that the term "pharmaceutically acceptable salts" in connection with the present invention is intended to encompass active ingredients which are represented by the general formulae (I), (I) and related formulae in the form of their salts, which salts contribute to the improved pharmacokinetic properties of the active ingredient, in particular if the salt form is present in comparison with the active ingredient in free form or any other form of active ingredient present as used hereinbefore. Pharmaceutically acceptable salts of the active ingredient may also provide desirable pharmacokinetic properties not previously available for the active ingredient for the first time, and may even exert a beneficial effect on the pharmacodynamics of the active ingredient in its therapeutic effect on the body.

The term "leaving group" means an atom or group of atoms that is readily cleaved, hydrolyzed, or replaced by an agent. Preferred leaving groups are halogens, alkyl sulfonates, aryl sulfonates, alcoholates or activated esters.

The term "reducing agent" means an agent that donates electrons. Preferred reducing agents are borane, catechol borane, copper hydride, copper (low valent), chromium (low valent), decaborane, DIBAL-H, diborane, diethyl 1, 4-dihydro-2, 6-dimethyl-3, 5-pyridinedicarboxylate, diisobutylaluminum hydride, dimethyldisulfide borane, DMSB, Fe, formaldehyde, formic acid, Hantzsch ester, hydrazine, hydrogen, indium (low valent), iron, isopropanol, LAH, lithium aluminum hydride, lithium aluminum tetrahydride, LiBH4, magnesium, manganese, 3-mercaptopropionic acid, 3-MPA, neodymium (low valent), nickel borohydride, niobium (low valent), phenylsilane, PMHS, polymethylhydrosiloxane, potassium, 2-propanol, aluminum rubrum, Rongalite, samarium (low valent), silane, sodium bis (2-methoxyethoxy) aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium dithionite, sodium bisulfite, sodium hydroxymethanesulfinate, sodium tetrahydroborate, sodium triacetoxyborohydride, strontium, tetramethyldisiloxane, tin hydride, titanium (low valent), TMDSO, tributylstannane, tributyltin hydride, trichlorosilane, triphenylphosphine, triphenylphosphite, triethylsilane, tris (trimethylsilyl) silane, TTMSS, zinc.

The term "prodrug derivative" or "prodrug" is intended to mean a compound of formula (I) or (I ″) modified with, for example, an alkyl or acyl group, a sugar or an oligopeptide, which is rapidly cleaved in the body to form the active form of the compound.

These also include biodegradable polymeric derivatives of the compounds of the invention, see, for example, int.115,61-67 (1995).

The term "metabolite" is used to indicate a compound of formula (I) or (I:) which is modified in vivo by a naturally occurring reaction in the body.

Depending on their molecular structure, the compounds of the general formulae (I), (I) and related formulae may be chiral compounds and may therefore exist in various enantiomeric forms. They may therefore also be present in racemic or optically active form.

Because there may be differences in the pharmaceutical activity of racemates or stereoisomers of the compounds of the present invention, it may be desirable to use enantiomers. In these cases, the final products and even intermediates can be resolved into enantiomeric compounds using chemical or physical methods known to those skilled in the art or even employed directly synthetically.

In the case of racemic amines present in the molecular structure, the mixture can form diastereomers with optically active resolving agents. Examples of suitable resolving agents are optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid and lactic acid in R or S form, suitable N-protected amino acids (e.g.N-benzoylproline or N-phenylsulphonylproline), or various camphorsulphonic acids which are optically active. Chromatographic resolution of the enantiomers with the aid of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylic acid polymers, which are immobilized on silica gel, is also advantageous. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example hexane/isopropanol/acetonitrile, for example in the ratio 82: 15: 3.

The invention also relates to application of the compound shown in the general formula (I) or (I) in preparing a medicament for preventing and/or treating phosphoinositide 3-kinase related diseases.

The invention also relates to the use of compounds of formula (I) or (I) for the preparation of a medicament for the prevention and/or treatment of inflammatory diseases, autoimmune diseases, multiple sclerosis, cancer, and related diseases.

The invention also relates to the use of a compound of formula (I) or (I) for the preparation of a medicament for the prevention and/or treatment of: rheumatoid arthritis, asthma and other autoimmune diseases, wherein the autoimmune diseases are selected from the group consisting of: acute Disseminated Encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid, Behcet's disease, celiac disease, anti-transglutaminase, Chagas 'disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes mellitus, endometriosis, pulmonary hemorrhage-nephritis syndrome, Graves 'disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, glomerulonephritis type A, immune thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, scleroderma, Multiple Sclerosis (MS), narcosis, sudden myasthenia gravis, neuromuscular sclerosis, pemphigus vulgaris, autoimmune diseases, rheumatoid arthritis, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, Wegener granuloma.

The invention also relates to the use of a compound of formula (I) or (I) for the preparation of a medicament for the prevention and/or treatment of: amyotrophic Lateral Sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, lupus, dermatomyositis, autoimmune optic neuropathy, immune platelet deficiency purpura, hemolytic anemia, inflammatory bowel disease, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, bone marrow or organ transplant rejection or graft-versus-host disease, Hashimoto's thyroiditis, myasthenia gravis, uveitis, posterior uveitis, rheumatic fever, inflammatory and hyperproliferative skin disorders, atopic dermatitis, contact dermatitis, alopecia areata, keratoconjunctivitis, autoimmune hemolytic anemia, granulocytopenia, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortic inflammation syndrome, polyarteritis nodosa, lung cancer, cancer metastasis and hypobaric disease, diseases caused by histamine or leukotriene-C4 release, autoimmune hepatitis, primary biliary cirrhosis, and Parkinson's disease.

The invention further relates to the use of compounds of general formula (I), (I) and related formulae in combination with at least one other pharmaceutically active ingredient, preferably a pharmaceutical ingredient for the treatment of inflammatory or immunological diseases, such as methotrexate, leflunomide, rituximab, or anti-TNF-like exemestane (etanercept), benzaximab, adalimumab, or an immunomodulator, such as fingolimod, cyclosporine, rapamycin or ascomycin, or an immunosuppressive analogue thereof, such as cyclosporine a, cyclosporine G, FK-506, ABT-281, ASM981, rapamycin, 40-O- (2-hydroxy) ethyl-rapamycin, and the like; a glucocorticoid; cyclophosphamide; thiazoyl-purinol; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualin; diflucortolone valerate; difluoro dragon acetate butyrate; alclometasone dipropionate; amcinonide; amfenadine; an asparaginase enzyme; azathioprine; basiliximab; beclomethasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone sodium phosphate; betamethasone valerate; budesonide; captopril; a nitrogen mustard hydrochloride; cladribine; clobetasol propionate; cortisone acetate; (ii) a kovar; cyclophosphamide; cytarabine; daclizumab; dactinomycin; desonide; desoximetasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinic acid; dexamethasone sodium metabisulphonate; dexamethasone phosphate; dexamethasone tert-butyrate; dichloropine acetate; doxorubicin hydrochloride; epirubicin hydrochloride; dichlorofluocinon; fludrocortisone acetate; fluoro-hydrogen shrinkage; flumethasone pivalate; flunisolide; dichlorofluocinon; fluocinolone acetonide; fluocortolone; fluocortolone caproate; flucolone pivalate; fluorometholone; prednisone acetate; fluticasone propionate; gemcitabine hydrochloride; cloxacarb; hydrocortisone; hydrocortisone acetate; hydrocortisone butyrate; hydrocortisone hemisuccinate; melphalan; methylprednisolone; mercaptopurine; methylprednisolone; methylprednisolone acetate; methylprednisolone hemisuccinate; misoprostol; moromona-cd 3; mycophenolate mofetil; (ii) paramethasone acetate; penazoline; prednisolone; prednisolone acetate; prednisolone hexanoate; prednisolone sodium metasulphobenzoate; prednisolone sodium phosphate; prednisone; prednisolone; rifampin; rifampicin sodium; tacrolimus; thalidomide; thiotepa; tixocortole pivalate; triamcinolone acetonide; triamcinolone hemisuccinate; triamcinolone acetonide; triamcinolone diacetate; triamcinolone acetonide caproate; immunosuppressive monoclonal antibodies, e.g., monoclonal antibodies against leukocyte receptors, such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 and their ligands; or other immunomodulatory compounds such as CTLA41g or other adhesion molecule inhibitors such as mAbs or low molecular weight inhibitors including selectin antagonists and VLA-4 antagonists. Preferred compositions are those formed with cyclosporin A, FK506, rapamycin or 40- (2-hydroxy) ethyl-rapamycin, and fingolimod. Other drugs such as interferon beta may be administered simultaneously or sequentially, for example by subcutaneous, intramuscular or oral routes.

The invention further relates to the use of compounds of general formula (I) and related structural formulae in combination with at least one other pharmaceutically active ingredient, preferably a medicament for the treatment of cancer, wherein said anti-cancer compounds may be selected from those known to the person skilled in the art.

These compositions are useful as medicinal and veterinary agents.

Other examples are as follows:

example 1: a compound of the general formula (I):

in the formula (I), the compound is shown in the specification,

R²represents H, Ar, Het, A, Cyc,

R³，R⁴each independently represents H, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，

R⁵Represents a group of H, Y or Ar,

U¹，U²，U³and U is⁴Represents CR¹Or U is¹，U²，U³And U⁴One or two of which are independently N and the remainder is CR¹，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，

T represents S, SO or SO₂，

r represents a number of 0, 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which heterocycle is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶Mono-, di-, or tri-substituted;

cyc denotes a saturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF ₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_{1- q}A_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein₂The radicals being optionally substituted by O, NR⁶，CONR⁶-, and/or is replaced by a-CH = CH-or-C ≡ C-group, or represents a cycloalkyl or cycloalkylalkylene group having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

R⁶is H, A or Ar.

Hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various proportions, as medicaments.

Example 2: a compound represented by the general formula (I) according to example 1 for use in the prevention and/or treatment of phosphoinositide 3-kinase related diseases.

Example 3: a compound according to example 2 for use in the prevention and/or treatment of inflammatory diseases, autoimmune diseases, cancer or multiple sclerosis, cancer, and related diseases.

Example 4: a compound according to embodiment 3, wherein the autoimmune disease is selected from the group consisting of: asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid, Behcet's disease, celiac disease, anti-transglutaminase, Chagas's disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, pulmonary hemorrhage-nephritis syndrome, Graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki's disease, glomerulonephritis type A, immune thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, scleroderma, Multiple Sclerosis (MS), myasthenia gravis, sudden pyemia, neuromuscular sclerosis, ankylosing spondylitis, neuro-type, chronic myelopathy including chronic myelopathy, chronic myelopathy, Pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, Wegener's granuloma.

Example 5: a kit consisting of the following individual packages:

(a) an effective amount of a compound of formula (I) and/or pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios, and

(b) an effective amount of another pharmaceutically active ingredient.

Example 6: a pharmaceutical composition comprising at least one compound of general formula (I) according to any one of embodiments 1 to 5.

Example 7: the pharmaceutical composition according to embodiment 6, wherein the compound of formula (I) is combined with at least one other drug for the treatment of inflammatory or immune diseases.

Example 8: the pharmaceutical composition according to embodiment 7, wherein the compound of formula (I) is combined with at least one other immunomodulator.

Example 9: a process for preparing the compounds of the general formula (I) according to examples 1 to 5, in which R and⁴are all H, comprising the steps of: the compound shown in the general formula (IIb),

wherein V is H or Y, and R²T, Y and U₁，U₂，U₃And U₄As defined in example 1, as described in example 1,

reaction with morpholine derivative D:

wherein R is⁵And r is as defined in example 1,

or with a compound of the formula (Ia),

Wherein R is⁵R, T and U₁，U₂，U₃And U₄As defined in example 1, as described in example 1,

then with the general formula R²Reaction of a compound represented by the formula-X, wherein R²As defined in example 1, X is a leaving group.

Example 10: the method of embodiment 9, further comprising the steps of: a compound represented by the general formula (Ib),

wherein R is⁵，R²R, T and U₁，U₂，U₃And U₄As defined in example 1, as described in example 1,

and R³-X and R⁴-carrying out the reaction of-X,

wherein X is a leaving group, R³And R⁴As defined in example 1.

Pharmaceutical dosage forms may be administered in dosage units, each containing a predetermined amount of the active ingredient. Such dosage units include, for example, from 0.5mg to 1g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound of the invention, depending on the disease state to be treated, the mode of administration, the age, weight and condition of the patient; or the pharmaceutical preparation may also be administered in dosage unit form containing a pre-determined amount of the active ingredient. Preferably the dosage unit dosage form is a dosage form comprising a daily dose or partial dose (as described above) of the active ingredient or a corresponding fraction thereof. In addition, such pharmaceutical preparations may be prepared by methods conventionally known in the art of pharmacy.

The pharmaceutical formulations may be adapted for administration by any desired suitable means, for example by oral (including buccal and sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or transdermal) means. These formulations may be prepared by known techniques of pharmacy, for example by mixing the active ingredient with excipients or adjuvants.

Pharmaceutical preparations suitable for oral administration can be administered in separate dosage units, for example as capsules or tablets, as powders or granules, as aqueous or non-aqueous solutions or suspensions; edible effervescent or foam food; or an oil-in-water emulsion or a water-in-oil emulsion.

Thus, for example, in the case of administration in the form of effervescent tablets or capsules for oral administration, the active ingredient may be mixed with inert excipients which are oral, non-toxic and pharmaceutically acceptable, such as ethanol, glycerol, water and the like. The compound is milled to a suitable particle size and mixed with a pharmaceutically acceptable excipient, such as an edible carbohydrate, e.g. starch or mannitol, milled in the same manner. Flavoring agents, preservatives, dispersing agents and coloring agents may also be added.

Capsules can be prepared by preparing the above powder mixture and filling into molded gelatin capsules. Glidants and lubricants, such as highly disperse silicic acid, talc, magnesium stearate, calcium stearate or solid polyethylene glycol, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can likewise be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose, beta-lactose, and corn steep liquor sweeteners, natural or synthetic high molecular weight polymers such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. An example of tablet preparation is as follows: preparing a powder mixture; granulating or dry-pressing the mixture; adding a lubricant and a disintegrant; the entire mixture was compressed into tablets. The powder mixture may be prepared by mixing the compound with the above-mentioned diluent or base by a suitable method, and optionally with a binder (such as carboxymethylcellulose, sodium alginate, gelatin or polyvinylpyrrolidone), a dissolution retardant such as a wax, an absorption enhancer such as a quaternary ammonium salt, and/or an absorbent such as bentonite, kaolin or calcium hydrogen phosphate, and the like. The powder mixture may be granulated by mixing, moistening with a binder such as syrup, starch paste, acadia gum or cellulose solution or a solution of a polymeric material and sieving. As an alternative to granulation, the powder mixture may also be granulated from irregularly shaped agglomerates by a tablet press. Stearic acid, stearate, talc or mineral oil may be added to prevent the pellets from sticking to the sheet casting mold. The mixture is compressed into tablets after adding a lubricant. The active ingredient may also be compressed with inert, free-flowing excipients into tablets without granulating or dry-compressing. Can be made into a transparent or opaque protective layer composed of shellac sealing layer, sugar coating or polymer material layer and a wax bright layer. To facilitate differentiation of the different dosage units, colorants may be added to these coating materials.

Oral liquid preparations such as solutions, syrups, and elixirs can be formulated into dosage unit forms containing predetermined amounts of the compound. Dissolving the compound in water solution containing appropriate correctant to obtain syrup; while elixirs may be prepared with non-toxic alcoholic vehicles. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Optionally adding solubilizer, emulsifier such as ethoxylated stearyl alcohol and polyoxyethylene sorbitol, antiseptic, and flavoring agent such as oleum Menthae Dementholatum or natural sweetener or saccharin or other artificial sweetener.

Dosage unit formulations of the orally administered formulations can be encapsulated in microcapsules, if desired. It can also be prepared into pharmaceutical preparations with delayed or sustained release effect, such as coating or embedding particulate materials in polymers, waxes, etc.

The compounds of formula (I), (I) and related formulae and salts, solvates, physiologically active derivatives and other active ingredients thereof may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various types of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of general formula (I), (I) and related formulae and their salts, solvates, physiologically active derivatives and other active ingredients may also be administered using monoclonal antibodies as independent carriers coupled to the compound molecules. The compounds may also be conjugated to soluble polymers as targeted pharmaceutical carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide, polyhydroxyethylaspartamidephenol, or palmitoyl-substituted polyethyleneoxidepolylysine. The compounds may further be coupled to a class of biodegradable polymers suitable for achieving controlled release of the drug, including, for example, polyacetic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered as a separate ointment which is in enlarged intimate contact with the epidermis of the recipient. For example, the active ingredient in an ointment may be delivered by iontophoresis, as described in general terms of Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, patches, gels, sprays, aerosols or oily preparations.

For ophthalmic or other external tissues such as oral and dermal applications, the formulations are preferably topical ointments or creams. In formulating ointments, paraffin or water-soluble cream bases may be used as bases for the active ingredients. Alternatively, the active ingredient may be formulated with an oil-in-water cream base or a water-in-oil base to form a cream.

Pharmaceutical formulations suitable for topical ocular administration include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration to the oral cavity include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration include suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration comprise a solid carrier material comprising a coarse powder having a particle size, for example in the range of from 20 to 500 microns. Nasal formulations can be administered in the same manner as snuff, i.e. the drug is administered by rapid inhalation through the nasal passage from a powder-containing container near the nasal cavity. Suitable formulations for administration as nasal sprays or nasal drops are liquid carrier materials containing aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations suitable for administration by inhalation include finely divided powders of pharmaceutical particles or aerosols, which may be produced by various types of pressurised dispensers equipped with an aerosol, nebuliser or insufflator.

Pharmaceutical formulations adapted for vaginal administration include pessaries, adhesives, creams, gels, pastes, effervescent formulations or sprays.

Pharmaceutical formulations suitable for parenteral administration include aqueous and non-aqueous sterile injections containing antioxidants, buffers, bacteriostats and solutes which, by virtue of their formulation, remain isotonic with the blood of the patient to be treated; and aqueous and non-aqueous sterile suspensions comprising a suspending medium and a thickening agent. The pharmaceutical preparations may be presented in unit-dose or multi-dose administration containers, for example sealed ampoules or vials, and stored by freeze-drying (lyophilisation) so that they can be administered by merely adding the sterile carrier liquid, for example sterile water for injections, immediately prior to use.

Injectable solutions and suspensions may be prepared as prescribed from sterile powders, granules and tablets.

It goes without saying that, in addition to the ingredients particularly indicated above, the particular type of pharmaceutical preparation according to the prescription may also comprise other substances useful in the art; thus, for example, the orally administered formulation may include a flavoring agent.

The therapeutically effective amount of the compounds of formula (I), (I) and related formulae and other active ingredients will depend on a variety of factors including, for example, the age and weight of the animal, the precise condition to be treated and its severity, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of the compound will generally be in the range of 0.1 to 100mg/kg of recipient (mammal) body weight per day, with a particularly typical range being 1 to 10mg/kg of body weight per day. Thus, an effective daily amount of 70 kg per adult mammal is typically 70-700mg, which may be administered once daily, or typically in a series of partial doses (e.g., twice, three, four, five or six times daily) such that the total daily dose is the same. An effective amount of a salt, solvate, or physiologically active derivative of a compound can be determined as a fraction of the effective amount of the compound itself.

The invention also relates to a method of treating a subject suffering from a PI 3K-related disease, comprising administering to the subject an effective amount of a compound of formula (I) and related formulae. More preferably, the invention relates to a method wherein the PI 3K-associated disease is an autoimmune disease or a condition associated with an overactive immune response or cancer. The present invention also relates to a method of treating a subject suffering from an immunoregulatory abnormality comprising administering to said subject a compound of formula (I), (I) and related formulae in a dose effective to treat said immunoregulatory abnormality. The present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune disease or a chronic inflammatory disease selected from the group consisting of: allergic diseases, Amyotrophic Lateral Sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granuloma, ichthyosis, Graves eye disease and asthma. The invention also relates to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease. The invention also relates to a method wherein the dysregulation is a disease selected from the group consisting of: organ or tissue transplantation, graft-versus-host disease resulting from transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal catarrhal conjunctivitis, Behcet's disease-associated uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, cavitating corneal ulceration, scleritis, Graves ' eye disease, Vogt-Koyanagi-Harada syndrome, heuchi-buerger's disease, pollen allergy, reversible airway obstructive disease, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dust asthma, chronic or refractory asthma, late asthma and airway hyper-reactivity, bronchitis, gastric ulcer, vascular injury caused by ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, enteropathy associated with heat burn, abdominal disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, simple red cell aplastic disorder, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoietic failure, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortic inflammation syndrome, polyarteritis nodosa, noninflammatory cardiomyopathy, scleroderma, Wegener's granuloma, Sjogren's syndrome, obesity, eosinophilic fasciitis, gingival injury, periodontal disease, alveolar bone, osteoodontopathy, glomerulonephritis, male pattern alopecia or alopecia senile preventing hair loss or growing hair and/or promoting hair formation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia reperfusion injury of organs after preservation, transplantation or ischemic disease, endotoxin-induced shock, pseudomembranous colitis, colitis caused by drugs or radiotherapy, ischemic acute renal insufficiency, chronic renal insufficiency, toxicity caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataract, hyperferremia, retinitis pigmentosa, senile macular degeneration, vitreous scarring, alkali burn, erythema multiforme dermatitis, IgA macrodermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, cancer metastasis and hypotony, diseases caused by the release of histamine or leukotriene-C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, toxin-induced necrosis, viral hepatitis, shock, or hypoxia, viral hepatitis b, non-a/non-b hepatitis, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, delayed-onset liver failure, "chronic plus acute" liver failure, enhanced chemotherapy effect, cytomegalovirus infection, HCMV infection, aids, cancer, senile dementia, parkinson's disease, trauma, and chronic bacterial infection.

Preferred compounds of formula (I), (I) and related formulae show IC binding to PI3K₅₀Values below about 5. mu.M, more preferably below about 1. mu.M, and even more preferably below about 0.100. mu.M.

The compounds of formula (I), (I) and related formulae can be synthesized starting from readily available starting materials by the following general methods and procedures. It is noted that while only typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagents, solvents, etc.) are given, other experimental conditions may be used unless otherwise indicated. Optimum reaction conditions may vary with the particular reactants or solvents, but such conditions may be determined by one skilled in the art using routine optimization procedures.

In general, the synthetic route for each particular compound of formula (I) and related formulae depends on the particular substituents per molecule and whether the desired intermediates are readily available; again, these factors are well known to those skilled in the art.

The compounds of the invention may be isolated from the solvent molecules by evaporative crystallization of a suitable solvent. Pharmaceutically acceptable acid addition salts of compounds of formula (I), (I) and related formulae, which contain a basic center, may be prepared according to conventional methods. For example, the free base solution may be reacted with a suitable acid, either neat or in a suitable solution, and the resulting salt isolated by filtration or evaporation of the reaction solvent under reduced pressure. Pharmaceutically acceptable base addition salts of compounds of formula (I), (I) and related formulae containing an acidic centre can be obtained in a similar manner by reaction with a suitable base. The two types of salts can be formed or converted to each other using ion exchange resin technology.

The invention will now be illustrated by means of some examples, which are not to be construed as limiting the scope of the invention.

Detailed Description

Examples section

Recording on a 400MHz spectrometer¹H NMR. Chemical shifts (. delta.) are reported in ppm relative to residual solvent signal (of DMSO-d 6)¹H NMR was δ =2.49 ppm).¹H NMR data are recorded as follows: chemical shifts (multiplicity, coupling constants and number of hydrogens). Multiplicity is expressed as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

The NMR, HPLC and MS data provided in the examples described below were obtained according to the following methods:

NMR: bruker DPX-300 was used, with residual signal of deuterated solvents as internal reflection.

HPLC: waters Alliance 2695, Waters XBridge C8 column (3.5 μm 4.6x50mm), conditions: solvent A (Water with 0.1% TFA), solvent B (ACN with 0.05% TFA), 8min elution gradient from 5% B to 100% B, UV detection with PDA Water 996(230-400 nm).

UPLC/MS: waters Acquity, column Waters Acquity UPLC BEH C181.7 μm 2.1x50mm, conditions: solvent A (10mM ammonium acetate in water +5% ACN), solvent B (ACN), gradient 5% B to 100% in 3 min, UV detection (PDA, 230-.

Autoprep purification: unless otherwise noted, preparative HPLC purification methods can be carried out by mass-guided automated purification system using a Waters Fractionlynx system equipped with a SunfirePrep C18OBD column 19X 100mm 5 m. The elution gradient used during all HPLC purifications was acetonitrile/water or acetonitrile/water/formic acid (0.1%).

Chiral analytical HPLC: waters Alliance 2695 using Alliance systems (Waters), columns Waters Chiralcel OJ-H, OB-H, OD-H, OZ-H or Chiralpak AD-H, AS, IA-3, IB, IC-3, AY-H or (SS) Whelk 01, (RR) Whelk 01, Chiralcel OJ-H, OB-H, OD-H, OZ-H or Chiralpak AD-H, AS, IA-3, IB, IC-3, AY-H, chiraltechnologies; or (SS) Whelk-01, regions Technologies; the flow rate was 1ml/min, and UV detection was performed with PDA water 996 (230-.

Chiral chromatographic separation is performed with a solid phase selected from chiralcel OJ-H, OD-H or chiralpakAD-H, IC-3, AY-H or Welk 01, on 2777C Sample Manager PAL, Prep LC4000, using Waters 2487 dual detector and Waters Fraction collector connected to the Fraction lynx software; solid phase or supported on Hipersep 80 (supperer. The detection wavelength is between 305 and 320 nm.

α D was measured at 25 ℃ using Polarimeter Jasco P-2000, the software being Spectra Manager.

The chiral centers of the enantiomerically enriched material are arbitrarily drawn. The isolated enantiomers were designated "enantiomer a" and "enantiomer B".

Intermediates

Intermediate a.0: 4-Chloronicotinic acid

4-chloropyridine hydrochloride (25g) over Na₂CO₃The aqueous solution (10%) was neutralized and extracted with DCM. Separating the organic layer, Na₂SO₄After drying and concentration under reduced pressure, 4-chloropyridine (19g) was obtained. To a solution of diisopropylamine (31mL, 217.6mmol) in dry THF at-78 deg.C under nitrogen was added dropwise n-butyllithium (115mL, 184.1 mmol). After 30 minutes, a solution of 4-chloropyridine (19g, 167.4mmol) in dry THF was slowly added in the presence of nitrogen. The mixture was stirred at-78 ℃ for 1 hour, then solid CO was added₂The temperature was allowed to slowly rise to room temperature, at room temperature under nitrogenStirring in the presence for 12 hours. Then, the reaction mixture was concentrated under reduced pressure and acidified with an aqueous HCl solution (15N) under ice-cooling conditions. The precipitate was filtered off under reduced pressure, dried in vacuo overnight to yield 15g (57%) of the title compound.¹H NMR(DMSO-d₆，400MHz)：δ13.83(bs，1H)，8.92(s，1H)，8.64-8.63(d，J=5.4Hz，1H)，7.66-7.65(d，J=5.4Hz，1H)。

Procedure A

Intermediate A.1: 3- [ (2-methoxyphenyl) thio]Propionic acid

To a solution of 2-methoxythiophenol (5.0g, 3.56mmol) in DMF (125mL) at 60 ℃ under nitrogen was added potassium carbonate (14.76g, 10.69mmol, 3 Eq). The reaction mixture was stirred for 30 minutes, bromopropionic acid (6.0g, 3.92mmol, 1.1Eq) was added and the resulting mixture was stirred for 90 minutes at 60 ℃ in the presence of nitrogen. The solvent was removed under reduced pressure and the residue was dissolved in water and washed with EtOAc. The aqueous layer was acidified with aqueous HCl and the product was extracted with EtOAc. The organic layer was MgSO ₄Drying and concentration under reduced pressure gave 5.7g (75%) of the title compound as a yellow oil.

¹H NMR (DMSO-d6, 400 MHz): δ 7.23-7.16(m, 2H), 6.98-6.91(m, 2H), 3.79(s, 3H), 3.03(t, J =7.0Hz, 2H), 2.51-2.48(m, 2H). MS (ESI +): 213.0. HPLC (max plot) 99.5%; rt 3.59 min.

Reference procedure a gave the following intermediates:

procedure B

Intermediate B.1: 8-methoxy-2, 3-dihydro-4H-thiochroman-4-one

To 3- [ (2-methoxyphenyl) thio at 0 DEG C]A solution of propionic acid (5.0g, 23.6mmol) in dry DCM (50mL) was added oxalyl chloride (6.01g, 4.09mL, 47.2mmol, 2Eq) followed by a few drops of DMF. The reaction mixture was stirred at 0 ℃ for 30 minutes. After 30 minutes, the solvent was removed under reduced pressure. To a solution of acid chloride in DCM (150mL) was added a solution of tin (IV) chloride in DCM (26mL, 1M, 26.0mmol, 1.1Eq) at 0 ℃ and the reaction mixture was stirred for 2 h. Water was added to quench the reaction and the product was extracted with DCM. The organic layer was MgSO₄And concentrating under reduced pressure. The crude residue was purified by flash chromatography (eluent: ethyl acetate/hexane 4/6) to give 3.2g of the title compound as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 7.59-7.57(m, 1H), 7.18(m, 2H), 3.84(s, 3H), 3.24-3.21(m, 2H), 2.84-2.81(m, 2H). MS (ESI +): 196.0. HPLC (max plot) 89.4%; rt 3.36 min.

Reference procedure B gave the following intermediates:

procedure C

Intermediate C.1: 2, 3-diHydrogen-4H-thiopyrano [3,2-c ]]Pyridin-4-ones

By 4- [ (2-carboxyethyl) thio according to procedure C]Nicotinic acid preparation 1.4g of the title compound: thiobenzene-bis-hydropyranone (2, 3-dihydro-4H-thio-pyran- [3, 2-c)]Pyridin-4-one) as a brown solid.¹H NMR(DMSO-d₆，400MHz)：δ8.89(s，1H)，8.41-8.40(d，J=5.4Hz，1H)，7.41-7.39(d，J=5.5Hz，1H)，3.42-3.39(m，2H)，2.93-2.90(m，2H)。

Procedure D

Intermediate D.1: 6-nitro-2, 3-dihydro-4H-thiochroman-4-one

To a solution of 4-nitrothiophenol (5.0g, 3.22mmol) in 40mL DMF at 60 ℃ under nitrogen was added potassium carbonate (13.4g, 9.69mmol, 3 Eq). Bromopropionic acid (5.43g, 3.54mmol, 1.1Eq) was added to the mixture and stirring was continued at 60 ℃ under nitrogen for an additional 90 minutes. At the end of the stirring, the solvent was removed in vacuo. The residue was extracted with ethyl acetate to remove non-polar impurities. The aqueous layer was then acidified with concentrated hydrochloric acid and extracted again with ethyl acetate. The organic layer was MgSO₄Dried and concentrated in vacuo to give a yellow oil (7.3 g). To the yellow oil (1.0g, 4.44mmol) was added polyphosphoric acid (15.0 g). The reaction mixture was stirred at 100 ℃ for 30 minutes. After 30 minutes, the solvent was removed under high vacuum and the compound was purified by column chromatography (1: 7 ethyl acetate/hexane) to give the title compound as a white solid. ¹H NMR(DMSO-d₆，400MHz)δ8.94(d，J=2.6Hz，1H)，8.20(dd，J=8.7Hz，J=2.6Hz，1H)，7.45(d，J=8.7Hz，1H)，3.36-3.33(m，2H)，3.07-3.04(m，2H) In that respect MS (ESI +): 210.0. HPLC (max plot) 99.7%; rt 5.44min.

Intermediate D.2: 1, 3-Thiazol-2-Ylcarbamic acid tert-butyl ester

To a suspension of 2-aminothiazole (50g, 499mmol, 1eq.) and 4-dimethylaminopyridine (0.1g) in acetonitrile (125mL) was added boc anhydride (130.6g, 599mmol, 1.2eq.) over 30 minutes at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated, partitioned between EtOAc and water, the solid precipitated, and filtered off to give 40g of product. The organic layer was washed with brine, separated, dried over sodium sulfate and concentrated to give the product (50g) which was combined with the initially obtained product to give 90g (90%) of the title compound.¹H NMR(DMSO-d6，400MHz)：δ11.41(bs，1H)，7.34-7.33(d，J=3.56Hz，1H)，7.13-7.12(d，J=3.56Hz，1H)，1.46(s，9H)。

Intermediate D.3: (5-bromo-1, 3-thiazol-2-yl) carbamic acid tert-butyl ester

Tert-butyl 1, 3-thiazol-2-ylcarbamate (90g, 449.8mmol, 1eq.) was placed in THF (1.4L) and N-bromosuccinimide (88.06g, 494.8mmol, 1.1eq.) was added portionwise. The reaction mixture was stirred at room temperature overnight. The reaction was concentrated to remove THF. The crude product was purified by column chromatography to give the title compound.¹H NMR(DMSO-d6，400MHz)：δ11.73(bs，1H)，7.42(s，1H)，1.46(s，9H)。

Intermediate D.4: 3- ({2- [ tert-butoxycarbonyl) amino]-1, 3-Thiazol-5-Yl } thio) propanoic acid methyl ester

Tert-butyl (5-bromo-1, 3-thiazol-2-yl) carbamate (12g, 43.17mmol, 1eq.), methyl 3-mercaptopropionate (5.7g, 47.4mmol, 1.1eq.), tris (dibenzylideneacetone) dipalladium (0) (1g, 1.07mmol, 0.025eq.), 9' -dimethyl-4, 5-bis (diphenylphosphino) xanthene (1.24g, 2.15mmol, 0.05eq.), and N, N-diisopropylethylamine (11.15g, 86.34mmol, 2eq.) were placed in a degassed 1, 4-dioxane (200mL) placed in a pressure tube, heated at 125 ℃ under sealed conditions, overnight. The reaction mixture was filtered through celite, concentrated in vacuo, and purified by flash chromatography to give 9.5g (69%) of the product. ¹H NMR(DMSO-d6，400MHz)：δ11.64(bs，1H)，7.38(s，1H)，3.58(s，3H)，2.90-2.87(t，J=6.8Hz，2H)，2.59-2.55(t，J=6.9Hz，2H)，1.46(s，9H)。

Intermediate D.5: 3- ({2- [ tert-butoxycarbonyl) amino]-1, 3-thiazol-5-yl } thio) propanoic acid

Reacting 3- ({2- [ tert-butoxycarbonyl) amino]Methyl-1, 3-thiazol-5-yl } thio) propanoate (9.5g, 29.8mmol, 1eq.) was taken in THF/water (3: 1) and LiOH (1.87g, 44.75mmol, 1.5eq.) and the reaction mixture is stirred at room temperature overnight, then evaporated in vacuo, diluted with water, acidified to pH (5-6) with citric acid, the solid formed is filtered off, washed with water and dried to give 8g (92%) of the title compound.¹H NMR(DMSO-d6，400MHz)：δ11.82(bs，2H)，7.38(s，1H)，2.86-2.83(t，J=6.8Hz，2H)，2.48-2.45(t，J=7.0Hz，2H)，1.46(s，9H)。

Intermediate D.6: 2-amino-5, 6-dihydro-7H-thiopyrano [3,2-d ]][1,3]Thiazol-7-ones

Reacting 3- ({2- [ tert-butoxycarbonyl) amino]-1, 3-Thiazol-5-yl } thio) propanoic acid (8g, 26.31mmol, 1eq) was placed in polyphosphoric acid (80g) and heated at 60 ℃ for 1 hour. The reaction mixture was diluted with ice water and NaHCO₃Neutralization and filtration of the solid formed. Dissolve the solid in EtOAc, wash with water, Na₂SO₄Drying and concentration gave the title compound.¹H NMR(DMSO-d6，400MHz)：δ7.21(bs，2H)，3.39-3.35(m，3H)，2.72-2.69(m，3H)。

Intermediate D.7: (7-oxo-6, 7-dihydro-5H-thiopyrano [3, 2-d)][1,3]Thiazol-2-yl) carbamic acid tert-butyl ester

To 2-amino-5, 6-dihydro-7H-thiopyrano [3,2-d ]][1,3]Dimethylaminopyridine (0.075g) was added to a solution of thiazol-7-one (3g, 16.1mmol, 1eq) in DMF (60 mL). The reaction mixture was cooled with ice, and boc anhydride (7.02g, 32.2mmol, 2eq) was added thereto, followed by stirring at room temperature for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with water, Na ₂SO₄Drying and concentrating. The crude product was purified by column chromatography to afford the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 11.80(bs, 1H), 3.46-3.42(m, 2H), 2.81-2.77(t, J =6.3Hz, 2H), 1.45(s, 9H). MS (ESI +): 287.0. HPLC (max plot): 96.63 percent; rt 3.95 min.

Procedure E

Intermediate e.1: oxo (4-oxo-3, 4-dihydro-2H-thiochroman-3-yl) acetic acid ethyl ester

A solution of diethyl oxalate (30.9 mL; 228.34 mmol; 1.5eq.) in toluene (250mL) was added dropwise at 0 ℃ to a solution of 21% w/w sodium ethoxide in EtOH (9.87 g; 182.67 mmol; 2 eq.). A solution of thiochroman-4-one (25 g; 152.23 mmol; 1eq.) in toluene (250mL) was added at 0 ℃ and the temperature of the reaction mixture was allowed to rise to room temperature. Stir overnight. Then, the solvent was removed, and DCM (200mL) and water (200mL) were added. The aqueous phase was washed with DCM and acidified with 5N HCl (-50 mL) to pH = 1-2. The product was extracted with EtOAc (2 × 200 mL). The organic phases were combined, dried over MgSO4 and the solvent was evaporated to give 39.4g (98%) of the title compound as an orange oil. MS (ESI +): 265.9.

reference procedure E gave the following intermediates:

procedure F

Intermediate F.1: (3E) -3- [ (tert-butoxycarbonyl) hydrazono group]Piperidine-1-carboxylic acid tert-butyl ester

1-Boc-3-piperidone (25 g; 125.47 mmol; 1.00eq.) was dissolved in toluene (250mL), tert-butyl hydrazinoformate (16.58 g; 125.47 mmol; 1.00eq.) was added and the reaction mixture was heated to 60 ℃ for 4 hours. The reaction mixture was then evaporated to dryness, redissolved in ethyl acetate (100mL) and heptane (100mL), the suspension was heated and cooled to room temperature, and the suspension was filtered and dried to yield 15g (95%) of the title compound as an off-white solid. MS (ESI-): 311.9.

reference procedure F gave the following intermediates:

procedure G

Intermediate G.1: 4- [2- (tert-butoxycarbonyl) hydrazino]Piperidine-1-carboxylic acid tert-butyl ester

To 4- [ (tert-butoxycarbonyl) hydrazono group]A solution of tert-butyl piperidine-1-carboxylate (15.7 g; 50.1 mmol; 1eq.) in water (78.5mL) and glacial acetic acid (78.5mL) was added sodium cyanoborohydride (3.15 g; 50.1 mmol; 1eq.) and the reaction mixture was stirred at room temperature overnight. The solvent was removed to dryness and the product was extracted with AcOEt. The organic phases were combined, washed with NaOH (1M), MgSO₄Drying, filtration and concentration gave 14.1g (89%) of the title compound.¹H NMR(300MHz，DMSO)：δ8.22(s，1H)，4.61-4.14(m，1H)，3.81-3.55(m，2H)，3.08-2.67(m，2H)，1.73-1.50(m，2H)，1.38(s，18H)，1.22-0.98(m，2H)。

Reference procedure G gave the following intermediates:

intermediate G.6: 2- (4-iodophenyl) -2-methylpropionaldehyde

To a solution of 2- (4-iodophenyl) -2-methylpropanenitrile (19g, 0.066mol) in toluene (150mL) was added diisobutylaluminum hydride (1.0M in THF, 200mL, 0.199mol) portionwise at-78 ℃. The reaction mixture was stirred at the same temperature for 30 minutes and at room temperature for 12 hours. To the completion of the reaction, the reaction mixture was quenched with saturated sodium sulfate solution (100mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (100mL), brine (50mL), dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a light brown liquid. ¹HNMR(DMSO-d₆，400MHz)：δ9.48(s，1H)，7.74-7.72(t，J=4Hz，2H)，7.11-7.09(t，J=1.4Hz，2H)，1.35(s，6H).MS(ESI+)：276.0。

Intermediate G.7: 2- (4-iodophenyl) propan-2-ol

To a solution of methylmagnesium bromide (59mL, 3M in THF, 17mmol) in THF (100mL) at-78 deg.C was added portionwise 4-iodobenzoic acid methyl esterA solution of the ester (20g, 76.2mmol) in THF (100 mL). The reaction mixture was stirred at the same temperature for 30 minutes and a second crop of methylmagnesium bromide (59mL of a 3M solution in THF, 17mmol) was added dropwise at-78 ℃. The mixture was stirred for an additional 2 hours, and the reaction quenched by addition of saturated ammonium chloride solution (100mL) and extracted with EtOAc (200 mL). The organic layers were combined, washed with water (100mL), brine (50mL), dried over sodium sulfate, and concentrated under reduced pressure to give 18g (90%) of the title compound as a light brown liquid.¹H NMR(DMSO-d₆，400MHz)：δ7.63-7.617(dd，J=2.0，6.8Hz，2H)，7.27-7.24(d，J=6.8Hz，2H)，5.071(s，1H)，1.37(s，6H)。

Intermediate G.8: 1- (1-chloro-1-methylethyl) -4-iodobenzene

To a solution of 2- (4-iodophenyl) propan-2-ol (15g, 0.057mol) in dry DCM (150mL) was added thionyl chloride (8.4mL, 7mmol) dropwise at 0 ℃ in the presence of nitrogen. The mixture was heated to 40 ℃ for 12 hours. After completion of the reaction, the reaction mixture was diluted with DCM (100mL), washed with 10% sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (10% EtOAc in petroleum ether) to give 15g (95%) of the title compound as a light brown solid. ¹H NMR(DMSO-d₆，400MHz)δ7.73-7.71(d，J=8.8Hz，2H)，7.41-7.38(d，J=8.8Hz，2H)，1.92(s，6H)。

Intermediate G.9: 4- [2- (4-iodophenyl) -2-methylpropyl]Morpholine

To a solution of 2- (4-iodophenyl) -2-methylpropionaldehyde (7g, 0.025mol) in 1, 2-dichloroethane (100mL) at 0 deg.CMorpholine (4.4mL, 0.051mol) was added dropwise. After 10 minutes, add NaBH in portions at 0 ℃₃CN (2g, 30mmol), followed by acetic acid (500. mu.L). The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 10 hours. The reaction mixture was then quenched by the addition of 10% sodium bicarbonate (50mL) and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (petroleum ether and EtOAc) to give the title compound as a pale yellow liquid.¹H NMR(DMSO-d₆，400MHz)：δ7.61-7.59(q，J=1.8，6.6Hz，2H)，7.19-7.17(q，J=1.9，6.6Hz，2H)，3.42-3.40(m，4H)，2.38-2.36(d，2H)，2.17-2.15(m，4H)，1.21(s，6H).MS(ESI+)：346.0。

Intermediate G.10: 4- [1- (4-iodophenyl) -1-methylethyl]Morpholine

To a solution of 1- (1-chloro-1-methylethyl) -4-iodobenzene (2g, 7mmol) in morpholine (10mL) was added potassium iodide (0.5 g). The mixture was heated for 20 minutes under microwave irradiation at 160 ℃ (x 10). The reaction mixtures were combined, dissolved in EtOAc, washed with water and brine, and dried over sodium sulfate. The solvent was concentrated in vacuo and purified by column chromatography (50% EtOAc in petroleum ether) to give the title compound as a light brown liquid.¹H NMR(DMSO-d₆，400MHz)：δ7.65-7.63(dd，J=2，6.8Hz，2H)，7.30-7.28(dd，J=2，6.8Hz，2H)，3.53-3.65(t，4H)，2.33-2.31(t，4H)，1.22(s，6H)。

Intermediate G.11: 1- [4- (1-methyl-1-morpholin-4-ylethyl) phenyl ] hydrazinecarboxylic acid tert-butyl ester

At room temperatureAnd argon gas to 4- [1- (4-iodophenyl) -1-methylethyl]A solution of morpholine (3.4g, 10mmol) in DMSO (35mL) was added cesium carbonate (5.1g, 15mmol) and tert-butyl hydrazinoformate (1.5g, 11 mmol). The reaction mixture was stirred at room temperature for 10 minutes, and copper (I) iodide (0.1g, 0.5mol) was added. The reaction mixture was stirred for 6 hours at 50 ℃ in the presence of nitrogen. The reaction mixture was then cooled to room temperature, diluted with water and extracted with MTBE. The organic layers were combined, concentrated in vacuo, and purified using 10% citric acid and sodium bicarbonate in an acid-base procedure to give the title compound as a light brown liquid.¹H NMR (DMSO-d₆400 MHz): δ 737(s, 4H), 5.00(bs, 2H), 3.54-3.521(m, 4H), 2.35-2.33(m, 4H), 1.43(s, 9H), 1.26(s, 6H). MS (ESI +): 249.0. HPLC (max plot): 96.0 percent; rt 2.57 min.

Intermediate G.12: 1- [4- (1, 1-dimethyl-2-morpholin-4-ylethyl) phenyl]Hydrazine carboxylic acid tert-butyl ester

4- [2- (4-iodophenyl) -2-methylpropyl under the conditions of room temperature and argon]A solution of morpholine (3.2g, 0.092mol) in DMSO (30mL) was added cesium carbonate (4.6g, 0.013mol) and tert-butyl hydrazinoformate (1.35g, 0.010 mol). The reaction mixture was stirred at room temperature for 10 minutes, and copper (I) iodide (0.09g, 0.4mmol) was added. The reaction mixture was stirred at 50 ℃ in the presence of nitrogen for 2 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layers were combined, washed with water and salt, dried over sodium sulfate and purified by column chromatography (natural alumina, petroleum ether and EtOAc) to give the title compound as a light brown liquid. ¹H NMR(DMSO-d₆400 MHz): δ 7.34-7.32(d, J =8Hz, 2H), 7.28-7.25(t, J =4Hz, 2H), 4.98(bs, 2H), 3.42-3.40(m, 4H), 2.36(s, 2H), 2.17-2.15(m, 4H), 1.41(s, 9H), 1.24(s, 6H). MS (ESI +): 350.0. HPLC (max plot): 91% and Rt 6.38 min.

Intermediate g.13: [2- (4-iodophenyl) -2-methylpropyl group]Dimethylamine

To a solution of 2- (4-iodophenyl) -2-methylpropionaldehyde (7g, 0.025mol) in 1, 2-dichloroethane (100mL) was added dimethylamine (2M in THF, 46mL, 92mmol) dropwise at 0 ℃. After 10 minutes, add NaBH in portions at 0 ℃₃CN (1.8g, 27mmol) and then acetic acid (500. mu.L) was added. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 10 hours. The reaction mixture was then quenched by the addition of 10% sodium bicarbonate (50mL) and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (petroleum ether and EtOAc) to give the title compound as a brown liquid.¹H NMR(DMSO-d₆，400MHz)δ7.62-7.60(q，J₁=4Hz，J₂=8Hz，2H)，7.17-7.15(d，J=8Hz，2H)，2.35(s，2H)，1.96(s，6H)，1.20(s，6H)。

Intermediate g.14: 1- {4- [2- (dimethylamino) -1, 1-dimethylethyl]Phenyl } hydrazinecarboxylic acid tert-butyl ester

To [2- (4-iodophenyl) -2-methylpropyl group at room temperature under argon]A solution of dimethylamine (5g, 0.01mol) in DMSO (50mL) was added cesium carbonate (3.6g, 0.01mol) and tert-butyl carbazate (2.4g, 0.018 mol). The reaction mixture was stirred at room temperature for 10 minutes, and copper (I) iodide (0.16g, 0.8mmol) was added. The reaction mixture was stirred at 50 ℃ in the presence of nitrogen for 2 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layers were combined, washed with water and salt, dried over sodium sulfate and purified by column chromatography (natural alumina, petroleum ether and EtOAc) to afford The title compound was a light brown liquid.¹H NMR(DMSO-d₆400 MHz): δ 7.34-7.32(d, J =8Hz, 2H), 7.25-7.23(d, J =8Hz, 2H), 4.99(bs, 2H), 2.37(s, 2H), 1.97(s, 6H), 1.41(s, 9H), 1.23(s, 6H). MS (ESI +): 350.0. HPLC (max plot): 89 percent; 2.66 min.

Intermediate g.15: 1- (4-iodophenyl) cyclopropanecarboxaldehyde

To a solution of 2- (4-iodophenyl) -2-methylpropanenitrile (9g, 0.033mol) in toluene (250mL) at-78 ℃ was added dropwise diisobutylaluminum hydride (1.0M in THF, 66mL, 66 mol). The reaction mixture was stirred at the same temperature for 2 hours. To the completion of the reaction, the reaction mixture was quenched with saturated sodium sulfate solution (100mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (100mL), brine (50mL), dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (7% EtOAc in petroleum ether) to give the title compound as a pale yellow liquid.¹H NMR(DMSO-d₆，400MHz)：δ8.85(s，1H)7.69-7.67(m，2)，7.09-7.07(m，2H)，1.57-1.54(m，2H)，1.40-1.37(m，2H)。

Intermediate g.16: 4- { [1- (4-iodophenyl) cyclopropyl]Methyl morpholine

To a solution of 1- (4-iodophenyl) cyclopropanecarboxaldehyde (7g, 0.025mol) in 1, 2-dichloroethane (100mL) was added morpholine (4.5mL, 0.051mol) dropwise at 0 ℃. After 10 minutes, add NaBH in portions at 0 ℃₃CN (3.2g, 30mmol), followed by acetic acid (500. mu.L). The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 10 hours. Then, the process of the present invention is carried out, The reaction mixture was quenched by the addition of 10% sodium bicarbonate (50mL) and extracted with EtOAc. The organic layers were combined, washed with water and brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography (petroleum ether and EtOAc) to give the title compound as a colorless liquid.¹H NMR(DMSO-d₆，400MHz)δ7.60-7.56(m，2H)，7.13-7.08(m，2H)，3.47-3.43(m，4H)，2.50-2.46(m，2H)，2.34(bs，4H)，0.80-0.77(m，2H)，0.72-.0.69(m，2H)。

Intermediate G.17: 1- {4- [1- (morpholin-4-ylmethyl) cyclopropyl]Phenyl } hydrazinecarboxylic acid tert-butyl ester

To 4- { [1- (4-iodophenyl) cyclopropyl under argon at room temperature]A solution of methyl } morpholine (4g, 11mmol) in DMSO (40mL) was added cesium carbonate (5.3g, 16mmol) and tert-butyl hydrazinoformate (1.59g, 0.012 mol). The reaction mixture was stirred at room temperature for 10 minutes, and copper (I) iodide (0.1g, 0.5mmol) was added. The reaction mixture was stirred at 50 ℃ in the presence of nitrogen for 2 hours, cooled to room temperature, diluted with water, and extracted with EtOAc. The organic layers were combined, washed with water and salt, dried over sodium sulfate and purified by column chromatography (natural alumina, petroleum ether and EtOAc) to give the title compound as a colorless liquid.¹H NMR(DMSO-d₆400 MHz): δ 7.30-7.28(d, J =8.7Hz, 2H), 7.21-7.18(d, J =8.7Hz, 2H), 5.00(bs, 2H), 3.47-3.44(m, 4H), 2.46(s, 2H), 2.36(m, 4H), 1.42(s, 9H), 0.76-0.75(t, J =5.2Hz, 2H), 0.68-0.67(t, J =5.2Hz, 2H). MS (ESI +): 348.0. HPLC (max plot): 90.3 percent; rt 5.72 min.

Procedure H

Intermediate H.1: 6-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

To a solution of diisopropylamine (0.67g, 0.9mL, 6.7mmol, 1.3Eq) in THF (8mL) at-78 deg.C under nitrogen was added n-butyllithium (3.8mL, 1.6M in hexane), and the reaction mixture was stirred at-20 deg.C for 30 min. The reaction mixture was cooled to-78 ℃ and a solution of 8-methoxy-2, 3-dihydro-4H-thiochroman-4-one (1.0g, 5.1mmol) in THF (15mL) was added slowly over 40 minutes, followed by a solution of diethyl oxalate (1.05g, 7.21mmol, 1.4Eq) in THF (10 mL). The resulting mixture was stirred at-78 ℃ for 2 hours and the temperature was allowed to rise to 0 ℃. The solvent was removed under reduced pressure at 25 ℃. The resulting yellow solid (1.3g, 4.4mmol) was dissolved in 1: 1 acetic acid/methanol (40mL), phenylhydrazine (0.7mL, 6.6mmol, 1.5 Eq., the resulting mixture stirred at 90 ℃ in the presence of nitrogen for 5 h, the solvent was removed under reduced pressure, 10% NaHCO was added to the residue₃After stirring the aqueous solution for 15 minutes, the solid formed was filtered off and recrystallized from diethyl ether to yield 1.2g (74%) of the title compound as a pale yellow solid.¹H NMR(DMSO-d₆400 MHz): δ 7.58-7.53(m, 3H), 7.43-7.41(m, 2H), 6.93(t, J =4.6Hz, 2H), 6.30(t, J =9.00Hz, 1H), 4.32(q, J =7.0Hz, 2H), 4.15(s, 2H), 3.85(s, 3H), 1.31(t, J =7.12Hz, 3H). MS (ESI +): 367.0. HPLC (max plot) 96.7%; rt 5.29min.

Intermediate H.2: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 8-methoxy-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound was prepared according to the procedure of procedure H: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR (DMSO-d6, 400 MHz): δ 7.48-7.46(m, 1H), 7.30(t, J =8.1Hz, 1H), 7.06(d, J =7.6Hz, 1H), 4.28(q, J =7.12Hz, 2H), 4.12(s, 3H), 4.06(s, 2H), 3.85(s, 3H), 1.30(t, J =7.12Hz, 3H). MS (ESI +): 305.0. HPLC (max plot) 97.0%; rt 4.28 min.

Intermediate H.3: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 7-methoxy-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound was prepared according to the procedure of procedure H: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ =7.78(d, J =8.7Hz, 1H), 7.09(d, J =2.6Hz, 1H), 6.90(dd, J =8.6Hz, J =2.5Hz, 1H), 4.28(q, J =7.1Hz, 2H), 4.12(s, 2H), 4.11(s, 3H), 3.79(s, 3H), 1.29(t, J =7.0Hz, 3H). MS (ESI +): 305.0. HPLC (max plot) 99.4%; rt 4.51 min.

Intermediate H.4: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, the title compound was prepared according to the procedure AA: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆，400MHz)：δ7.59-7.57(m，3H)，7.49-7.45(m，3H)，7.20(t，J=7.6Hz，1H)，6.96(d，J=6.36Hz，1H)，6.66(d，J=7.92Hz，1H) 4.33(q, J =7.04Hz, 2H)4.24(s, 2H), 1.31(d, J =7.08Hz, 3H). MS (ESI +): 337.0. HPLC (max plot) 98.7%; rt 6.64 min.

Intermediate H.5: 1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting with 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound, 1-methyl-1, 4-dihydrothiochroman [4,3-c ], was prepared according to procedure AA]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400 MHz): δ 7.85(dd, J =7.1Hz, J =1.6Hz, 1H), 7.52(dd, J =7.2Hz, J =1.3Hz, 1H), 7.37-7.29(m, 2H), 4.30(q, J =7.1Hz, 2H), 4.15(d, J =4.8Hz, 2H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 275.0. HPLC (max plot) 98.9%; rt 4.50 min.

Intermediate H.6: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, following the procedure AA, 0.87g (80%) of the title compound was prepared: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 14.0(s, 1H), 7.83-7.72(m, 1H), 7.36-7.33(m, 1H), 7.23(brs, 2H), 4.35-4.21(m, 4H), 1.34-1.29(m, 3H). MS (ESI +): 261.0. HPLC (max plot) 98.2%; rt 4.34 min.

Intermediate H.7: 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester

Starting from 7-methoxy-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, 1.32g (81%) of the title compound were prepared according to the procedure AA: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(400MHz，DMSO-d₆) δ 7.59-7.56(m, 3H), 7.46-7.43(m, 2H), 7.05(s, 1H), 6.58(m, 2H), 4.31(q, J =8.8Hz, 2H), 4.21(s, 2H), 3.71(s, 3H), 1.31(t, J =7.0Hz, 3H). MS (ESI +): 367.0. HPLC (max plot) 98.9%; rt 5.46 min.

Intermediate H.8: 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 3-methylphenylhydrazine, the title compound was prepared according to procedure AA: 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.49-7.39(m, 3H), 7.31(s, 1H), 7.21-7.18(m, 2H), 7.01-6.97(m, 1H), 6.70(dd, J =7.9Hz, J =1.0Hz, 1H), 4.32(q, J =7.1Hz, 2H), 4.23(s, 2H), 2.37(m, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 351.0. HPLC (max plot) 99.2%; rt 5.84 min.

Intermediate H.9: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 4-methylphenylhydrazine, the title compound was prepared according to procedure AA: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.47(d, J =7.8Hz, 1H), 7.38-7.31(m, 4H), 7.19(t, J =7.6Hz, 1H), 6.99(t, J =7.8Hz, 1H), 6.70(d, J =7.8Hz, 1H), 4.32(q, J =7.1Hz, 2H), 4.22(s, 2H), 2.41(m, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 351.0. HPLC (max plot) 99.7%; rt 5.79 min.

Intermediate H.10: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (5-fluoro-2-methylphenyl) -hydrazine, the title compound was prepared according to the procedure AA: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.52-7.42(m, 4H), 7.22-7.18(m, 1H), 7.00-6.96(m, 1H), 6.58(d, J =7.0Hz, 1H), 4.35-4.22(m, 4H), 1.78(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 369.0. HPLC (max plot) 99.2%; rt 5.76 min.

Intermediate H.11: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 3-methoxyphenylhydrazine hydrochloride, the title compound was prepared according to the procedure AA: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.48-7.44(m, 2H), 7.22-7.15(m, 2H), 7.06-6.95(m, 2H), 6.73(d, J =7.9Hz, 2H), 4.32(q, J =7.0Hz, 2H), 4.23(s, 2H), 3.78(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 367.0. HPLC (max plot) 97.5%; rt 5.55 min.

Intermediate H.12: 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 4-methoxyphenylhydrazine, 1.38g (71%) of the title compound were prepared according to the procedure AA: 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.47(d, J =7.8Hz, 1H), 7.38(d, J =8.6Hz, 1H), 7.19(t, J =7.4Hz, 1H), 7.10(d, J =8.7Hz, 2H), 7.00(t, J =7.7Hz, 1H), 6.71(d, J =7.9Hz, 2H), 4.32(q, J =7.1Hz, 2H), 4.22(s, 2H), 3.84(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 367.0. HPLC (max plot) 98.6%; rt 5.51 min.

Intermediate H.13: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 4-methoxyphenylhydrazine, the title compound was prepared according to procedure AA: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 8.51(dd, J =4.8Hz, J =0.8Hz, 1H), 8.18-8.13(m, 1H), 7.79(d, J =7.9Hz, 1H), 7.65-7.62(m, 1H), 7.48(d, J =7.8Hz, 1H), 7.23-7.19(m, 1H), 7.02-6.98(m, 1H), 6.64-6.62(m, 1H),. 4.34(q, J =7.1Hz, 2H), 4.22(s, 2H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 338.0. HPLC (max plot) 98.5%; rt 4.81 min.

Intermediate H.14: 1-cyclohexyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and cyclohexylhydrazine, the title compound was prepared according to the procedure AA: 1-cyclohexyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.61(d, J =7.8Hz, 1H), 7.55(d, J =7.6Hz, 1H), 7.39(t, J =7.5Hz, 1H), 7.32(t, J =7.5Hz, 1H), 4.57-4.52(m, 1H), 4.30(q, J =7.1Hz, 2H), 4.09(s, 2H), 2.00-1.81(m, 4H), 1.69-1.66(m, 2H), 1.49-1.42(m, 3H), 1.38(t, J =7.1Hz, 3H). MS (ESI +): 343.0. HPLC (max plot) 99.5%; rt 5.98 min.

Intermediate H.15: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 8-bromo-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound was prepared according to procedure AA: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆，400MHz)δ7.86(dd，J=7.8Hz，J=1.0Hz，1H)，7.62(dd，J=8.0Hz，J=1.0Hz，1H)，7.27(t，J=8.0Hz，1H)，4.29(q，J=7.1Hz，2H)，4.21(s，2H)，4.13(s，3H)，1.30(t，J=7.0Hz，3H)。MS(ESI+)：354.0。HPLC：RT 5.03min(HPLC purity 98.6%，97.6%)。

Intermediate H.16: 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 6-nitro-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound was prepared according to procedure AA: 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 8.56(d, J =2.3Hz, 1H), 8.11(dd, J =8.7Hz, J =2.4Hz, 1H), 7.77(d, J =8.7Hz, 1H), 4.31-4.21(m, 4H), 4.24(s, 3H), 1.31(t, J =7.12Hz, 3H). MS (ESI +) 320.0. HPLC (max plot) 98.3%; rt 4.53 min.

Intermediate H.17: 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Takes 8-fluoro-2, 3-dihydro-4H-sulfo benzopyran-4-ketone, diethyl oxalate and methylhydrazine as raw materialsThe title compound, 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c, was prepared according to the procedure AA]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.72(d, J =7.8Hz, 1H), 7.41-7.35(m, 1H), 7.29-7.26(m, 1H), 4.29(q, J =7.1Hz, 2H), 4.19(s, 2H), 4.16(s, 3H), 1.30(t, J =7.1Hz, 3H). MS (ESI +): 293.0. HPLC (max plot) 98.2%; rt 4.61 min.

Intermediate H.18: 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester

Starting with 8-fluoro-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, the title compound was prepared according to procedure AA: 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆，400MHz)δ7.60-7.55(m，3H)，7.48-7.46(m，2H)，7.18(t，J=8.6Hz，1H)，7.06-7.01(m，1H)，6.51(d，J=7.8Hz，1H)，4.33(q，J=7.1Hz，2H)，4.28(s，2H)，1.31(t，J=7.1Hz，3H)。MS(ESI+)：355.0。

Intermediate h.19: 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 6-fluoro-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and methylhydrazine, the title compound was prepared according to procedure AA: 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆，400MHz)δ7.72(dd，J=10.1Hz，J=2.4Hz，1H)，7.57-7.53(m，1H) 7.22-7.17(m, 1H), 4.29(q, J =7.1Hz, 2H), 4.17(s, 2H), 4.13(s, 3H), 1.30(t, J =7.1Hz, 3H). MS (ESI +): 293.0. HPLC (max plot) 98.8%; rt 3.79 min.

Intermediate H.20: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester

Starting with 6-fluoro-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, the title compound was prepared according to procedure AA: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.63-7.59(m, 2H), 7.55-7.48(m, 3H), 7.13-7.08(m, 2H), 6.33(dd, J =10.3Hz, J =2.7Hz, 1H), 4.33(q, J =7.1Hz, 2H), 4.24(s, 2H), 1.30(t, J =7.1Hz, 3H). MS (ESI +): 355.0. HPLC (max plot) 98.7%; rt 5.67 min.

Intermediate h.21: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 8-bromo-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, the title compound was prepared according to procedure AA: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.58-7.51(m, 3H), 7.45(d, J =8.0Hz, 2H), 6.92(t, J =8.0Hz, 2H), 6.68(d, J =7.9Hz, 1H), 4.36-4.30(m, 4H), 1.31(t, J =7.0Hz, 3H). MS (ESI +): 416.0. HPLC (max plot) 98.4%; rt 5.96min.

Intermediate h.22: 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 6-nitro-2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and phenylhydrazine, the title compound was prepared according to procedure AA: 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 8.01(dd, J =8.8Hz, J =2.4Hz, 1H), 7.50(d, J =8.8Hz, 1H), 7.66-7.60(m, 3H), 7.53(dd, J =8.0Hz, J =1.2Hz, 1H), 7.42(s, 1H), 4.41(s, 2H), 4.34(q, J =7.1Hz, 2H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 382.0. HPLC (max plot) 90.6%; rt 7.10 min.

Intermediate h.23: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 2-methylphenylhydrazine, the title compound was prepared according to procedure AA: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.56-7.42(m, 5H), 7.20-7.16(m, 1H), 6.95-6.90(m, 1H), 6.53-6.51(m, 1H), 4.32(q, J =7.0Hz, 2H), 4.28(d, J =3.5Hz, 2H), 1.85(s, 3H), 1.31(t, J =7.0Hz, 3H). MS (ESI +): 351.0. HPLC (max plot) 98.0%; rt 7.27 min.

Intermediate H.24: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acidAcid ethyl ester

Starting with 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 2-bromophenylhydrazine, the title compound was prepared according to procedure AA: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆，400MHz)δ7.90(dd，J=7.6Hz，J=1.2Hz，1H)，7.73-7.58(m，1H)，7.46(d，J=8.0Hz，1H)，7.19(t，J=7.6Hz，1H)，6.96(t，J=7.8Hz，1H)，6.52(d，J=8.0Hz，1H)，4.35-4.24(m，4H)，1.32(t，J=7.0Hz，3H)。MS(ESI+)：416.0。

Intermediate h.25: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 2-fluorophenylhydrazine, 0.77g (73%) of the title compound was prepared according to the procedure AA: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.74-7.67(m, 2H), 7.53-7.45(m, 3H), 7.23-7.19(m, 1H), 7.02-6.98(m, 1H), 6.68(d, J =7.8Hz, 1H), 4.36-4.25(m, 4H), 1.31(d, J =7.1Hz, 3H). MS (ESI +): 355.0. HPLC (max plot) 97.7%, Rt 6.99 min.

Intermediate h.26: 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 2-chlorophenylhydrazine, 0.8g (73%) of the title compound was prepared according to the procedure AA: 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.76-7.67(m, 2H), 7.64-7.60(m, 1H), 7.47(d, J =7.8Hz, 1H), 7.21-7.17(m, 2H), 6.98-6.94(m, 1H), 6.54(d, J =7.8Hz, 1H)4.35-4.30(m, 2H), 4.28-4.23(s, 2H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 370.0. HPLC (max plot) 99.2%; rt 7.12 min.

Intermediate h.27: 1- [2- (methylthio) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester Esters

With 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and [2- (methylthio) phenyl group ]Hydrazine as starting material the title compound was prepared following the procedure of procedure AA: 1- [2- (methylthio) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.63-7.61(m, 1H), 7.51(d, J =7.2Hz, 1H), 7.45(d, J =2.4Hz, 1H), 7.38-7.36(m, 1H), 7.17-7.16(m, 1H), 6.94-6.93(m, 1H), 6.58(dd, J =8.0Hz, J =1.2Hz, 1H), 4.30(q, J =7.0Hz, 2H), 4.26(s, 2H), 2.34(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 415.0. HPLC (max plot) 97.6%; rt 5.55 min.

Intermediate h.28: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester

The title compound was prepared according to procedure AA starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 2, 3-dihydro-1, 4-benzodioxin-6-ylhydrazine: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.47(d, J =7.8Hz, 1H), 7.22-7.18(m, 1H), 7.05-7.00(m, 3H), 6.87-6.84(m, 1H), 6.79-6.77(m, 1H), 4.34-4.30(m, 6H), 4.21(s, 2H), 1.30(t, J =7.1Hz, 3H). MS (ESI +): 427.0. HPLC (max plot) 99.2%; rt 5.39min.

Intermediate H.29: 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3- Carboxylic acid ethyl ester

Starting with 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and 6-hydrazino-2-methyl-1, 3-benzothiazole, the title compound was prepared according to the procedure AA: 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 8.28(d, J =2.0Hz, 1H), 8.05(d, J =8.2Hz, 1H), 7.53-7.48(m, 2H), 7.19(t, J =7.5Hz, 1H), 6.95(t, J =7.8Hz, 1H), 6.64(d, J =8.0Hz, 1H), 4.33(q, J =7.0Hz, 2H), 4.26(s, 2H), 2.85(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 408.0. HPLC (max plot) 97.1%; rt 7.30 min.

Intermediate H.30: 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (3-bromophenyl) hydrazine, the title compound was prepared according to the procedure AA: 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.81-7.78(m, 2H), 7.54-7.45(m, 3H), 7.25-7.20(m, 1H), 7.06-7.02(m, 1H), 6.74-6.72(m, 1H), 4.33(q, J =7.0Hz, 2H), 4.23(s, 2H), 1.31(t, J =7.0Hz, 3H). MS (ESI +): 416.0. HPLC (max plot) 98.4%; rt 7.56 min.

Intermediate h.31: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (3-chlorophenyl) hydrazine, 0.56g (79%) of the title compound was prepared according to the procedure AA: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.68-7.66(m, 1H), 7.59(t, J =7.8Hz, 1H), 7.50(t, J =7.8Hz, 1H), 7.44-7.41(m, 1H), 7.24-7.20(m, 1H), 7.06-7.02(m, 1H), 6.74-6.72(m, 1H), 4.33(q, J =7.2Hz, 2H), 4.23(s, 2H), 1.31(t, J =7.2Hz, 3H). MS (ESI +): 370.0. HPLC (max plot) 98.7%; rt 7.51 min.

Intermediate H.32: 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (4-bromophenyl) hydrazine, 1.1g (70%) of the title compound was prepared according to the procedure AA: 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.77(dd, J =6.7Hz, J =2.0Hz, 1H), 7.50(d, J =7.8Hz, 2H), 7.45-7.43(m, 2H), 7.24-7.20(m, 1H), 7.07-7.03(m, 1H), 6.75-6.73(m, 1H), 4.32(q, J =7.1Hz, 2H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 416.0. HPLC (max plot) 99.6%; rt 5.94 min.

Intermediate h.33: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (4-fluorophenyl) hydrazine, 0.35g (82%) of the title compound was prepared according to the procedure AA: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.53-7.40(m, 5H), 7.23-7.18(m, 1H), 7.04-7.00(m, 1H), 6.70-6.68(m, 1H), 4.32(q, J =7.1Hz, 2H), 4.23(s, 2H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 355.0. HPLC (max plot) 99.5%; rt 7.26 min.

Intermediate H.34: 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (4-chlorophenyl) hydrazine, the title compound was prepared according to the procedure AA: 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.64(dd, J =6.6Hz, J =1.6Hz, 1H), 7.52-7.48(m, 3H), 7.24-7.20(m, 1H), 7.07-7.03(m, 1H), 6.74-6.72(m, 1H), 4.33(q, J =7.1Hz, 2H), 4.22(s, 2H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 371.0. HPLC (max plot) 99.4%; rt 7.48 min.

Intermediate H.35: 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Starting from 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and (4-isopropylphenyl) hydrazine, the title compound was prepared according to procedure AA: 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.49-7.42(m, 3H), 7.37-7.34(m, 2H), 7.19(t, J =7.5Hz, 1H), 6.98(t, J =7.7Hz, 1H), 6.70(d, J =8.1Hz, 1H), 4.32(q, J =7.1Hz, 2H), 3.05-2.98(m, 1H), 1.30(t, J =7.1Hz, 3H), 1.25(d, J =6.8Hz, 6H). MS (ESI +): 379.0. HPLC (max plot) 98.5%; rt 7.80 min.

Intermediate H.36: 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

With 2, 3-dihydro-4H-thiochroman-4Starting from ketone, diethyl oxalate and 3-hydrazino-4-methylpyridine, the title compound was prepared according to the procedure AA: 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 8.35(d, J =2.1Hz, 1H), 7.96(dd, J =8.1Hz, J =1.8Hz, 1H), 7.67(d, J =8.1Hz, 1H), 7.48-7.46(m, 1H), 7.22-7.18(m, 1H), 7.02-6.98(m, 1H), 6.63(dd, J =7.9Hz, J =1.0Hz, 1H), 4.33(q, J =7.0Hz, 2H), 4.22(s, 2H), 2.41(s, 3H), 1.32(t, J =7.0Hz, 3H). MS (ESI +): 352.0. HPLC (max plot) 98.6%; rt 5.11 min.

Intermediate h.37: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester Esters

Starting with 2, 3-dihydro-4H-thiochroman-4-one, diethyl oxalate and tetrahydro-2H-pyran-4-ylhydrazine, the title compound was prepared according to the procedure AA: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester.¹H NMR(DMSO-d₆400MHz) δ 7.70(d, J =7.3Hz, 1H), 7.55(dd, J =7.6Hz, J =1.2Hz, 1H), 7.40-7.30(m, 2H), 4.88-4.84(m, 1H), 4.30(q, J =7.0Hz, 1H), 4.10(s, 2H), 3.98-3.94(m, 2H), 3.51(t, J =11.1Hz, 3H), 2.16-2.10(m, 2H), 1.97-1.94(m, 2H), 1.31(t, J =7.0Hz, 3H). MS (ESI +): 345.0. HPLC (max plot) 98.0%; rt 4.79 min.

Reference procedure AA gave the following intermediates:

procedure I:

intermediate I.1: 4- [3- (ethoxycarbonyl) thiochromeno [4,3-c ]]Pyrazol-1 (4H) -yl]Benzoic acid

To a solution of ethyl oxy (4-oxy-3, 4-dihydro-2H-thiochroman-3-yl) acetate (10.1 g; 38.21 mmol; 1eq.) in ethanol (100mL) and acetic acid (6.56mL) was added 97% (8.39 g; 53.5 mmol; 1.4 eq.). The reaction mixture was heated to reflux and refluxed for 2 hours. The precipitate was filtered off and washed with water. The filtrate was evaporated to dryness. Water was added and the mixture was sonicated, then filtered off, washed with water (x3) and dried under reduced pressure to give an orange solid. The two solid residues were combined and taken up in MTBE (250ml) and then heated to reflux and refluxed for 30 min. The precipitate was filtered off and washed with MTBE (X2) and dried under reduced pressure to yield 19.05g of the title compound. ¹H NMR(DMSO-d₆) δ 13.30(br s, 1H), 8.11(d, J =8.6Hz, 2H), 7.60(d, J =8.6Hz, 2H), 7.53-7.51(m, 1H), 7.27-7.19(m, 1H), 7.07-7.01(m, 1H), 6.77-6.73(m, 1H), 4.35(q, J =7.1Hz, 2H), 4.24(s, 2H), 1.33(t, J =7.1Hz, 3H). HPLC (max plot) 61.0%; rt 4.15 min. MS (ESI +): 380.9.

reference procedure I gave the following intermediates:

procedure J

Intermediate J.1: 1-piperidin-3-yl-7- (trifluoromethoxy) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid Ethyl ester acid:

to oxo [ 4-oxo-7- (trifluoromethoxy) -3, 4-dihydro-2H-thiochroman-3-yl]Ethyl acetate (3.00 g; 8.61 mmol; 1eq.) and 3- [2- (tert-butoxycarbonyl) hydrazino]A solution of piperidine-1-carboxylic acid ethyl ester (4.08 g; 12.92 mmol; 1.50eq.) in ethanol (80mL) was added dropwise to HCl (4M, solution in dioxane, 42.38 mL). The reaction mixture was heated at 75 ℃ for 5 hours, then concentrated in vacuo and concentrated in NaHCO₃The saturated solution (pH7-8) was separated from EtOAc. NaHCO for organic layer₃Saturated solution and brine, MgSO₄Drying gave 3.1g (88%) of the title compound as a brown solid.¹H NMR(DMSO，300MHz)：δ7.77(d，J=9.43Hz，1H)，7.62(s，1H)，7.39(d，J=7.7Hz，1H)，4.61-4.46(m，1H)，4.40-4.26(m，2H)，4.17(s，1H)，4.09-3.98(m，1H)，3.19-3.06(m，1H)，2.97-2.82(m，2H)，2.17-2.05(m，2H)，1.99(s，1H)，1.80-1.67(m，1H)，1.67-1.45(m，1H)，1.32(t，J=7.0Hz，3H)，1.18(t，J=6.9Hz，1H)。

Reference procedure J gave the following intermediates:

procedure K

Intermediate K.1: 1- [1- (tert-Butoxycarbonyl) piperidin-4-yl ]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3- Carboxylic acid ethyl ester

1-piperidin-4-yl-1, 4-dihydrothiochromeno [4,3-c ] is reacted with a compound of formula (I)]Ethyl pyrazole-3-carboxylate (2.95 g; 8.59 mmol; 1eq.), di-tert-butyl dicarbonate (2.25 g; 10.31 mmol; 1.2eq.) and triethylamine (1.2 ml; 8.59 mmol; 1eq.) were dissolved in DCM (29.5ml) and the reaction mixture was stirred at room temperature for 3 days. DCM was added and the organic phase was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5-5% EtOAc in cyclohexane to give, after concentration of the desired fraction, 3.05g (80%) of the title compound as a beige foam.¹H NMR(DMSO-d₆) δ 7.69(d, 1H, J =7.6 Hz): 7.56(dd, 1H, J =7.5 Hz): 7.43-7.30(m, 2H), 4.84(m, 1H), 4.1(q, 2H, J =7.7 Hz): 4.10(s, 2H), 3.10-2.85(m, 2H), 2.06-1.86(m, 4H), 1.49(s, 9H), 1.31(t, 3H, J =7.7 Hz). HPLC (max plot) 85.2%; rt 5.79 min.

Reference procedure K gave the following intermediates:

general procedure L.

Intermediate L.1: 1- [3- (3-methyl-1, 2, 4-oxadiazol-5-yl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Oxazole-3-carboxylic acid ethyl ester 5, 5-dioxide

To 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] in the presence of nitrogen ]Pyrazol-1 (4H) -yl]Benzoic acid (100mg, 0.24mmol) in EtOAc was added methylamidoxime (17mg, 0.24mmol) followed by TEA (0.1mL, 0.73mmol) and propanephosphonic cyclic anhydride (0.4mL, 0.60 mmol) at 0 ℃ in the presence of nitrogen at reflux for 12 h at 80 ℃ in the presence of nitrogen, EtOAc was added and the organic layer was refluxed with 10% Na₂CO₃Washing with saturated solution, Na₂SO₄Drying, and concentrating under reduced pressure. The resulting crude material was purified by silica gel column chromatography (1.5% MeOH in DCM) to give the title compound.

Intermediate L.2: 1- (3- {3- [ (dimethylamino) methyl group]-1,2, 4-oxadiazol-5-yl } phenyl) -1, 4-dihydrothioxobenzene Pyrano [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

Starting from 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] benzoic acid and (1Z) -2- (dimethylamino) -N' -hydroxyethaneiminoamide, the title compound, ethyl 1- (3- {3- [ (dimethylamino) methyl ] -1,2, 4-oxadiazol-5-yl } phenyl) -1, 4-dihydrothiochromano [4,3-c ] pyrazole-3-carboxylate 5, 5-dioxide, was prepared according to the procedure L. MS (ESI +): 494.0.

intermediate L.3: 1- {3- [3- (methoxymethyl) -1,2, 4-oxadiazol-5-yl ]Phenyl } -1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] sulfide]Pyrazol-1 (4H) -yl]Starting from benzoic acid and (1Z) -N' -hydroxy-2-methoxyethaneimidamide, the title compound was prepared according to the procedure of procedure L: 1- {3- [3- (methoxymethyl) -1,2, 4-oxadiazol-5-yl]Phenyl } -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆，400MHz)：δ8.38-8.36(d，J=6.8Hz，1H)，8.24(s，1H)，8.06-8.04(d，J=7.7Hz，1H)，7.90-7.86(m，2H)，7.68-7.56(m，2H)，6.98-6.96(d，J=7.8Hz，1H)，5.01-4.97(s，2H)，4.62(s，2H)，4.40-4.35(m，2H)，3.35(s，3H)，1.36-1.32(t，J=7.1Hz，3H)。MS(ESI+)：481.2。

Intermediate L.4: n' -hydroxy-3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazole- 1(4H) -yl]Benzamidine

To a solution of 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] benzonitrile (0.3g, 0.69mmol) in ethanol (20mL) was added 50% aqueous hydroxylamine solution (0.14mL, 2.07 mmol). The reaction was heated to 85 ℃ for 12 hours. The solvent was removed completely under reduced pressure to give 150mg (89%) of the title compound as a white solid. MS (ESI +): 468.0.

intermediate L.5: 1- [3- (5-methyl-1, 3, 4-oxadiazol-2-yl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Oxazole-3-carboxylic acid ethyl ester 5, 5-dioxide

To 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] in nitrogen atmosphere ]Pyrazol-1 (4H) -yl]A solution of benzoic acid (200mg, 0.485mmol) in EtOAc was added acethydrazide (35mg, 0.485 mmol). Then, TEA (0.2mL, 1.45mmol) and propane phosphoric cyclic anhydride (0.4mL, 0.60mmol) were added at 0 ℃ under nitrogen. The reaction mixture was refluxed at 80 ℃ for 12 h, diluted with EtOAc and washed with 10% Na₂CO₃Washing with saturated solution. Separating the organic layer, Na₂SO₄Drying, and concentrating under reduced pressure. The resulting crude solid was purified by silica gel column chromatography (1.5% MeOH in DCM) to afford the title compound. MS (ESI +): 451.2.

intermediate L.6: 1- [3- (5-methyl-1, 3, 4-thiadiazol-2-yl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Oxazole-3-carboxylic acid ethyl ester 5, 5-dioxide

In nitrogenTo 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] in a gas atmosphere]Pyrazol-1 (4H) -yl]A solution of benzoic acid (0.4g, 0.97mmol) in EtOAc was added acethydrazide (72mg, 0.97 mmol). Then, TEA (0.4mL, 2.93mmol), Lawson's reagent (0.6g, 1.46mmol) and propane phosphoric cyclic anhydride (2mL, 2.93mmol) were added at 0 ℃ under nitrogen. The reaction mixture was refluxed at 80 ℃ for 12 hours in the presence of nitrogen and additional EtOAc was added. Organic layer with 10% Na₂CO₃Washing with saturated solution, Na ₂SO₄Drying, and concentrating under reduced pressure. The resulting crude material was purified by silica gel column chromatography (1.5% MeOH in DCM) to give the title compound. MS (ESI +): 467.0.

and (5) a program M.

Intermediate M.1: 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothieno [3',2':5,6]Thiopyrano [4,3-c ]] Pyrazole-3-carboxylic acid ethyl ester

To a solution of 1- (6-methoxypyridin-3-yl) -1, 4-dihydrothieno [3',2':5,6]Thiopyrano [4,3-c ]]A suspension of pyrazole-3-carboxylic acid ethyl ester (200mg, 0.535mmol) and sodium iodide (80mg, 0.535mmol) in dry ACN was added to trimethylchlorosilane (350mg, 3.22 mmol). The reaction was heated to 80 ℃ under nitrogen, held for 48 hours, and then cooled to 0 ℃. The reaction mixture is washed with Na₂CO₃The saturated aqueous solution and the saturated aqueous solution of sodium thiosulfate were washed, and stirred for 0.5 hour. The precipitated solid was filtered off in vacuo, washed with water, dried and left overnight to yield 190mg (98%) of the title compound. MS (ESI +): 360.0.

intermediate M.2: 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid Acid ethyl ester

Starting from ethyl 1- (6-methoxypyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylate, the title compound was prepared according to the procedure of AN: 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid ethyl ester to give 230mg (69%) of the title compound. MS (ESI +): 354.2.

And (4) a procedure N.

Intermediate N.1: 1- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothieno [3',2':5,6]Thiopyrans And [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester

To a solution of 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothieno [3',2':5,6]Thiopyrano [4,3-c ]]A solution of pyrazole-3-carboxylic acid ethyl ester (75mg, 0.208mmol) in water/DCM (1: 2) was added tetrabutylammonium bromide (0.135g, 0.417mmol), sodium hydroxide (17mg, 0.417mmol) and methyl iodide (0.13mL, 2.08 mmol). The reaction was stirred at room temperature for 12 h, then the reaction mixture was diluted with DCM and washed with water. Separating the organic layer, Na₂SO₄Dried, concentrated by reduction, and purified by column chromatography (5% MeOH in DCM) to give the title compound. MS (ESI +): 374.0.

intermediate N.2: 1- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) Azole-3-carboxylic acid ethyl ester

With 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure N starting from pyrazole-3-carboxylic acid ethyl ester: 1- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester. ¹H NMR(DMSO-d₆，400MHz)：δ8.25(m，1H)，7.49-7.46(m，2H)，7.26-7.22(m，1H)，7.18-7.15(m，2H)，6.50-6.47(d，J=9.6Hz，1H)，4.35-4.29(m，2H)，4.22(s，2H)，3.46(s，3H)，1.32-1.29(t，J=7.1Hz，3H)。MS(ESI+)：368.2。

Intermediate O.1: 1- {3- [ (tert-Butoxycarbonyl) amino group]Phenyl } -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole- 3-Carboxylic acid ethyl ester 5, 5-dioxide

To 3- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-c ] in nitrogen atmosphere]Pyrazol-1 (4H) -yl]Benzoic acid (500mg, 1.21mmol) in t-butanol: TEA (0.68mL, 4.85mmol) was added to the DMF (8: 2) solution, followed by diphenyl azidophosphate (0.4mL, 1.82 mmol). The mixture was heated to 60 ℃ and held at 20mi, the temperature was allowed to slowly rise to 100 ℃ and heated at this temperature for 2 hours. Then, the solvent was evaporated under reduced pressure, and extracted with water, ethyl acetate. The organic layer was separated, washed with brine and Na₂SO₄Drying, concentration under reduced pressure, and purification by column chromatography (20% EtOAc, petroleum ether) gave the title compound as a white solid. MS (ESI +): 484.0.

intermediate O.2: 1- {3- [ (Phenoxycarbonyl) amino]Phenyl } -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3- Carboxylic acid ethyl ester 5, 5-dioxide

To 1- (3-aminophenyl) -1, 4-dihydrothiochromeno [4,3-c ] at room temperature]To a solution of pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide hydrochloride (100mg, 0.243mmol) in THF (10mL) were added 2,4, 6-trimethylpyridine (0.06mL, 0.487mmol), phenylchloroform (0.04mL, 0.365mmol), and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was concentrated under reduced pressure, diluted with water, and extracted with ethyl acetate. The organic layer was separated, washed with brine and Na ₂SO₄Drying and concentration under reduced pressure gave 100mg of the title compound. MS (ESI +): 504.0.

intermediate O.3: 1- {3- [ (morpholin-4-ylcarbonyl) amino]Phenyl } -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole- 3-Carboxylic acid ethyl ester 5, 5-dioxide

A mixture of ethyl 1- {3- [ (phenoxycarbonyl) amino ] phenyl } -1, 4-dihydrothiochromeno [4,3-C ] pyrazole-3-carboxylate 5, 5-dioxide (100mg, 0.198mmol), morpholine (0.03mL, 0.3mmol), triethylamine (0.03mL, 0.3mmol) in N-methyl-2-pyrrolidine was heated under microwave irradiation at 55 ℃ for 15 minutes. The reaction mixture was diluted with water and stirred for an additional hour. The precipitate was filtered off and dried in vacuo to yield 80mg (81%) of the title compound. MS (ESI +): 497.2.

intermediate O.4: 6-cyano-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester

Will be in DMF/water (10: 1,4.4 m)6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] in L)]Ethyl pyrazole-3-carboxylate (200mg, 0.483mmol) was placed in a sealed tube and purged with nitrogen for 10 minutes. Zinc cyanide (64mg, 0.545mmol), Pd2(dba)3(18mg, 0.019mmol) and s-phos (20mg, 0.483mmol) were then added and heated to 120 ℃ for 2 hours. The reaction mixture was then diluted with DCM, filtered over celite, washed with water, Na ₂SO₄Drying and concentration under reduced pressure gave 200mg of the title compound.¹H NMR(DMSO-d₆，400MHz)：δ7.74-7.72(m，1H)，7.60-7.55(m，3H)，7.48-7.46(m，2H)，7.18-7.14(m，1H)，6.91-6.89(dd，J=1.1，8.0Hz，1H)，4.40(s，2H)，4.36-4.31(m，2H)，1.33-1.29(t，J=7.1Hz，3H)。MS(ESI+)：362.2。

Program P

Intermediate P.1: 6-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5,5- Dioxide compounds

Under nitrogen atmosphere, 6-methoxy-1-phenyl-1, 4-dihydrobenzothiopyrano [4,3-c]A solution of pyrazole-3-carboxylic acid ethyl ester (0.30g, 0.81mmol) in acetic acid (5mL) was heated at 100 ℃. 30% aqueous hydrogen peroxide (0.5mL, 3.6mmol, 4.5Eq) was added and the reaction mixture was heated for an additional 30 minutes. After 30 minutes, the solvent was removed under reduced pressure. To the residue was added 10% NaHCO₃An aqueous solution. After stirring for 15 minutes, the solid was filtered off and dried to yield 0.26g (79%) of the title compound.¹H NMR(DMSO-d₆400 MHz): δ 7.63-7.58(m, 3H), 7.46-7.42(m, 3H), 7.26(d, J =8.6Hz, 1H), 6.34(d, J =7.92Hz, 1H), 4.90(s, 2H), 4.36(q, J =7.0Hz, 2H), 3.33(s, 3H), 1.32(t, J =7.08Hz, 3H). MS (ESI +): 399.0. HPLC (max plot) 94.0%; rt 4.17 min.

Intermediate P.2: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5,5- Dioxide compounds

With 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4,3-c ] ]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400 MHz): δ 7.78(t, J =8.16Hz, 1H), 7.53(d, J =7.44Hz, 1H), 7.38(d, J =8.4Hz, 1H), 4.79(s, 2H), 4.32(q, J =7.08Hz, 2H), 4.20(s, 3H), 3.92(s, 3H), 1.31(t, J =7.12Hz, 3H). MS (ESI +): 337.0. HPLC (max plot) 96.5%; rt 4.01 min.

Intermediate P.3: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400 MHz): δ 8.03-8.01(m, 1H), 7.68-7.62(m, 4H), 7.59-7.52(m, 3H), 6.80(d, J =7.7Hz, 1H), 4.99(s, 2H), 4.36(q, J =7.0Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 369.0. HPLC (max plot) 96.9%; rt 4.42 min.

Intermediate P.4: 1-methyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acidsEthyl ester 5, 5-dioxide

With 1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400 MHz): δ 8.07-8.02(m, 2H), 7.91-7.87(m, 1H), 7.75-7.71(m, 1H), 4.88(s, 2H), 4.32(q, J =7.0Hz, 2H), 4.29(s, 3H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 307.0.. HPLC (max plot) 96.6%; rt 3.25 min.

Intermediate P.5: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 1.0g (90%) of the title compound are prepared according to the procedure P: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 14.6(s, 1H), 8.06-7.93(m, 2H), 7.88-7.78(m, 1H), 7.70-7.63(m, 1H), 4.88(s, 2H), 4.40-4.32(m, 2H), 1.37-1.31(m, 3H). MS (ESI +): 293.0. HPLC (max plot) 93.1%; rt 3.19 min.

Intermediate P.6: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5,5- Dioxide compounds

With 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.49g (87%) of the title compound was prepared according to the procedure P: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 10.20(s, 1H), 8.00(d, J =8.8Hz, 1H), 7.48(s, 1H), 7.43-7.40(m, 1H), 4.85(s, 2H), 4.32(q, J =7.1Hz, 2H), 4.25(s, 3H), 3.92(s, 3H), 1.31(t, J =7.1Hz, 3H). MS (ESI +): 337.0. HPLC (max plot) 98.7%; rt 3.55 min.

Intermediate P.7: 7-methoxy-1-phenyl-14-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5,5- Dioxide compounds

With 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 1.01g (85%) of the title compound are prepared according to the procedure P: 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 7.65-7.62(m, 3H), 7.53-7.45(m, 3H), 7.17(dd, J =8.8Hz, J =3.1Hz, 1H), 6.73(d, J =8.8Hz, 1H), 4.95(s, 2H), 4.36(q, J =7.1Hz, 2H), 3.84(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 399.0. HPLC (max plot) 98.0%; rt 4.63 min.

Intermediate P.8: 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 1.08g (97%) of the title compound are prepared according to the procedure P: 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.02(dd, J =7.7Hz, J =1.3Hz, 1H), 7.66-7.56(m, 3H), 7.53-7.46(m, 2H), 7.38(s, 1H), 7.28(d, J =7.4Hz, 1H), 4.98(s, 2H), 4.36(q, J =7.1Hz, 2H), 2.40(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 383.0. HPLC (max plot) 97.3%; rt 4.85 min.

Intermediate P.9: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 1.1g (92%) of the title compound are prepared according to the procedure P: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.01(d, J =7.4Hz, 1H), 7.63-7.57(m, 2H), 7.45-7.39(m, 4H), 6.84(s, 1H), 4.97(s, 2H), 4.36(q, J =7.1Hz, 2H), 2.44(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 383.0. HPLC (max plot) 97.5%; rt 4.77 min.

Intermediate P.10: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.7g (92%) of the title compound are prepared according to the procedure P: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.03(dd, J =7.6Hz, J =1.1Hz, 1H), 7.65-7.60(m, 3H), 7.54-7.50(m, 2H), 6.74(d, J =7.9Hz, 1H), 5.01(s, 2H), 4.39-4.34(m, 2H), 1.76(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 401.0. HPLC (max plot) 98.4%; rt 4.71min.

Intermediate P.11: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.625g (88%) of the title compound is prepared according to the procedure P: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.03-8.01(m, 1H), 7.66-7.58(m, 1H), 7.52(t, J =8.0Hz, 1H), 7.23(dd, J =8.1Hz, J =1.3Hz, 1H), 7.15-7.13(m, 1H), 7.13(s, 1H), 7.02(d, J =7.8Hz, 1H), 6.87(d, J =7.5Hz, 1H), 4.98(s, 2H), 4.36(q, J =7.1Hz, 2H), 3.81(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 399.0. HPLC (max plot) 92.3%; rt 4.55 min.

Intermediate p.12: 1- (4-methoxyphenyl) -1, 4-dihydrothiophenesAnd pyrano [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from ethyl pyrazole-3-carboxylate and hydrogen peroxide, 1.0g (82% of the title compound 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c) was prepared according to the procedure P]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.02-8.00(m, 1H), 7.65-7.58(m, 2H), 7.47-7.43(m, 2H), 7.17-7.13(m, 2H), 6.86-6.84(m, 1H), 4.97(s, 2H), 4.36(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 399.0. HPLC (max plot) 95.4%; rt 4.49 min.

Intermediate p.13: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.55-8.54(m, 1H), 8.24-8.20(m, 2H), 8.01(dd, J =7.7Hz, J =1.0Hz, 1H), 7.90(d, J =8.0Hz, 2H), 7.70-7.57(m, 1H), 6.87(d, J =7.9Hz, 1H), 4.98(s, 2H), 4.36(q, J =7.1Hz, 2H), 1.34(t, J =7.1Hz, 3H). MS (ESI +): 370.0. HPLC (max plot) 97.9%; rt 3.76 min.

Intermediate p.14: 1-cyclohexyl-1,4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide Article (A)

With 1-cyclohexyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 1.1g (92%) of the title compound are prepared according to the procedure P: 1-cyclohexyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.04(d, J =7.6Hz, 1H), 7.93(t, J =7.2Hz, 1H), 7.85(d, J =7.7Hz, 1H), 7.74(t, J =7.6Hz, 1H), 4.85(s, 2H), 4.76-4.71(m, 1H), 4.34(q, J =7.1Hz, 2H), 2.02-1.82(m, 6H), 1.70-1.67(m, 1H), 1.56-1.49(m, 2H), 1.38(t, J =7.1Hz, 3H). MS (ESI +): 375.0. HPLC (max plot) 98.5%; rt 4.91 min.

Intermediate P.15: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(400MHz，DMSO-d₆400MHz) δ 8.02(d, J =7.8Hz, 1H), 7.93(dd, J =8.0Hz, J =1.0Hz, 1H), 7.71(t, J =8.0Hz, 1H), 4.98(s, 2H), 4.33(q, J =7.1Hz, 2H), 4.22(s, 3H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 386.0. HPLC (max plot) 98.7%; rt 3.80 min.

Intermediate p.16: 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 7.94-7.85(m, 1H), 7.59-7.54(m, 1H), 4.97(s, 2H), 4.32(q, J =7.1Hz, 2H), 4.26(s, 3H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 325.0. HPLC (max plot) 98.7%; rt 3.45 min.

Intermediate P.17: 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound, 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c, was prepared according to procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 7.65-7.57(m, 4H), 7.52-7.45(m, 3H), 6.63(d, J =7.9Hz, 1H), 5.08(s, 2H), 4.36(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 387.0. HPLC (max plot) 97.9%; rt 4.55 min.

Intermediate p.18: 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆，400MHz)δ10.2(b rs，1H)，8.11-8.08(m，1H)，7.91(dd，J=9.9Hz，J=2.4Hz，1H)，7.60-7.55(m，1H)，4.90(m，2H)，4.32(q，J=7.1Hz，2H)，1.32(t，J=7.1Hz，3H).MS(ESI+)：325.0。

Intermediate p.19: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.71g (73%) of the title compound was prepared according to the procedure P: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.12-8.09(m, 1H), 7.70-7.49(m, 1H), 6.42(d, J =10.1Hz, 2H), 5.02(m, 2H), 4.37(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 387.0. HPLC (max plot) 98.6%; rt 4.71 min.

Intermediate P.20: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

With 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.4g (79%) of the title compound are prepared according to the procedure P: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 7.84(d, J =8.0Hz, 1H), 7.61(d, J =6.8Hz, 2H), 7.48-7.46(m, 2H), 7.38(t, J =8.0Hz, 2H), 6.83(d, J =8.0Hz, 1H), 5.08(s, 2H), 4.37(q, J =7.1Hz, 2H), 1.33(t, J =7.0Hz, 3H). MS (ESI +): 448.0. HPLC (max plot) 99.2%; rt 4.84 min.

Intermediate p.21: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5,5- Dioxide compounds

With 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.62g (88%) of the title compound was prepared following the procedure P: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.8Hz, J =1.0Hz, 1H), 7.65-7.50(m, 6H), 6.65(d, J =7.4Hz, 1H), 5.01(s, 2H), 4.37-4.34(m, 2H), 1.85(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 383.0. HPLC (max plot) 96.7%; rt 5.85 min.

Intermediate p.22: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.55g (82%) of the title compound was prepared according to the procedure P: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.03(dd, J =7.8Hz, J =1.2Hz, 1H), 7.95(dd, J =7.8Hz, J =1.6Hz, 1H), 7.80(dd, J =7.8Hz, J =1.6Hz, 1H), 7.73-7.58(m, 4H), 6.76(d, J =6.7Hz, 1H), 5.08-4.97(m, 2H), 4.37(q, J =7.0Hz, 2H), 1.34(t, J =7.0Hz, 3H). MS (ESI +): 448.0. HPLC (max plot) 97.6%; rt 4.61 min.

Intermediate p.23: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.65g (78%) of the title compound was prepared according to the procedure P: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide. ¹H NMR(DMSO-d₆400MHz) δ 8.04(dd, J =7.7Hz, J =1.2Hz, 1H), 7.81-7.53(m, 6H), 6.84(d, J =7.6Hz, 1H), 5.01(d, J =7.0Hz, 2H), 4.37(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 387.0. HPLC (max plot) 97.4%; rt 4.43 min.

Intermediate p.24: 1- (2-chlorophenyl) 1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.74g (90%) of the title compound is prepared according to the procedure P: 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.04-8.02(m, 1H), 7.85-7.73(m, 3H), 7.70-7.56(m, 3H), 6.69(d, J =7.7Hz, 1H), 5.03-4.97(m, 2H), 4.37(q, J =7.0Hz, 1H), 1.34(t, J =7.1Hz, 3H). MS (ESI +): 403.0. HPLC (max plot) 99.1%; rt 5.94 min.

Intermediate p.25: 1- [2- (methylsulfonyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester Ester 5, 5-dioxides

With 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.5g (71%) of the title compound are prepared according to the procedure P: 1- [2- (methylsulfonyl) phenyl ]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.30-8.28(m, 1H), 8.03-7.94(m, 3H), 7.64-7.56(m, 3H), 6.60(dd, J =7.8Hz, J =1.0Hz, 1H), 5.04(s, 2H), 4.38(q, J =7.0Hz, 2H), 3.40(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 447.0. HPLC (max plot) 97.7%; rt 3.98min.

Intermediate p.26: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.2g (93%) of the title compound are prepared according to the procedure P: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.0Hz, 1H), 7.64-7.61(m, 2H), 7.09-7.05(m, 2H), 6.94-6.90(m, 2H), 4.96(m, 2H), 4.38-4.33(m, 6H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 427.0. HPLC (max plot) 96.3%; rt 4.45 min.

Intermediate p.27: 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3- Carboxylic acid ethyl ester 5, 5-dioxide

With 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]The title compound was prepared following procedure P starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide: 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.38(d, J =1.3Hz, 1H), 8.11(d, J =8.2Hz, 1H), 8.03(d, J =6.6Hz, 1H), 7.64-7.52(m, 3H), 6.79(d, J =7.8Hz, 1H), 5.01(s, 2H), 4.37(q, J =7.2Hz, 2H), 2.86(s, 3H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 440.0. HPLC (max plot) 95.5%; rt 4.31 min.

Intermediate p.28: 1- (3-bromobenzene)1, 4-dihydrothiochromeno [4,3-c ] yl]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.417g (86%) of the title compound was prepared according to the procedure P: 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.04(d, J =7.0Hz, 1H), 7.88-7.87(m, 2H), 7.67-7.63(m, 2H), 7.57-7.53(m, 2H), 6.90(d, J =7.0Hz, 1H), 4.99(s, 2H), 4.39-4.36(m, 2H), 1.33(t, J =7.0Hz, 3H). MS (ESI +): 448.0. HPLC (max plot) 96.9%; rt 4.91 min.

Intermediate P.29: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.39g (79%) of the title compound are prepared according to the procedure P: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.05-8.03(m, 1H), 7.77-7.74(m, 2H), 7.67-7.62(m, 3H), 7.50-7.47(m, 1H), 6.91-6.88(m, 1H), 4.99(s, 2H), 4.35(q, J =7.2Hz, 2H), 1.33(t, J =7.2Hz, 3H). MS (ESI +): 403.0. HPLC (max plot) 97.7%; rt 4.84 min.

Intermediate P.30: 1- (4-bromophenyl)-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.3g (85%) of the title compound are prepared according to the procedure P: 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.04-8.02(m, 1H), 7.84-7.82(m, 2H), 7.66-7.62(m, 2H), 7.52-7.50(m, 2H), 6.92-6.90(m, 1H), 4.98(s, 2H), 4.36(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 448.0. HPLC (max plot) 99.7%; rt 4.90 min.

Intermediate p.31: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.38g (94%) of the title compound are prepared according to the procedure P: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.03(dd, J =7.7Hz, J =1.6Hz, 1H), 7.67-7.59(m, 4H), 7.50-7.46(m, 2H), 6.85-6.83(m, 1H), 4.98(m, 2H), 4.36(q, J =7.1Hz, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 387.0. HPLC (max plot) 98.6%; rt 4.54 min.

Intermediate p.32: 1- (4-chlorophenyl) -1, 4-dihydrothiochromanAnd [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-bis Oxide compound

With 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.32g (84%) of the title compound are prepared according to the procedure P: 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.04-8.02(m, 2H), 7.71-7.57(m, 5H), 6.91-6.89(m, 1H), 4.98(s, 2H), 4.37(q, J =7.1Hz, 2H), 4.22(s, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 403.0. HPLC (max plot) 97.3%; rt 4.82 min.

Intermediate p.33: 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.6g (79%) of the title compound are prepared according to the procedure P: 1- (4-isopropylphenyl) -1, 4-dihydrosulfide.¹H NMR(DMSO-d₆400MHz) δ 8.02(q, J =7.6Hz, 1H), 7.65-7.56(m, 2H), 7.51-7.43(m, 4H), 6.83(d, J =7.8Hz, 1H), 4.98(s, 2H), 4.36(q, J =7.0Hz, 2H), 3.06-3.03(m, 1H), 1.33(t, J =7.1Hz, 3H), 1.25(d, J =6.8Hz, 6H). MS (ESI +): 411.0. HPLC (max plot) 98.2%; rt 6.79 min.

Intermediate P.34: 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

With 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.3g (83%) of the title compound are prepared according to the procedure P: 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.38(d, J =1.4Hz, 1H), 8.04-7.99(m, 2H), 7.78(d, J =8.1Hz, 1H), 7.66-7.57(m, 2H), 6.86(d, J =7.6Hz, 1H), 4.97(s 2H), 4.37(q, J =7.1Hz, 2H), 2.43(s, 3H), 1.34(t, J =7.1Hz, 3H). MS (ESI +): 384.0. HPLC (max plot) 96.1%; rt 4.13 min.

Intermediate p.35: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester Ester 5, 5-dioxides

With 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester and hydrogen peroxide, 0.6g (91%) of the title compound are prepared according to the procedure P: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.06-8.04(m, 1H), 7.96-7.89(m, 2H), 7.77-7.73(m, 1H), 5.09-5.04(m, 1H), 4.86(s, 2H), 4.34(q, J =7.0Hz, 1H), 4.00-3.96(m, 2H), 3.60-3.54(m, 3H), 2.21-2.11(m, 2H), 2.02-1.99(m, 2H), 1.33(t, J =7.1Hz, 3H). MS (ESI +): 377.0. HPLC (max plot) 94.4%; rt 3.61 min.

Reference procedure P gave the following intermediates:

intermediate P.80: 1-pyridin-3-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxo Article of manufacture

To 1- (1-oxide pyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Iron powder (175mg, 3.12mmol) was added to a solution of pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide (300mg, 0.78mmol) in glacial acetic acid (15 mL). The reaction was heated to 85 ℃ in the presence of nitrogen and held for 1 hour. The progress of the reaction was checked by TLC salts. The solvent was completely removed under reduced pressure. The resulting crude material was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound. ¹H NMR(400MHz，DMSO-d₆) δ =8.85-8.84(d, J =4.7Hz, 1H), 8.79-8.78(m, 1H), 8.07-8.03(m, 2H), 7.70-7.59(m, 3H), 6.87-6.85(d, J =7.84Hz, 1H), 5.00(s, 2H), 4.40-4.35(q, 2H), 1.35-1.32(t, J =7.12Hz, 3H). MS (ESI +): 370.2. HPLC (max plot): 97.29 percent; rt 3.24min.

Intermediate P.81: 1-phenyl-1, 4-dihydropyrazolo [3 ', 4': 4,5]Thiopyrano [3,2-c ] s]Pyridine-3-carboxylic acid ethyl ester 5, 5-dioxide

To a solution of 1-phenyl-1, 4-dihydropyrazolo [3 ', 4': 4,5]Thiopyrano [3,2-c ] s]A solution of pyridine-3-carboxylic acid ethyl ester 5,5, 8-trioxide (0.1g, 0.259mmol) (300mg, 0.78mmol) in glacial acetic acid was added iron powder (58mg, 1.038mmol) and the reaction was heated to 85 ℃ and held for 1 h. The reaction was completely concentrated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give 80mg, 83% (yield) of the title compound.¹H NMR(400MHz，DMSO-d₆)δ=8.85-8.84(d，J=5.2Hz，1H)，8.00-7.98(m，2H)，7.68-7.66(m，3H)，7.61(m，1H)，5.12(s，2H)，4.38-4.36(q，2H)，1.35-1.32(t，J=7.12Hz，3H)。MS(ESI+)：370.0。

Procedure Q

Intermediate Q.1: 1- [1- (tert-Butoxycarbonyl) piperidin-4-yl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3- Carboxylic acid ethyl ester 5, 5-dioxide

1- [1- (tert-Butoxycarbonyl) piperidin-4-yl in DCM (36.6ml) at 0 ℃]-1, 4-dihydrothiochromeno [4,3-c ]Pyrazole-3-carboxylic acid ethyl ester (3.05 g; 6.88 mmol; 1eq.) was added to 3-chloroperoxybenzoic acid (2.97 g; 17.19 mmol; 2.5eq.) and the reaction mixture was stirred at room temperature for 30 minutes. DCM was added and the organic phase was washed with NaHCO₃Washing with saturated aqueous solution three times, MgSO₄Drying and concentration gave 2.8g (86%) of the title compound. HPLC (max plot) 64.9%; rt 4.90 min. MS (ESI-): 474.3.

reference procedure Q gave the following intermediates:

intermediate q.25: 7-amino-1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydropyrazolo [3',4':4,5]Thiopyranos [3,2-d][1,3]Thiazole-3-carboxylic acid ethyl ester 5, 5-dioxide

To a solution of 7- [ (tert-butoxycarbonyl) amino ] -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydropyrazolo [3',4': a suspension of 4,5] thiopyrano [3,2-d ] [1,3] thiazole-3-carboxylic acid ethyl ester 5, 5-dioxide (182 mg; 0.37 mmol; 1.00eq.) in DCM (540. mu.l) was added TFA (180. mu.l; 2.34 mmol; 6.40 eq.). The mixture was stirred at room temperature overnight, and then water was added to the reaction mixture. The precipitate was washed with water and dried in vacuo to give the title compound as a cream powder. 1H NMR (DMSO) δ 8.34(bs, 2H), 5.61-5.43(m, 1H), 4.91(s, 2H), 4.33(q, J =7.1Hz, 2H), 4.12-3.93(m, 2H), 3.52-3.35(m, 2H), 3.20-1.87(m, 4H), 1.33(t, J =7.1Hz, 3H). HPLC (max plot) 95.1%; rt 2.28 min. MS (ESI +): 398.7.

Procedure R

Intermediate R.1: 1- [4- (hydroxymethyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide

To 4- [3- (ethoxycarbonyl) -5, 5-thiobenzopyrano [4,3-C ] at 0 ℃ under a nitrogen atmosphere]Pyrazol-1 (4H) -yl]A solution of benzoic acid (21.88 g; 53.05 mmol; 1eq.) in THF (350ml) was added triethylamine (14.71 ml; 106.11 mmol; 2eq.) and further isobutyl chloroformate (13.83 ml; 106.11 mmol; 2 eq.). The reaction mixture was stirred at room temperature for 30 minutes and cooled to 0 ℃. Sodium borohydride (10 g; 265.27 mmol; 5eq.) was added portionwise. After 5 hours, THF (100mL) was added and the reaction mixture was heated at 35 ℃ for 1 day and allowed to stand at room temperature for 2 days. Sodium borohydride (1eq) was added, stirred for 6 hours, water was added dropwise at 0 ℃ for 2 hours, and the reaction was quenched. The product was extracted with ethyl acetate and the organic layer was washed with HCl 1m (2X) and brine, MgSO₄Drying. After evaporation of the solvent, the residue was taken up in DCM and HCl 1 m. The precipitate formed was filtered off and recrystallized in DCE to give the title compound as a white solid.¹H NMR(DMSO-d₆)δ8.05-8.02(m，1H)，7.68-7.48(m，6H)，6.88-6.84(m，1H)，5.76(s，2H)，4.99(s，2H)，437(q, J =7.1Hz, 2H), 3.90(s, 1H), 1.35(t, J =7.1Hz, 3H). HPLC (max plot) 68.2%; rt 3.02 min. MS (ESI +): 398.9.

Reference procedure R gave the following compounds:

procedure S

Intermediate S.1: 6-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

To 6-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-C ] at 0 DEG C]A solution of pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide (0.23g, 0.57mmol) in THF (10mL) was added aqueous NaOH (2.8mL, 1M, 2.85mmol, 5Eq) and the reaction mixture stirred for 4 h. The solvent was removed under reduced pressure and aqueous HCl 1M was added. The product was extracted with EtOAc (2 ×). The organic layer was washed with brine, MgSO₄Drying and concentration under reduced pressure gave 0.2g (70%) of the title compound as a white solid.¹H NMR(DMSO-d₆400MHz) δ 13.5(brs, 1H), 7.61-7.57(m, 3H), 7.46-7.42(m, 3H), 7.26(d, J =8.6Hz, 1H), 6.35(d, J =8.0Hz, 1H), 4.88(s, 2H), 3.90(s, 3H). MS (ESI +): 371.0. HPLC (max plot) 98.9%; rt 3.30 min.

Intermediate S.2: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

With 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide as a white solid.¹H NMR (DMSO-d6, 400 MHz): δ 13.3(bs, 1H), 7.78(t, J =8.12Hz, 1H), 7.52(t, J =7.76Hz, 1H), 7.37(d, J =8.5Hz, 1H), 4.77(s, 2H), 4.15(s, 3H), 3.92(s, 3H). MS (ESI +): 309.0. HPLC (max plot) 96.3%; rt 2.12 min.

Intermediate S.3: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.47g (quantitative) of the title compound are prepared following the procedure of procedure S: 1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 13.5(brs, 1H), 8.01(d, J =7.72Hz, 1H), 7.65-7.57(m, 5H), 7.55-7.51(m, 2H), 6.80(d, J =7.64Hz, 1H), 4.97(s, 2H). MS (ESI +): 341.0. HPLC (max plot) 97.0%; rt 3.48 min.

Intermediate S.4: 1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide as starting material 0.69g (94%) of the title compound was prepared following the procedure of procedure S: 1-methyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 13.32(s, 1H), 8.06-8.01(m, 2H), 7.90-7.86(m, 1H), 7.72(t, J =7.6Hz, 1H), 4.86(s, 2H), 4.27(s, 3H). MS (ESI +): 279.0. HPLC (max plot) 95.4%; rt 2.3min.

Intermediate S.5: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.32g (71%) of the title compound are prepared according to the procedure of procedure S: 1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400 MHz): δ 8.01(d, J =7.6Hz, 1H), 7.94(d, J =7.7Hz, 1H), 7.81(t, J =7.52Hz, 1H), 7.64(t, J =7.7Hz, 1H), 4.85(s, 2H). MS (ESI +): 265.0 HPLC (max plot) 93.5%; rt 2.32 min.

Intermediate S.6: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

By 7-methoxy-1-Methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.34g (89%) of the title compound was prepared following the procedure of procedure S: 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.26(brs, 1H), 7.99(d, J =8.7Hz, 1H), 7.47(s, 1H), 7.43-7.40(m, 1H), 4.83(s, 2H), 4.23(s, 3H), 3.91(s, 3H). MS (ESI +): 309.0. HPLC (max plot) 99.4%; rt 2.63 min.

Intermediate S.7: 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

With 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.49g (87%) of the title compound was prepared according to the procedure of procedure S: 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 7.64-7.61(m, 3H), 7.52-7.45(m, 2H), 7.17-7.14(m, 2H), 6.73(d, J =8.8Hz, 1H), 4.93(s, 2H), 3.84(s, 3H). MS (ESI +): 371.0. HPLC (max plot) 97.9%; rt 3.72 min.

Intermediate S.8: 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article (A)

With 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide as a starting material according to procedure SPreparation 0.70g (83% of the title Compound 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.7Hz, J =1.3Hz, 1H), 7.65-7.56(m, 2H), 7.52-7.45(m, 2H), 7.37(s, 1H), 7.28(d, J =7.4Hz, 1H), 6.85-6.83(m, 1H), 4.96(s, 2H), 2.39(s, 3H). MS (ESI +): 355.0. HPLC (max plot) 97.9%; rt 3.85 min.

Intermediate S.9: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article (A)

With 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.88g (95%) of the title compound was prepared according to the procedure of procedure S: 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 13.55(brs, 1H), 8.01(dd, J =7.6Hz, J =1.4Hz, 1H), 7.64-7.56(m, 2H), 7.44-7.38(m, 4H), 6.84(d, J =7.8Hz, 1H), 4.95(s, 2H), 2.43(s, 3H). MS (ESI +): 355.0. HPLC (max plot) 98.0%; rt 3.84 min.

Intermediate S.10: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5,5- Dioxide compounds

With 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide is used as raw material according to the formulaProcedure of sequence S preparation of 0.54g (96%) of the title compound: 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.62(brs, 1H), 8.02(dd, J =7.7Hz, J =1.3Hz, 1H), 7.66-7.47(m, 5H), 6.74-6.72(m, 1H), 4.99(s, 2H), 1.77(s, 3H). MS (ESI +): 373.0. HPLC (max plot) 97.6%; rt 3.84 min.

Intermediate S.11: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

With 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.35g (75%) of the title compound was prepared according to the procedure of procedure S: 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.7Hz, J =1.3Hz, 1H), 7.65-7.57(m, 2H), 7.51(t, J =8.1Hz, 1H), 7.21(dd, J =8.2Hz, J =2.2Hz, 1H), 7.12(s, 1H), 7.02-7.00(m, 1H), 6.88-6.86(m, 1H), 4.96(s, 2H), 3.80(s, 3H). MS (ESI +): 371.0. HPLC (max plot) 93.5%; rt 3.62 min.

Intermediate S.12: 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

With 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide isStarting material, following the procedure of procedure S, 0.83g (99%) of the title compound was prepared: 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.54(brs, 1H), 8.00(dd, J =7.6Hz, J =1.4Hz, 2H), 7.64-7.58(m, 2H), 7.44(d, J =8.8Hz, 1H), 7.15(d, J =8.8Hz, 1H), 6.86-6.83(m, 2H), 4.95(s, 2H), 2.43(s, 3H). MS (ESI +): 371.0. HPLC (max plot) 92.3%; rt 3.57min.

Intermediate S.13: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.22g (95%) of the title compound are prepared according to the procedure of procedure S: 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 13.68(brs, 1H), 8.54(dd, J =4.7Hz, J =0.8Hz, 1H), 8.23-8.19(m, 1H), 8.00(dd, J =7.5Hz, J =1.0Hz, 1H), 7.89(d, J =7.9Hz, 1H), 7.69-7.56(m, 3H), 6.89(d, J =7.6Hz, 1H), 4.95(s, 2H). MS (ESI +): 342.0. HPLC (max plot) 98.0%; rt 2.79 min.

Intermediate S.14: 1-cyclohexyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1-cyclohexyl-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide is used as raw material according to the formulaProcedure of sequence S preparation of 0.88g (95%) of the title compound: 1-cyclohexyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.34(brs, 1H), 8.03(d, J =7.8Hz, 1H), 7.92(t, J =7.8Hz, 1H), 7.85(d, J =8.0Hz, 1H), 7.31(d, J =7.6Hz, 1H), 4.83(s, 2H), 4.72(t, J =11.0Hz, 1H), 2.04-1.82(m, 8H), 1.70-1.67(m, 1H), 1.56-1.49(m, 1H). MS (ESI +): 347.0. HPLC (max plot) 98.8%; rt 3.89 min.

Intermediate S.15: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.3(brs, 1H), 8.01(d, J =8.0Hz, 1H), 7.92(d, J =8.0Hz, 1H), 7.70(t, J =8.0Hz, 1H), 4.96(s, 2H), 4.20(s, 3H). MS (ESI +): 357.0. HPLC (max plot) 99.2%; rt 2.89 min.

Intermediate S.16: 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acids

With 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid ethyl ester as starting material 0.088g (72%) of the title compound was prepared according to the procedure of procedure S: 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles-3-carboxylic acid d the title compound as a white solid.¹H NMR(DMSO-d₆400MHz,) δ 13.1(brs, 1H), 8.55(d, J =2.3Hz, 1H), 8.11(dd, J =8.7Hz, J =2.3Hz, 1H), 7.76(d, J =8.6Hz, 1H), 4.29(s, 2H), 4.22(s, 2H). MS (ESI +): 292.0. HPLC (max plot) 96.8%; rt 3.55 min.

Intermediate S.17: 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.24g (77%) of the title compound are prepared according to the procedure of procedure S: 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) delta 13.3(brs, 1H), 7.93-7.84(m, 2H), 7.56(m, 1H), 4.96(s, 2H), 4.24(s, 3H). MS (ESI +): 297.0. HPLC (max plot) 96.3%; rt 2.46 min.

Intermediate S.18: 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid 5, 5-dioxides

Starting from ethyl 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylate 5, 5-dioxide, according to the procedure S, 0.29g (78%) of the title compound was prepared: 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid 5, 5-dioxide. MS (ESI +): 359.0.

intermediate S.19: 8-fluoro-1-methyl-1, 4-dihydrothiochromanesAnd [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆，400MHz)δ8.11-8.07(m，1H)，7.91-7.88(m，1H)，7.59-7.55(m，1H)，4.27(s，2H)，3.72(s，3H)。MS(ESI+)：297.0。

Intermediate S.20: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid 5, 5-dioxide. ¹H NMR(DMSO-d₆，400MHz)δ8.12-8.08(m，1H)，7.69-7.63(m，2H)，7.57-7.48(m，2H)，7.25-7.11(m，2H)，6.43-6.40(m，1H)，4.97(s，2H)。MS(ESI+)：359.0。

Intermediate S.21: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(b rs, 1H), 7.83(d, J =8.0Hz, 1H), 7.61-7.57(m, 3H), 7.46(d, J =7.9Hz, 1H), 7.38(t, J =8.0Hz, 1H), 7.25-7.13(m, 1H), 6.83(d, J =8.0Hz, 1H), 5.08(s, 2H), 4.37(q, J =7.1Hz, 2H), 1.33(t, J =7.9Hz, 3H). MS (ESI +): 420.0. HPLC (max plot) 97.8%; rt 3.96 min.

Intermediate S.22: 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acids

With 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid ethyl ester, 0.7g (71%) of the title compound are prepared according to the procedure of procedure S: 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid.¹H NMR(DMSO-d₆400MHz) δ 13.3(brs, 1H), 8.01-7.98(m, 1H), 7.50(d, J =8.8Hz, 1H), 7.74(d, J =8.2Hz, 3H), 7.65-7.59(m, 3H), 7.52(dd, J =8.2Hz, J =1.2Hz, 1H), 7.42(s, 1H), 4.40(s, 2H). MS (ESI +): 354.0. HPLC (max plot) 93.2%; rt 4.33 min.

Intermediate S.23: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article (A)

With 1- (2-methylphenyl)-1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.4g (85%) of the title compound are prepared according to the procedure of procedure S: 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(brs, 1H), 8.00(dd, J =7.8Hz, J =1.2Hz, 1H), 7.63-7.48(m, 6H), 6.65(d, J =7.8Hz, 1H), 5.00(s, 2H), 1.85(s, 3H). MS (ESI +): 355.0. HPLC (max plot) 96.9%; rt 3.74 min.

Intermediate S.24: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.3g (71%) of the title compound are prepared according to the procedure of procedure S: 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(s, 1H), 8.02(dd, J =7.8Hz, J =1.2Hz, 1H), 7.95(dd, J =7.8Hz, J =1.2Hz, 1H), 7.79(dd, J =7.8Hz, J =1.2Hz, 1H), 7.73-7.58(m, 4H), 6.66-6.64(m, 1H), 5.06-4.95(m, 2H). MS (ESI +): 420.0. HPLC (max plot) 98.0%; rt 3.70min.

Intermediate S.25: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide is used as raw material according to the formulaThe procedure of sequence S prepares the title compound: 1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(brs, 1H), 8.02(dd, J =7.7Hz, J =1.2Hz, 1H), 7.81-7.74(m, 2H), 7.67-7.50(m, 4H), 6.84(d, J =7.6Hz, 1H), 4.99(d, J =7.0Hz, 2H). MS (ESI +): 359.0. HPLC (max plot) 99.0%; rt 3.48 min.

Intermediate S.26: 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(brs, 1H), 8.02(d, J =7.6Hz, 1H), 7.83-7.56(m, 6H), 6.68(d, J =7.7Hz, 1H), 5.06-4.95(m, 2H). MS (ESI +): 375.0. HPLC (max plot) 97.6%; rt 3.65 min.

Intermediate S.27: 1- [2- (methylsulfonyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acids 5, 5-dioxide

With 1- [2- (methylsulfonyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.35g (74%) of the title compound was prepared according to the procedure of procedure S: 1- [2- (methylsulfonyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acids5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 8.29(dd, J =7.8Hz, J =1.2Hz, 1H), 8.02-7.92(m, 3H), 7.65-7.54(m, 3H), 6.60(d, J =7.2Hz, 1H), 5.02(s, 2H), 3.42(s, 3H). MS (ESI +): 419.0. HPLC (max plot) 96.6%; rt 3.09 min.

Intermediate S.28: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.15g (97%) of the title compound are prepared according to the procedure of procedure S: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide. ¹H NMR(DMSO-d₆400MHz) δ 13.5(brs, 1H), 8.00(dd, J =7.2Hz, J =4.2Hz, 1H), 7.65-7.60(m, 2H), 7.07-7.04(m, 2H), 6.93-6.89(m, 2H), 4.94(s, 2H), 4.35-4.34(m, 4H). MS (ESI +): 399.0. HPLC (max plot) 96.4%; rt 3.35 min.

Intermediate S.29: 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3- Carboxylic acid 5, 5-dioxides

With 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide as starting material 0.090g (79%) of the title compound was prepared following the procedure of procedure S: 1- (2-methyl-1, 3-benzoThiazol-6-yl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹HNMR(DMSO-d₆400MHz) δ 13.6(brs, 1H), 8.36(d, J =2.0Hz, 1H), 8.11(d, J =8.3Hz, 1H), 8.02(dd, J =7.8Hz, J =1.1Hz, 1H), 7.64-7.53(m, 3H), 6.79(d, J =7.8Hz, 1H), 4.99(s, 2H), 2.86(s, 3H). MS (ESI +): 412.0. HPLC (max plot) 95.9%; rt 3.24 min.

Intermediate S.30: 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c ]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.29g (88%) of the title compound was prepared following the procedure of procedure S: 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) delta 13.6(brs, 1H), 8.04-8.02(m, 1H), 7.87-7.85(m, 2H), 7.67-7.50(m, 4H), 6.91-6.89(m, 1H), 4.97(s, 2H). MS (ESI +): 420.0. HPLC (max plot) 98.7%; rt 3.95 min.

Intermediate S.31: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.28g (97%) of the title compound are prepared according to the procedure of procedure S: 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz)13.6(brs, 1H), 8.04-8.02(m, 1H), 7.75-7.73(m, 2H), 7.67-7.60(m, 1H), 7.48-7.46(m, 1H), 6.91-6.89(m, 1H), 4.97(s, 2H). MS (ESI +): 375.0. HPLC (max plot) 98.0%; rt 5.87 min.

Intermediate S.32: 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.6(brs, 1H), 8.03-8.01(m, 1H), 7.83(d, J =8.6Hz, 2H), 7.67-7.62(m, 2H), 7.52-7.49(m, 2H), 6.93-6.90(m, 1H), 4.96(s, 2H). MS (ESI +): 420.0. HPLC (max plot) 96.4%; rt 4.03 min.

Intermediate S.33: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆，400MHz)δ13.6(brs，1H)，8.02(d，J=7.7Hz，1H)，7.66-7.59(m，4H)，7.50-7.45(m，2H)，6.85-6.83(m，1H)，4.96(m，2H)。MS(ESI+)：359.0。HPLC (max plot) 99.0%; rt 3.57 min.

Intermediate S.34: 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4,3-c]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) delta 13.63(m, 1H), 8.04-8.02(m, 1H), 7.71-7.56(m, 6H), 6.92-6.89(m, 1H), 4.96(s, 2H). MS (ESI +): 343.0. HPLC (max plot) 98.5%, Rt 3.93 min.

Intermediate S.35: 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides Article of manufacture

With 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.45g (88%) of the title compound was prepared following the procedure of procedure S: 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.5(brs, 1H), 8.01(d, J =7.6Hz, 1H), 7.64-7.56(m, 2H), 7.50-7.42(m, 4H), 6.83(d, J =7.7Hz, 1H), 4.95(s, 2H), 3.07-3.00(m, 1H), 1.27(d, J =6.9Hz, 6H). MS (ESI +): 383.0. HPLC (max plot) 95.2%; rt 4.56 min.

Intermediate S.36:1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5,5- Dioxide compounds

With 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure S starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide: 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR((DMSO-d₆400MHz) δ 13.65(brs, 1H), 8.37(d, J =1.6Hz, 1H), 8.03-7.98(m, 2H), 7.77(d, J =8.0Hz, 1H), 7.65-7.56(m, 2H), 6.88-6.86(m, 1H), 4.95(s 2H), 2.43(s, 3H). MS (ESI +): 356.0. HPLC (max plot) 97.4%; rt 3.22 min.

Intermediate s.37: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acids 5, 5-dioxide

With 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide, 0.35g (75%) of the title compound was prepared according to the procedure of procedure S: 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide.¹H NMR(DMSO-d₆400MHz) δ 13.3(brs, 1H), 8.04(q, J =7.9Hz, 1H), 7.95-7.89(m, 2H), 7.74(t, J =6.7Hz, 1H), 5.07-5.02(m, 1H), 4.84(s, 2H), 4.00-3.96(m, 2H), 3.60-3.54(m, 1H), 2.21-2.18(m, 1H), 2.17-2.12(m, 2H). MS (ESI +): 349.0. HPLC (max plot) 94.6%; rt 2.69 min.

Reference procedure S gave the following intermediates:

intermediate S.118: 6- (aminocarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]Pyrazole-3-carboxylic acid 5,5- Dioxide compounds

To 6-cyano-1-phenyl-1, 4-dihydrothiochromeno [4,3-C ] at 100 DEG C]A solution of pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide (100mg, 0.254mmol) in EtOH (10mL) was added aqueous NaOH (10%, 1mL) and 30% hydrogen peroxide (2mL) and heating was continued for 2 h. The reaction mixture was evaporated in vacuo, acidified with HCl (1.5N) and extracted with EtOAc. Separating the organic layer, Na₂SO₄Dried and concentrated under reduced pressure to give the title compound. MS (ESI +): 384.0.

procedure T

Intermediate T.1: 1-methyl-3- (morpholin-4-ylcarbonyl) -8-nitro-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles

To 1-methyl-8-nitro-1, 4-dihydrothiochromeno [4,3-c ] in THF]Pyrazole-3-carboxylic acid (0.088g, 0.30mmol) was added triethylamine (0.13mL, 0.9mmol, 3Eq), followed by 50% T3P (propanephosphonic anhydride) in EtOAc (0.50mL,0.81mmol, 2.7 Eq). The reaction mixture was cooled to 0 ℃, morpholine (0.38mL, 0.60mmol, 2Eq) was added and the reaction mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue was diluted with EtOAc. The organic layer was washed with 10% NaHCO₃And washed again with brine. The organic layer was MgSO₄Drying and concentration in vacuo gave 0.084g (77%) of the title compound as a white solid. ¹H NMR(DMSO-d₆400MHz) δ 8.55(d, J =2.4Hz, 1H), 8.10(dd, J =8.5Hz, J =2.4Hz, 1H), 7.76(d, J =8.7Hz, 1H), 4.20(s, 3H), 4.19(s, 2H), 3.95(brs, 2H), 3.63(brs, 6H). MS (ESI +): 359.0. HPLC (max plot) 96.9%; rt 3.78 min.

Intermediate T.2: 3- (morpholin-4-ylcarbonyl) -8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles

Starting from 8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylic acid and morpholine, 0.628G (79%) of the title compound were prepared according to the procedure G: 3- (morpholin-4-ylcarbonyl) -8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole. MS (ESI +): 423.0.

reference procedure T yielded the following intermediates:

procedure W

Intermediate W.1: 4- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Benzyl methane sulfonyl ester

To {4- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-C ] pyrazol-1 (4H) -yl ] phenyl } methanol (300 mg; 0.68 mmol; 1eq.) in DCM (15mL) was added triethylamine (190.28. mu.l; 1.37 mmol; 2eq.) and methanesulfonyl chloride (105.67. mu.l; 1.37 mmol; 2eq.) at 0 ℃ under nitrogen. The reaction mixture was stirred at room temperature for 1 hour. Water was added to stop the reaction and the product was extracted with DCM. The organic layer was dried over MgSO4 and the solvent was evaporated to give 400mg (quantitative) of the title compound as a rice oil. It was used directly in the next step without further purification. MS (ESI +): 518.0.

Intermediate W.2: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Benzyl methane sulfonyl ester

Starting from {4- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] phenyl } methanol, following the procedure W (new: mesylate formation) 1.85g (quantitative) of the title compound were prepared: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] benzyl methanesulfonyl ester. HPLC (max plot) 62.6%; rt 3.69 min. HPLC (max plot) 78.4%; rt 3.66 min. MS (ESI +): 517.9.

the following compounds were obtained with reference to the program AW:

procedure Y

Intermediate Y.1: 4-hydrazinylpiperidine (hydrochloride)

To a solution of tert-butyl 4- [2- (tert-butoxycarbonyl) hydrazino ] piperidine-1-carboxylate (15 g; 47.56 mmol; 1eq.) in DCM (100ml) was added a solution of hydrogen chloride in 1, 4-dioxane (30 ml; 4M; 120 mmol; 2.52 eq.). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The resulting solid was dried in vacuo to give 9.1g (100%) of the title compound as a white powder. 1H NMR (300MHz, DMSO). delta.9.26-9.06 (m, 2H), 7.95(bs, 5H), 3.39-3.05(m, 3H), 3.02-2.69(m, 2H), 2.21-1.95(m, 2H), 1.84-1.61(m, 2H).

Referring to procedure Y, the following compound was obtained:

procedure Z

Intermediate Z.1: 1- [1- (2-chloroethyl) piperidin-4-yl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

To a suspension of 3- (morpholin-4-ylcarbonyl) -1-piperidin-4-yl-1, 4-dihydrothiochromeno [4,3-C ] pyrazole 5, 5-dioxide hydrochloride (100 mg; 0.23 mmol; 1eq.) and chloroacetaldehyde (31.13 mg; 0.24 mmol; 1.1eq.) in DCE (4.2ml) was added sodium triacetoxyborohydride (229.27 mg; 1.08 mmol; 1.4eq) and the reaction mixture was stirred at 65 ℃ overnight. The reaction mixture was diluted with DCM and the organic phase was washed with saturated aqueous NaHCO3, dried over MgSO and concentrated. The residue was purified by flash chromatography (eluent 100% to 30% AcOEt and MeOH) to give the title compound as a brown oil after concentration of the desired fraction. HPLC (max plot) 89.6%; rt 2.33 min.

Reference procedure Z gave the following intermediates:

intermediate z.19: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] phenol

To 1- [3- (benzyloxy) phenyl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]A solution of pyrazole 5, 5-dioxide (8g, 155mmol) in MeOH (500mL) was added 10% Pd/C (0.5g) and the reaction mixture was cooled at room temperature and 2Kg/cm ²Hydrogenation was carried out in an autoclave under hydrogen pressure for 20 hours. The catalyst was filtered off through celite and the filtrate was concentrated to give 4.9g (89%) of the title compound as a brown solid.¹H NMR(DMSO-d₆400 MHz): δ 10.08(s, 1H), 8.02-8.00(dd, J =2.4,3.2Hz, 1H), 7.65-7.59(m, 2H), 7.42-7.38(t, J =8.0Hz, 1H), 7.01-6.99(t, J =8.4Hz, 1H), 6.93-6.88(m, 3H), 4.88(s, 2H), 3.95(m, 2H), 3.66-3.61(m, 4H), 3.56(s, 2H). MS (ESI +): 426.0. HPLC (max plot): 96 percent; rt 3.25 min.

Intermediate Z.20: 1- {6- [ (acetyloxy) methyl group]Pyridin-3-yl } -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) Oxazole-3-carboxylic acid ethyl ester 5, 5-dioxide.

A solution of ethyl 1- (1-oxidopyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-C ] pyrazole-3-carboxylate 5, 5-dioxide (637mg) in acetic anhydride (30mL) was heated to 130 ℃ for 2 hours under a nitrogen atmosphere. After completion of the reaction, the reaction was concentrated under reduced pressure, triturated in water, filtered and dried to yield 700mg (99%) of the title compound. MS (ESI +): 442.0.

intermediate z.21: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl ] Aniline

Reacting 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (0.15g, 0.308mmol), copper acetate (6mg, 0.03mmol), cesium carbonate (200mg, 0.616mmol) and acetylacetone (13 μ L, 0.123mmol) were placed in DMF and purged with ammonia gas. The reaction mixture was heated to 90 ℃ for 24 hours. The reaction mixture was then concentrated under reduced pressure and purified by column chromatography (100% EtOAc) to give the title compound as a light brown solid.¹H NMR(400MHz，DMSO-d₆) δ =7.99-7.97(m, 1H), 7.62-7.60(m, 1H), 7.24-7.20(t, J =7.84Hz, 1H), 6.98-6.95(m, 1H), 6.75-6.73(d, J =9.32Hz, 1H), 6.58-6.56(m, 2H), 5.57(s, 2H), 4.87(s, 2H), 3.95(m, 2H), 3.66(m, 6H). MS (ESI +): 425.0. HPLC (max plot): 94.69 percent; rt 2.65 min.

Intermediate z.22: 7- (acetylamino) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydropyrazolo [3 ', 4': 4,5]Sulfur Substituted pyrano [3,2-d ] s][1,3]Thiazole-3-carboxylic acid ethyl ester 5, 5-dioxide

To a solution of 7-amino-1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydropyrazolo [3 ', 4': 4,5]Thiopyrano [3,2-d][1,3]A suspension of thiazole-3-carboxylic acid ethyl ester 5, 5-dioxide (71 mg; 0.18 mmol; 1eq.) and triethylamine (98.8. mu.L; 0.71 mmol; 4eq.) in DCM (710. mu.L) was added acetyl chloride (30. mu.L; 0.46 mmol; 2.5 eq.). The suspension was stirred at room temperature overnight and then heated to 100 ℃ and held for 1 day. Water was added to the reaction mixture and the product was extracted with DCM (X2). The organic layers were combined, washed with brine, Na ₂SO₄Dried and concentrated in vacuo to give a beige solid residue. The residue was taken up in Et₂Trituration in O and sonication filtered off the solid to give the title compound. HPLC (max plot) 98.8%; rt 3.28 min. MS (ESI +): 441.1.

intermediate z.23: 4- [ (4-Nitro-1H-pyrazol-3-yl) carbonyl]Morpholine

Starting from 4-nitro-1H-pyrazole-3-carboxylic acid and morpholine, 3.0g (41%) of the title compound were prepared according to the procedure AD (see below): 4- [ (4-nitro-1H-pyrazol-3-yl) carbonyl ] morpholine as a white solid. 1HNMR 14.22(brs, 1H), 8.92(brs, 1H), 3.66(s, 4H), 3.52-3.45(m, 2H), 3.25-3.18(m, 2H). MS (ESI +): 226.9.

intermediate z.24: 4- [ (4-Nitro-1-phenyl-1H-pyrazol-3-yl) carbonyl]Morpholine

Reacting 4- [ (4-nitro-1H-pyrazol-3-yl) carbonyl]Morpholine (1.50 g; 6.63 mmol; 1.00eq.) anda solution of copper acetate (1204.49 mg; 6.63 mmol; 1.00eq.) in DCM (5mL) was stirred at room temperature for 18 h, then phenylboronic acid (808.58 mg; 6.63 mmol; 1.00eq.) and TEA (1.83mL) were added and the reaction mixture stirred at room temperature for 18 h. After this time, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered through a short plug of silica gel and concentrated in vacuo to give a yellow oil. Purification by column chromatography (DCM to 15% ethyl acetate in DCM) and recrystallisation from MTBE gave 60mg of the title compound as a white solid. ¹H NMR(DMSO)9.76(s，1H)，8.00-7.91(m，2H)，7.65-7.54(m，2H)，7.53-7.43(m，1H)，3.70(s，4H)，3.60-3.48(m，2H)，3.41-3.32(m，2H)。MS(ESI+)：303.0。

Intermediate z.25: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-amine

To a solution of 4- [ (4-nitro-1-phenyl-1H-pyrazol-3-yl) carbonyl ] morpholine (376 mg; 1.24 mmol; 1.00eq.) in AcOEt (10mL) was added Pd/C10% (-50% water) (13.24 mg; 0.12 mmol; 0.10eq.) under 1 hydrogen pressure. After 18 hours, the reaction mixture was filtered over a bed of celite, washing with AcOEt, to give 310mg (92%) of the title compound as a purple solid. 1H NMR (DMSO): δ 7.85(s, 1H), 7.77-7.72(m, 2H), 7.53-7.44(m, 2H), 7.30(t, J =7.4Hz, 1H), 5.14-4.90(m, 2H), 4.31-4.14(m, 2H), 3.73-3.58(m, 4H), 3.43-3.23(m, 2H). HPLC (max plot) 95.6%; rt 2.01min. ms (ESI +): 272.9.

intermediate z.26: 2-bromo-N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl]Benzenesulfonamides

To a solution of 3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-amine (260 mg; 0.95 mmol; 1eq.) in DCM (10mL) was added pyridine (151. mu.L; 1.91 mmol; 2.00eq.) and 2-bromobenzene-1-sulfonyl chloride (317 mg; 1.24 mmol; 1.30 eq.). The reaction mixture was stirred at room temperature for 48 hours. Then DCM was added to the reaction mixture, NH₄Washed with saturated solution of Cl, MgSO₄Drying and flash chromatography (AcOEt/heptane 4: 1) afforded 440mg (94%) of the title compound as a white solid. ¹H NMR (DMSO). delta.9.93 (s, 1H), 8.43(s, 1H), 8.11-8.02(m, 1H), 7.91-7.84(m, 1H), 7.84-7.76(m, 2H), 7.59-7.45(m, 4H), 7.40-7.31(m, 1H), 3.81-3.69(m, 2H), 3.67-3.49(m, 6H). HPLC (max plot) 94.6%; rt 4.83 min. MS (ESI +): 493.2.

intermediate z.27: 2-bromo-N- (methoxymethyl) -N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl]Benzene and its derivatives Sulfonamides

To 2-bromo-N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl]A solution of benzenesulfonamide (200 mg; 0.41 mmol; 1.00eq.) in THF (30mL) was added portionwise NaH (24 mg; 0.61 mmol; 1.50eq.) and the resulting mixture was stirred at room temperature for 15 minutes, after which chloromethyl methyl ether (82. mu.l; 0.81 mmol; 2.00eq.) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, NaHCO was added₃The reaction was quenched with saturated aqueous solution. Extraction with ethyl acetate (2 ×), washing with brine, drying over magnesium sulphate and concentration in vacuo gave 240mg (quantitative) of the title compound as a colourless oil.¹H NMR(DMSO)δ8.82(s，1H)，7.93-7.8(m，4H)，7.64-7.46(m，4H)，7.39(t，J=7.4Hz，1H)，5.32(s，2H)，3.59-3.51(m，2H)，3.42(s，3H)，3.46-3.37(m，4H)，3.15-3.06(m，2H)。MS(ESI+)：505.2。

Intermediate z.28: 2-bromo-N-methyl-N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl]Benzenesulfonamides

To a solution of 2-bromo-N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl ] benzenesulfonamide (30 mg; 0.06 mmol; 1.00eq.) in THF (6mL) was added sodium hydride (3 mg; 0.07 mmol; 1.20eq.), the reaction was stirred for 10 minutes, and then iodomethane (4. mu.L; 0.07 mmol; 1.10eq.) was added. After 12 h DCM was added to the reaction mixture, washed with water (× 2) and the organic phase dried over MgSO4 to give 30mg (97%) of the title compound as a white solid. 1H NMR (DMSO). delta.8.64 (s, 1H), 7.93-7.86(m, 2H), 7.80-7.73(m, 2H), 7.62-7.47(m, 4H), 7.41-7.32(m, 1H), 3.65-3.51(m, 6H), 3.48-3.42(m, 2H), 3.35(s, 3H). HPLC (max plot) 89.7%; rt 3.98 min. MS (ESI +): 507.2..

Intermediate z.29: ethyl 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of phenylhydrazine (10g, 92.6mmol) in anhydrous ethanol (100mL) was added dry K₂CO₃(15.3g, 111mmol) and then diethyl butynedioate (10.6g, 62.03mmol) was added slowly and the reaction mixture was heated at 85 ℃ for 12 h. The reaction mixture was cooled to room temperature and 38mL of 6N HCl was added dropwise. The reaction mixture was diluted with 150mL of water and extracted with ethyl acetate. The organic layer was washed twice with water, Na₂SO₄Drying and vacuum concentrating. The residue was triturated in MTBE and the solid formed was filtered off, washed with MTBE and dried to give the title compound.¹H NMR(DMSO-d6，400MHz)：δ12.12(bs，1H)，7.72-7.70(m，2H)，7.51-7.47(m，2H)，7.37-7.34(m，1H)，5.93(s，1H)，4.26(q，J=4.1Hz，2H)，1.27(t，J=7.1Hz，3H)。MS(ESI+)：233.2。

Intermediate Z.30: 5-bromo-4-formyl-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of ethyl 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate (6.47g, 27.52mmol) in DCE (70mL) was added phosphorus oxybromide (13.86g, 48.16mmol) and DMF (4mL, 51.46 mmol). The reaction mixture was refluxed at 90 ℃ for 3 hours. Phosphorus oxybromide (34.8g, 121.38mmol) was again added and the reaction mixture refluxed at 90 ℃ for 20 hours. The reaction mixture was poured into ice and extracted twice with DCM. The organic layer was washed with Na₂SO₄Drying and concentrating. The crude product was purified by column chromatography to give the title compound. ¹H NMR (DMSO-d6, 400 MHz): δ 10.30(s, 1H), 7.63-7.61(m, 5H), 4.38(q, J =3.6Hz, 2H), 1.32(t, J =7.1Hz, 3H). MS (ESI +): 325.0. HPLC (max plot) 97.37%, Rt 4.42 min.

Intermediate z.31: 5-bromo-4- (hydroxymethyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of ethyl 5-bromo-4-formyl-1-phenyl-1H-pyrazole-3-carboxylate (3.82g, 11.86mmol, 1eq) in HF: 1 of EtOH: 1 sodium borohydride (0.5g, 13.04mmol, 1.1eq) was added portionwise to the ice solution in the mixture. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl solution and extracted with EtOAc. Na for organic layer₂SO₄Drying and concentrating. The crude product was purified by column chromatography to yield 2.91g (75%) of the title compound.¹H NMR(DMSO-d6，400MHz)：δ7.60-7.56(m，5H)，4.95(t，J=5.4Hz，1H)，4.60-4.58(d，J=5.4Hz，2H)，4.32(q，J=7.01Hz, 2H), 1.30(t, J =7.7Hz, 3H). HPLC (max plot) 96.75%; rt 3.69 min.

Intermediate z.32: 5-bromo-4- (bromomethyl) -1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To ethyl 5-bromo-4- (hydroxymethyl) -1-phenyl-1H-pyrazole-3-carboxylate (2.91g, 8.98mmol, 1eq) cooled to-10 ℃ in Et₂Phosphorus tribromide (1.02mL, 10.77mmol, 1.2eq) was added to the solution in O and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice and extracted with MTBE. The organic layer was washed with brine, Na ₂SO₄Drying and concentration gave 2.1g (60%) of the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 7.65-7.57(m, 5H), 4.77(s, 2H), 4.35(q, J =6.0Hz, 2H), 1.32(t, J =6.6Hz, 3H). HPLC (max plot) 83.30%; rt 5.33 min.

Intermediate z.33: 5-bromo-4- [ (1H-imidazo l-2 ylthio) methyl]-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester

To a solution of ethyl 5-bromo-4- (bromomethyl) -1-phenyl-1H-pyrazole-3-carboxylate (2.1g, 5.44mmol, 1eq) and 2-mercaptoimidazole (0.6g, 5.98mmol, 1.1eq) in ACN (30mL) was added K₂CO₃(2.25g, 16.32mmol, 3eq) and the reaction mixture was heated to 85 ℃ for 1 hour. The reaction mixture was diluted with DCM and filtered. The filtrate was concentrated and the residue was partitioned between DCM and water. Na for organic layer₂SO₄Drying and concentration gave the title compound.¹H NMR(DMSO-d6，400MHz)：δ12.29(bs，1H)，7.59-7.53(m，5H)，7.16(d，J=1.4Hz，1H)，6.94(d，J=1.4Hz，1H)，4.28-4.26(m，2H)，4.19(s，2H)，1.29(t，J=7.7Hz，3H)。

Intermediate z.34: 1-phenyl-1, 4-dihydroimidazo [2, 1-b]Pyrazolo [3,4-d][1,3]Thiazine-3-carboxylic acid ethyl ester

Reacting 5-bromo-4- [ (1H-imidazo l-2 ylthio) methyl]-ethyl 1-phenyl-1H-pyrazole-3-carboxylate (0.3g, 0.74mmol, 1eq), CuI (14mg, 0.074mmol, 0.1eq), NN-dimethylglycine (15mg, 0.147mmol, 0.2eq), K₂CO₃(0.2g, 1.47mmol, 2eq) was placed in DMSO (6mL) and heated at 180 ℃ for 0.5 h with microwave radiation. The reaction mixture was diluted with DCM and filtered through a pad of celite. The filtrate was partitioned between DCM and water. The organic layer was washed with brine, Na ₂SO₄Drying and concentrating. The crude product was purified by flash chromatography to afford the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 7.67-7.59(m, 5H), 6.93(d, J =1.5Hz, 1H), 6.48(d, J =1.4Hz, 1H), 4.40(s, 2H), 4.34(q, J =7.7Hz, 2H), 1.31(t, J =7.7Hz, 3H). MS (ESI +): 313.2. HPLC (max plot) 97.73%; rt 2.73 min.

Intermediate z.35: 2H-1, 4-benzothiazin-3 (4H) -ones

Sodium methoxide was prepared by dissolving 920mg of metallic sodium in 40Ml of ethanol, 5g of o-aminothiophenol was added, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled with ice, 4.8mL of ethyl bromoacetate was added dropwise, and the reaction mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off, the filtrate was concentrated, triturated in ether and the solid formed was washed with water and hexane and dried. The solid was azeotroped with toluene and used in the following reactionIn one step.¹H NMR(DMSO-d6，400MHz)：δ10.55(bs，1H)，7.31-7.29(d，J=8.2Hz，1H)，7.17-7.13(m，1H)，6.97-6.93(m，2H)，3.49(s，2H)。MS(ESI+)：166.0。

Intermediate z.36: 4H-imidazo [5, 1-c ]][1,4]Benzothiazine-3-carboxylic acid ethyl ester

To a solution of 2H-1, 4-benzothiazin-3 (4H) -one (0.7g, 4.24mmol, 1eq) in DMF (20mL) was added potassium tert-butoxide (0.50g, 4.49mmol, 1.06eq) and the reaction mixture was stirred at room temperature for 10 min. The reaction mixture was cooled with ice, diethyl chlorophosphate (1.1mL, 7.63mmol, 1.8eq) was added, and the reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was cooled with ice, a solution of ethyl isocyanoacetate (0.65mL, 5.94mmol, 1.4eq) in DMF and potassium tert-butoxide (0.66g, 5.93mmol, 1.4eq) were added successively, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with 10mL of acetic acid, diluted with water, poured into ice and extracted with ethyl acetate. Na for organic layer ₂SO₄And (5) drying. The crude product was purified by column chromatography to afford the title compound.¹H NMR (DMSO-d6, 400 MHz): δ 8.50(s, 1H), 7.90-7.88(d, J =7.3Hz, 1H), 7.56-7.54(m, 1H), 7.39-7.36(m, 1H), 7.32-7.30(m, 1H), 4.42(s, 2H), 4.27(q, J =7.7Hz, 2H), 1.29(t, J =6.6Hz, 3H). MS (ESI +): 261.2. HPLC (max plot) 95.13%; rt 3.62 min.

Intermediate z.37: 1-phenyl-4H-imidazo [5, 1-c)][1,4]Benzothiazine-3-carboxylic acid ethyl ester

Iodobenzene (0.15mL, 1.15mmol, 2eq), palladium (II) acetate (6.4mg, 0.03mmol, 0.05eq) and CuI (0.22g, 1.15mmol, 2eq) were placed in a pressurized tube, to which was added 4H-imidazo [5, 1-C ] [1,4] benzothiazine-3-carboxylic acid ethyl ester (0.15g, 0.576mmol, 1eq) in degassed DMF (6mL), and the contents were heated at 140 ℃ for 12 hours. 1 the reaction mixture was diluted with DCM and filtered through celite. The filtrate was concentrated and filtered through a short plug of silica gel. The filtrate was again concentrated, filtered through a short plug of silica gel, and concentrated to give 60mg of crude product, which was used directly in the next step. MS (ESI +): 337.2.

examples

Procedure AA

Example 1: 6-methoxy-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]Pyrazoles 5, 5-dioxide

To 6-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]A solution of pyrazole-3-carboxylic acid 5, 5-dioxide (0.20g, 0.54mmol) in THF (20mL) was added triethylamine (0.20mL, 1.63mmol) and a solution of 50% propanephosphoric anhydride in EtOAc (0.70mL, 0.347g, 1.09mmol) was added. The reaction mixture was cooled to 0 ℃, morpholine (0.049g, 0.59mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with EtOAc. The organic layer was washed with 10% NaHCO₃Aqueous and brine washes MgSO₄Drying, and concentrating under reduced pressure. The residue was purified by column chromatography (eluent 1 to 2% MeOH in DCM) to give the title compound as a cream solid.¹H NMR(DMSO-d₆400 MHz): δ 7.59-7.58(m, 3H)7.46-7.42(m, 3H)7.25(d, J =8.60Hz, 1H), 6.35(d, J =7.92Hz, 1H), 4.82(s, 2H), 3.95(br, 2H), 3.90(s, 3H), 3.65(br, 4H), 3.59(br, 2H). MS (ESI +): 440.0. HPLC (max plot) 96.0%; rt 4.81 min.

Example 2: 6-methoxy-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 6-methoxy-1-methyl-1, 4-dihydrothiochromeno [4,3-c ] ]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.15g (98%) of the title compound was prepared according to the procedure AA: 6-methoxy-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 7.77(t, J =8.08Hz, 1H), 7.51(d, J =7.84Hz, 1H), 7.36(d, J =8.44Hz, 1H), 4.72(m, 2H), 4.15(s, 3H), 3.95(br, 2H), 3.91(s, 3H), 3.64-3.62(m, 6H). MS (ESI +): 378.0. HPLC (max plot) 97.0%; rt 2.51 min.

Example 3: 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

With 2, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 7.99-7.94(m, 2H), 7.83(t, J =7.28Hz, 1H), 7.65(t, J =7.6Hz, 1H), 4.81(s, 2H), 4.57(q, J =7.12Hz, 2H), 3.82-3.54(m, 8H). MS (ESI +): 334.0. HPLC (max plot) 97.5%; rt 2.32 min.

Example 4: 7-methoxy-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c ]Pyrazoles 5, 5-dioxide

With 7-methoxy-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 7-methoxy-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 7.98(d, J =8.7Hz, 1H), 7.47(d, J =2.6Hz, 1H), 7.42-7.40(m, 1H), 4.77(s, 2H), 4.20(s, 3H), 3.95(brs, 2H), 3.91(s, 3H), 3.65-3.62(m, 6H). MS (ESI +): 378.0. HPLC (max plot) 99.0%; rt 2.94 min.

Example 5: 7-methoxy-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 7-methoxy-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.13g (74%) of the title compound was prepared according to the procedure AA: 7-methoxy-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 7.63-7.61(m, 3H), 7.54-7.44(m, 3H), 7.17-7.14(m, 1H), 6.75(d, J =8.8Hz, 1H), 4.86(s, 2H), 3.96-3.94(m, 2H), 3.84(s, 3H), 3.66-3.59(m, 6H). MS (ESI +): 440.0. HPLC (max plot) 98.8%; rt 4.04mi n。

Example 6: 1- (3-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (3-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.14g (78%) of the title compound was prepared according to the procedure AA: 1- (3-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide the title compound is a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.00(dd, J =7.7Hz, J =1.3Hz, 1H), 7.64-7.55(m, 3H), 7.52-7.43(m, 2H), 7.37(s, 1H), 6.84(dd, J =7.9Hz, J =1.2Hz, 1H), 4.89(s, 2H), 3.94-3.92(m, 2H), 3.66-3.32(m, 6H), 2.38(s, 3H). MS (ESI +): 424.0. HPLC (max plot) 98.8%; rt 4.18 min.

Example 7: 1- (4-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (4-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆，400MHz)δ8.00(dd，J=8.0Hz，J=1.5Hz，1H)，7.62-7.58(m，2H)，7.41(m，4H)，6.85(dd，J=6.5Hz，J=1.4Hz，1H)，4.88(s，2H) 3.94(m, 2H), 3.66-3.60(m, 6H), 2.43(s, 3H). MS (ESI +): 424.0. HPLC (max plot) 98.3%; rt 4.18 min.

Example 8: 1- (5-fluoro-2-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)] Pyrazole 5, 5-dioxides

With 1- (5-fluoro-2-methylphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.15g (89%) of the title compound was prepared according to the procedure AA: 1- (5-fluoro-2-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.01(d, J =7.6Hz, 1H), 7.65-7.45(m, 5H), 6.73(d, J =7.6Hz, 1H), 4.97-4.86(m, 2H), 3.92-3.90(m, 2H), 3.70-3.60(m, 6H), 1.79(s, 3H). MS (ESI +): 442.0. HPLC (max plot) 99.3%; rt 4.13 min.

Example 9: 1- (3-methoxyphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) 5, 5-dioxide

With 1- (3-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.13g (73%) of the title compound was prepared according to the procedure AA: 1- (3-methoxyphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆，400MHz)δ8.00(dd，J=7.8Hz，J=1.5Hz，1H)，765-7.57(m, 2H), 7.53-7.48(m, 2H), 7.20(dd, J =8.1Hz, J =2.2Hz, 1H), 7.13(s, 1H), 7.02(d, J =8.1Hz, J =1.3Hz, 1H), 4.89(s, 2H), 3.93-3.92(m, 2H), 3.80(s, 3H), 3.66-3.59(m, 6H). MS (ESI +): 440.0. HPLC (max plot) 98.7%; rt 3.94min.

Example 10: 1- (4-methoxyphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) Azole 5, 5-dioxide

With 1- (4-methoxyphenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-methoxyphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) delta 8.01-7.99(m, 1H), 7.64-7.57(m, 2H), 7.47-7.43(m, 2H), 7.16-7.12(m, 2H), 6.87-6.85(m, 1H), 4.88(s, 2H), 3.95-3.93(m, 2H), 3.85(s, 3H), 3.66-3.59(m, 6H). MS (ESI +): 440.0. HPLC (max plot) 97.1%; rt 3.90 min.

Example 11: 3- (morpholin-4-ylcarbonyl) -1-pyridin-2-yl-1, 4-dihydrothiochromeno [4,3-c ]Pyrazole 5,5- Dioxide compounds

With 1-pyridin-2-yl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 3- (morpholin-4-ylcarbonyl) -1-pyridin-2-yl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-bisOxide, white solid.¹H NMR(DMSO-d₆400MHz) δ 8.53(dd, J =7.6Hz, J =1.6Hz, 1H), 8.19(dd, J =7.8Hz, J =1.8Hz, 1H), 7.99(dd, J =8.0Hz, J =1.6Hz, 1H), 7.89(d, J =8.0Hz, 1H), 7.66-7.56(m, 3H), 6.92(d, J =7.6Hz, 1H), 4.88(s, 2H), 3.92-3.91(m, 2H), 3.67-3.60(m, 6H). MS (ESI +): 411.0. HPLC (max plot) 98.4%; rt 3.11 min.

Example 12: 1-cyclohexyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-bis Oxide compound

With 1-cyclohexyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1-cyclohexyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.03(d, J =7.6Hz, 1H), 7.91(t, J =7.2Hz, 1H), 7.84(d, J =7.7Hz, 1H), 7.72(t, J =7.5Hz, 1H), 4.76(s, 2H), 4.73-4.68(m, 1H), 3.93(m, 2H), 3.64(m, 6H), 2.03-1.81(m, 6H), 1.70-1.67(m, 1H), 1.56-1.53(m, 2H), 1.49-1.47(m, 1H). MS (ESI +): 416.0. HPLC (max plot) 99.0%; rt 4.31 min.

Example 13: 6-bromo-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5,5- Dioxide compounds

With 6-bromo-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxidesStarting from the compound and morpholine, 0.13g (73%) of the title compound was prepared following the procedure AA: 6-bromo-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400MHz) δ 7.99(d, J =7.8Hz, 1H), 7.92(d, J =7.9Hz, 1H), 7.70(t, J =8.0Hz, 1H), 4.91(s, 2H), 4.17(s, 3H), 3.96(brs, 2H), 3.65-3.62(m, 6H). MS (ESI +): 427.0. HPLC (max plot) 97.6%; rt 3.05 min.

Example 14: 6-fluoro-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5,5- Dioxide compounds

With 6-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 6-fluoro-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) delta 7.92-7.83(m, 2H), 7.57-7.53(m, 1H), 4.90(s, 2H), 4.21(s, 3H), 3.94(brs, 2H), 3.65-3.62(m, 6H). MS (ESI +): 366.0. HPLC (max plot) 97.2%; rt 2.67 min.

Example 15: 6-fluoro-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5,5- Dioxide compounds

With 6-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine as raw materials according to the procedureAA procedure the title compound was prepared: 6-fluoro-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) delta 7.63-7.56(m, 4H), 7.52-7.43(m, 3H), 6.64-6.62(m, 1H), 5.00(s, 2H), 3.95-3.93(m, 2H), 3.66-3.59(m, 6H). MS (ESI +): 428.0. HPLC (max plot) 97.95%; rt 3.83 min.

Example 16: 8-fluoro-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5,5- Dioxide compounds

With 8-fluoro-1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 8-fluoro-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.08(dd, J =8.7Hz, J =5.6Hz, 1H), 7.88(dd, J =10.0Hz, J =2.3Hz, 1H), 7.58-7.54(m, 1H), 4.82(s, 2H), 4.26(s, 3H), 3.92(brs, 2H), 3.65-3.62(m, 6H). MS (ESI +): 366.0. HPLC (max plot) 98.0%; rt 2.85 min.

Example 17: 8-fluoro-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5,5- Dioxide compounds

With 8-fluoro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine as starting materials, and the preparation of the target was carried out according to the procedure AATitle compound: 8-fluoro-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.09(dd, J =8.7Hz, J =5.5Hz, 1H), 7.66-7.63(m, 3H), 7.57-7.55(m, 2H), 7.52-7.47(m, 1H), 6.43(dd, J =10.0Hz, J =2.4Hz, 1H), 4.93(s, 2H), 3.93(brs, 2H), 3.66-3.60(m, 6H). MS (ESI +): 428.0. HPLC (max plot) 96.1%; rt 4.11 min.

Example 18: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxides

With 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 6-bromo-1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 7.82(dd, J =8.0Hz, J =0.7Hz, 1H), 7.61-7.57(m, 3H), 7.48-7.45(m, 2H), 7.38(t, J =8.0Hz, 1H), 5.01(s, 2H), 3.96-3.94(m, 2H), 3.66-3.59(m, 6H). MS (ESI +): 488.0. HPLC (max plot) 98.2%; rt 4.24 min.

Example 19: 1- (2-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (2-methylphenyl) -1, 4-dihydrothiochromeno [4,3-c ]]Pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine as starting materials, according to procedure AAPreparation of the title compound: 1- (2-methylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.00(dd, J =7.7Hz, J =1.0Hz, 1H), 7.63-7.45(m, 5H), 6.65(d, J =7.5Hz, 1H), 4.92(s, 2H), 3.95-3.90(m, 2H), 3.69-3.60(m, 6H), 1.88(s, 3H). MS (ESI +): 424.0. HPLC (max plot) 97.2%; rt 4.11 min.

Example 20: 1- (2-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (2-bromophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (2-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.8Hz, J =1.1Hz, 1H), 7.94(dd, J =7.7Hz, J =1.4Hz, 1H), 7.79(dd, J =7.6Hz, J =1.8Hz, 1H), 7.69-7.56(m, 4H), 6.65(d, J =7.2Hz, 1H), 4.98-4.87(m, 2H), 3.95-3.92(m, 2H), 3.70-3.59(m, 6H). MS (ESI +): 488.0. HPLC (max plot) 98.7%; rt 4.01 min.

Example 21: 1- (2-fluorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

1- (2-fluorophenyl) -1, 4-dihydrothiochromeno [4,3-c]starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.104g (73%) of the title compound was prepared according to the procedure AA: 1- (2-fluorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400MHz) δ 8.02(dd, J =7.7Hz, J =1.4Hz, 1H), 7.82-7.70(m, 2H), 7.67-7.49(m, 4H), 6.84(d, J =7.5Hz, J =1.4Hz, 1H), 4.94-4.89(m, 2H), 3.90(brs, 2H), 3.66-3.60(m, 6H). MS (ESI +): 428.0. HPLC (max plot) 99.0%; rt 3.75 min.

Example 22: 1- (2-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (2-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (2-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid. ¹H NMR(DMSO-d₆400MHz) δ 8.01(d, J =7.4Hz, 1H), 7.83-7.78(m, 2H), 7.74-7.55(m, 4H), 6.68(d, J =7.7Hz, 1H), 4.98-4.86(m, 2H), 3.93-3.84(m, 2H), 3.70-3.61(m, 6H). MS (ESI +): 444.0. HPLC (max plot) 99.3%; rt 3.89 min.

Example 23: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothio Substituted benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

With 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.103g (77%) of the title compound was prepared according to the procedure AA: 1- (2, 3-dihydro-1, 4-benzodioxin-6-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a yellow solid.¹H NMR(DMSO-d₆400MHz) δ 8.05-8.02(m, 1H), 7.63-7.61(m, 2H), 7.10(d, J =2.4Hz, 1H), 7.04(d, J =8.5Hz, 1H), 6.91-6.90(m, 2H), 4.87(s, 2H), 4.34-4.33(m, 4H), 3.95(brs, 2H), 3.65-3.59(m, 6H). MS (ESI +): 468.0. HPLC (max plot) 98.3%; rt 3.85 min.

Example 24: 1- (2-methyl-1, 3-benzothiazol-6-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochroman And [4,3-c ]]Pyrazole 5, 5-dioxides

With 1- (2-methyl-1, 3-benzothiazol-6-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.03g (76%) of the title compound was prepared according to the procedure AA: 1- (2-methyl-1, 3-benzothiazol-6-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.36(d, J =2.0Hz, 1H), 8.09(d, J =8.6Hz, 1H), 8.01(dd, J =7.8Hz, J =1.0Hz, 1H), 7.63-7.51(m, 3H), 6.79(d, J =7.8Hz, 1H), 4.91(s, 2H), 3.96-3.94(m, 2H), 3.67-3.60(m, 6H), 2.86(s, 3H). MS (ESI +): 481.0. HPLC (max plot) 97.2%; rt 3.70 min.

Example 25: 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (3-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a light brown solid. ¹H NMR(DMSO-d₆400MHz) delta 8.03-8.01(m, 1H), 7.88-7.83(m, 1H), 7.67-7.60(m, 2H), 7.57-7.50(m, 2H), 6.91-6.89(m, 1H), 4.89(s, 2H), 3.93-3.91(m, 2H), 3.66-3.59(m, 6H). MS (ESI +): 488.0. HPLC (max plot) 96.7%; rt 4.29 min.

Example 26: 1- (3-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (3-chlorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.12g (78%) of the title compound was prepared according to the procedure AA: 1- (3-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400MHz) δ 8.02(dd, J =7.7Hz, J =1.9Hz, 1H), 7.77-7.60(m, 4H), 7.48-7.46(m, 1H), 6.91-6.89(m, 1H), 4.89(s, 2H), 3.93-3.91(m, 2H), 3.66-3.59(m, 6H). MS (ESI +): 444.0. HPLC (max plot) 97.8%; rt 4.22 min.

Example 27: 1- (4-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazoles 5, 5-dioxide

With 1- (4-bromophenyl) -1, 4-dihydrothiochromeno [4,3-c ]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 7.78-7.76(m, 1H), 7.81(dd, J =6.7Hz, J =1.7Hz, 2H), 7.67-7.63(m, 2H), 7.51(dd, J =8.6Hz, J =1.8Hz, 1H), 6.94-6.92(m, 2H), 4.89(s, 2H), 3.93-3.90(m, 2H), 3.66-3.58(m, 6H). MS (ESI +): 488.0. HPLC (max plot) 98.3%; rt 3.85 min.

Example 28: 1- (4-fluorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 1- (4-fluorophenyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.1g (70%) of the title compound was prepared according to the procedure AA: 1- (4-fluorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹HNMR(DMSO-d₆400MHz) δ 8.01(d, J =7.7Hz, 2H), 7.63-7.60(m, 3H), 7.48-7.44(m, 2H), 6.85(d, J =7.4Hz, 1H), 4.89(s, 2H), 3.94-3.92(m, 2H), 3.66-3.60(m, 6H). MS (ESI +): 428.0. HPLC (max plot) 99.0%; rt 3.89 min.

Example 29: 1- (4-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 1- (4-chlorophenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-chlorophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.03-8.01(m, 1H), 7.69-7.67(m, 2H), 7.65-7.63(m, 2H), 7.58(d, J =8.2Hz, 1H), 6.95-6.93(m, 2H), 4.89(s, 2H), 3.93-3.91(m, 2H), 3.66-3.60(m, 6H). MS (ESI +): 444.0. HPLC (max plot) 98.9%; rt 4.25 min.

Example 30: 1- (4-isopropylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Azole 5, 5-dioxide

With 1- (4-isopropylphenyl) -1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-isopropylphenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid. ¹H NMR(DMSO-d₆400MHz) δ 8.00(dd, J =7.6Hz, J =1.7Hz, 1H), 7.64-7.55(m, 2H), 7.49-7.42(m, 4H), 6.84(dd, J =7.6Hz, J =1.2Hz, 1H), 4.89(s, 2H), 3.95-3.94(m, 2H), 3.66-3.60(m, 6H), 3.06-2.99(m, 1H), 1.26(d, J =6.9Hz, 6H). MS (ESI +): 452.0. HPLC (max plot) 96.0%; rt 4.91 min.

Example 31: 1- (4-methylpyridin-3-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)] Pyrazole 5, 5-dioxides

With 1- (4-methylpyridin-3-yl) -1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure AA: 1- (4-methylpyridin-3-yl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹HNMR(DMSO-d₆400MHz) δ 8.36(s, 1H), 8.01-7.98(m, 2H), 7.77(d, J =8.1Hz, 1H), 7.65-7.58(m, 2H), 6.91(d, J =7.2Hz, 1H), 4.88(s, 2H), 3.92-3.91(m, 2H), 3.67-3.61(m, 6H), 2.49(s, 3H). MS (ESI +): 425.0. HPLC (max plot) 98.4%; rt 3.50 min.

Example 32: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, c]Pyrazole 5, 5-dioxides

With 1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide and morpholine, 0.05g (86%) of the title compound was prepared according to the procedure AA: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆，400MHz)δ8.03(d，J=7.5Hz，1H)，7.94-7.88(m，2H)，7.75-7.71(m，1H)，5.05-5.00(m，1H)，4.78(s，2H)，3.98-3.95(m，4H)，3.66-3.65(m，6H)，3.60-3.55(m，2H)，2.18-2.11(m 2H)，2.09-1.99(m, 2H). MS (ESI +): 418.0. HPLC (max plot) 97.7%; rt 3.03 min.

Reference procedure AA gave the following compounds:

procedure AC

Example 141: {3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Phenyl } carbinols

To a solution of aluminum chloride (5.13 g; 38.49 mmol; 4.93eq.) in THF (30mL) stirred at 4 ℃ for 25 minutes was added morpholine (5.40 mL; 61.36 mmol; 7.86eq.) and the reaction mixture was stirred at 4 ℃ for 1 hour. Ethyl 1- [3- (hydroxymethyl) phenyl ] -1, 4-dihydrothiochromeno [4,3-c ] pyrazole-3-carboxylate 5, 5-dioxide (3.11 g; 7.81 mmol; 1eq.) was added and the temperature of the reaction mixture was allowed to rise to room temperature. After 22 hours, the reaction mixture was cooled to 0 ℃ and water was added slowly (total addition was 25 mL). After stirring for 30 min, the product was extracted with DCM. The organic phase was washed with aqueous sodium potassium tartrate (-0.7 m; pH =5) and brine, dried over MgSO 4. Evaporation of the solvent under reduced pressure gave 3.39g (99%) of the title compound as a pale yellow solid. HPLC (max plot) 95.6%; rt 3.08 min. MS (ESI +): 440.0.

Reference procedure AC gave the following compound:

procedure AD

Example 33: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides Article of manufacture

1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-3-carboxylic acid 5, 5-dioxide (150.00 mg; 0.44 mmol; 1.00Eq) was suspended in DCM (4.00mL) and 2 drops of DMF and oxalyl chloride (3mL) were added dropwise in that order. The reaction mixture was stirred at room temperature for 30 minutes. The solution was evaporated to dryness. The residue was suspended in DCM (4.00ml) and morpholine (350.00. mu.L; 4.02 mmol; 9.12Eq) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and diluted with 0.05M aqueous HCl. Two layers were separated. The aqueous layer was extracted with DCM (2 ×). NaHCO for organic layer₃Saturated solution and brine, MgSO₄Drying and evaporating to obtain foam. The foam was recrystallized from ethanol to give the title compound as a white solid.¹H NMR(DMSO-d₆300MHz) delta 8.04-8.01(m, 1H), 7.67-7.53(m, 7H), 6.85-6.82(m, 1H), 4.91(s, 2H), 3.98-3.94(m, 2H), 3.68-3.61(m, 6H). UPLC/MS: (ES +): 410.1, (ES-): 408.1. HPLC (max plot) 100.0%; rt 3.36 min.

Example 34: 1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c ]Pyrazole 5, 5-dioxides Article of manufacture

With 1-methyl-1, 4-dihydrothiochromeno [4,3-c ]]Starting from pyrazole-3-carboxylic acid 5, 5-dioxide, oxalyl chloride and morpholine, 0.62g (83%) of the title compound are prepared according to the procedure AD: 1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆300MHz) delta 8.07-8.02(m, 2H), 7.92-7.87(m, 1H), 7.76-7.71(m, 1H), 4.81(s, 2H), 4.26(s, 3H), 3.99-3.93(m, 2H), 3.70-3.60(m, 6H). UPLC/MS: (ES +): 347.9, (ES-): 346.1. HPLC (max plot) 99.9%; rt 2.15 min.

Reference procedure AD gave the following compounds:

procedure AE

Example 250: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-6-carboxylic acid Amine 5, 5-dioxides

To 6-cyano-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]A solution of pyrazole-3-carboxylic acid ethyl ester 5, 5-dioxide (50mg, 0.135mmol) in dry DCM (10mL) was added morpholine (0.02mL, 0.156mmol) and TEA (0.03mL, 0.196mmol) and the reaction mixture was cooled to 0 ℃. EDC.HCl (38mg, 0.196mmol) and HOBt (2mg, 0.013mmol) were added to the reaction mixture, and stirred at room temperature under a nitrogen atmosphere for 12 hours. Then DCM was added and the organic phase was washed with Na ₂CO₃Washing with saturated aqueous solution, Na₂SO₄Dried, concentrated under reduced pressure, and purified by silica gel chromatography (3% MeOH in DCM) to give the title compound as a pale yellow solid.¹H NMR(DMSO-d₆400 MHz): δ 7.89(s, 1H), 7.63-7.60(m, 3H), 7.55-7.44(m, 4H), 6.84-6.82(d, J =7.8Hz, 1H), 5.74(s, 2H), 4.78(s, 2H), 3.97(m, 2H), 3.66-3.61(m, 6H). MS (ESI +): 453.0. HPLC (max plot) 96.54%; rt 3.98 min.

Procedure AF

Example 35: 1-methyl-3- (morpholin-4-ylcarbonyl) -8-nitro-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

Heating 1-methyl-3- (morpholin-4-ylcarbonyl) -8-nitro-1, 4-dihydrothiochromeno [4,3-C ] at 100 ℃ under nitrogen]Pyrazole (0.084g, 0.23mmol) in acetic acid. Aqueous hydrogen peroxide (30% 0.5mL, 3.6mmol, 15Eq) was added and the reaction mixture was heated for more than 30 minutes. After 30 minutes, the solvent was removed under reduced pressure. Mixing 10% NaHCO₃The aqueous solution was added to the residue. The mixture was stirred for several minutes and extracted with DCM. The organic layer was concentrated, purified by column chromatography,the title compound was obtained as a yellow solid.¹H NMR(DMSO-d₆400MHz) δ 8.66(s, 1H), 8.48(dd, J =8.5Hz, J =2.3Hz, 1H), 8.28(J =11.8Hz, 1H), 4.96(s, 2H), 4.33(s, 3H), 3.94(brs, 2H), 3.66-3.63(m, 6H). MS (ESI +): 393.0. HPLC (max plot) 90.8%; rt 3.08 min.

Example 36: 3- (morpholin-4-ylcarbonyl) -8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]]The title compound was prepared following procedure AF starting from pyrazole and hydrogen peroxide: 3- (morpholin-4-ylcarbonyl) -8-nitro-1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a yellow solid.¹H NMR(DMSO-d₆400MHz) δ 8.38(dd, J =8.5Hz, J =2.2Hz, 1H), 8.27(d, J =8.6Hz, 1H), 7.70-7.59(m, 5H), 7.51(d, J =2.1Hz, 1H), 5.06(s, 2H), 3.95-3.93(m, 2H), 3.67-3.60(m, 6H). MS (ESI +): 455.0. HPLC (max plot) 95.5%; rt 4.18 min.

Program AG

Example 37: 1-Ethyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides Article of manufacture

To 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]A neutralized solution of pyrazole 5, 5-dioxide (0.400g, 1.2mmol) in acetonitrile (10mL) was added potassium carbonate (0.49g, 3).6mmol) and iodoethane (0.56g, 3.6mmol) was added. The reaction mixture was heated at 60 ℃ overnight. The crude reaction mixture was filtered off over celite and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a cream solid. ¹H NMR(DMSO-d₆400 MHz): δ 8.02(d, J =7.72Hz, 1H), 7.94(d, J =7.84Hz, 1H), 7.89(t, J =7.52Hz, 1H), 7.72(t, J =7.64Hz, 1H), 4.79(s, 2H), 4.57(q, J =7.12Hz, 2H), 3.94(brs, 2H), 3.66-3.63(m, 6H), 1.46(t, J =7.16Hz, 3H). MS (ESI +): 362.0. HPLC (max plot) 95.0%; rt 2.99 min.

Example 38: 1- (4-methoxybenzyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Azole 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 4-methoxybenzyl bromide, the title compound was prepared according to the procedure AG: 1- (4-methoxybenzyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹HNMR(DMSO-d₆300MHz) δ 8.01-7.98(m, 1H), 7.84-7.76(m, 2H), 7.70-7.65(m, 1H), 7.08(d, J =8.8Hz, 2H), 6.91(d, J =8.8Hz, 2H), 5.79(s, 2H), 4.84(s, 2H), 3.96-3.93(m, 2H), 3.71(s, 3H), 3.70-3.60(m, 6H). UPLC/MS: (ES +): 454.0, (ES-): 452.1. HPLC (max plot) 100.0%; rt 3.40 min.

Example 39: 3- (morpholin-4-ylcarbonyl) -1-propyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole 5, 5-dioxides Article of manufacture

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and propyl bromide, the title compound was prepared according to the procedure of procedure AG: 3- (morpholin-4-ylcarbonyl) -1-propyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.02(d, J =7.8Hz, 1H), 7.95(d, J =7.7Hz, 1H), 7.88(t, J =7.7Hz, 1H), 7.89(t, J =7.8Hz, 1H), 4.79(s, 2H), 4.51(t, J =7.1Hz, 2H), 3.93(brs, 2H), 3.65-3.62(m, 6H), 1.97-1.81(m, 2H), 0.86(t, J =7.2Hz, 3H). MS (ESI +): 376.0. HPLC (max plot) 99.0%; rt 3.39 min.

Example 40: 1-benzyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides Article of manufacture

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and benzyl bromide, the title compound was prepared according to the procedure AG: 1-benzyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 7.98(d, J =7.7Hz, 1H), 7.75-7.74(m, 2H), 7.67-7.63(m, 1H), 7.36-7.26(m, 3H), 7.10(d, J =7.4Hz, 1H), 5.87(s, 2H), 4.84(s, 2H), 4.02-3.92(m, 2H), 3.65-3.62(m, 6H). MS (ESI +): 424.0. HPLC (max plot) 99.0%; rt 3.92min.

Example 41: 3- (morpholin-4-ylcarbonyl) -1- (2-phenylethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and (2-bromoethyl) benzene, the title compound was prepared according to the procedure of procedure AG: 3- (morpholin-4-ylcarbonyl) -1- (2-phenylethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.03-7.98(m, 2H), 7.87(t, J =7.5Hz, 1H), 7.71(t, J =7.6Hz, 1H), 7.20-7.13(m, 3H), 7.06(d, J =7.6Hz, 1H), 4.85(t, J =6.5Hz, 2H), 4.74(s, 2H), 3.61-3.29(m, 8H), 3.08(t, J =6.5Hz, 2H). MS (ESI +): 438.0. HPLC (max plot) 98.4%; rt 4.02 min.

Example 42: n, N-dimethyl-2- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4, 3-c)]Pyridine (II) Oxazol-1 (4H) -yl]Ethylamine (ethylamine)

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting with pyrazole 5, 5-dioxide and 2-bromo-N, N-dimethylethylamine, the title compound was prepared according to the procedure of procedure AG: n, N-dimethyl-2- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4, 3-c) ]Pyrazol-1 (4H) -yl]Ethylamine as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.05-8.01(m, 2H), 7.89(t, J =7.6Hz, 1H), 7.71(t, J =7.6Hz, 1H), 4.77(s, 2H), 4.61(t, J =6.4Hz, 1H), 3.93(br, 2H), 3.65-3.63(m, 6H), 2.73(t, J =6.5Hz, 1H), 2.13(s, 6H). MS (ESI +): 405.0. HPLC (max plot) 97.9%; rt 2.00 min.

Example 43: 4- { [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Methyl } piperidine-1-carboxylic acid tert-butyl ester

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and tert-butyl 4- (bromomethyl) piperidine-1-carboxylate, the title compound was prepared according to the procedure AG: 4- { [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl]Methyl } piperidine-1-carboxylic acid tert-butyl ester as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.03-7.98(m, 2H), 7.89-7.86(m, 1H), 7.71(t, J =8.0Hz, 1H), 4.78(s, 2H), 4.48(d, J =7.2Hz, 2H), 3.91-3.85(m, 3H), 3.65-3.63(m, 6H), 2.66-2.62(m, 2H), 2.04(t, J =3.6Hz, 2H), 1.47-1.44(m, 2H), 1.35(s, 9H), 1.14-1.08(m, 2H). MS (ESI +): 431.0. HPLC (max plot) 96.8%; rt 4.41 min.

Example 44: 1- (3-methoxypropyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) Azole 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 1-bromo-3-methoxypropane, the title compound was prepared according to the procedure of procedure AG: 1- (3-methoxypropyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆，400MHz)δ8.03-7.98(m，2H)，7.90-7.86(m，1H)，7.73-7.70(m，1H)，4.78(s，2H)，4.59(t，J=7.0Hz，2H)，3.93(m，2H)，3.65-3.63(m，6H)，3.27-3.21(m，2H)，3.13(s，3H)，2.09(t, J =6.28Hz, 2H). MS (ESI +): 406.0. HPLC (max plot) 97.2%; rt 3.07 min.

Example 45: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydrofuran-2-ylmethyl) -1, 4-dihydrothiochromeno [4,3- c]Pyrazole 5, 5-dioxides

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 2- (bromomethyl) tetrahydrofuran, the title compound was prepared according to the procedure of procedure AG: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydrofuran-2-ylmethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.17(d, J =7.9Hz, 1H), 8.00(d, J =7.1Hz, 1H), 7.87(t, J =6.9Hz, 1H), 7.70(t, J =7.6Hz, 2H), 4.84-4.80(m, 2H), 4.77-4.73(m, 2H), 4.34-4.31(m, 1H), 3.92(brs, 2H), 3.69-3.56(m, 8H), 2.49(m, 2H), 2.03(t, J =6.6Hz, 2H). MS (ESI +): 418.0. HPLC (max plot) 95.0%; rt 3.14 min.

Example 46: 2- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Ethanol

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 2-bromoethanol, the title compound was prepared according to the procedure of procedure AG: 2- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl]Ethanol as a light brown solid.¹H NMR(DMSO-d₆，400MHz)δ826(d, J =7.9Hz, 1H), 8.01(d, J =7.7Hz, 1H), 7.87(t, J =7.7Hz, 1H), 7.71(t, J =7.6Hz, 1H), 5.22(t, J =5.2Hz, 1H), 4.78(s, 2H), 4.54(t, J =5.2Hz, 2H), 3.95-3.93(m, 4H), 3.66-3.62(m, 6H). MS (ESI +): 378.0. HPLC (max plot) 93.9%; rt 2.32 min.

Example 47: 3- (morpholin-4-ylcarbonyl) -1- (pyridin-2-ylmethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Azole 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 2- (bromomethyl) pyridine, the title compound was prepared according to the procedure of procedure AG: 3- (morpholin-4-ylcarbonyl) -1- (pyridin-2-ylmethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a light brown solid. ¹HNMR(DMSO-d₆400MHz) δ 8.53(d, J =4.7Hz, 1H), 8.00-7.97(m, 2H), 7.82-7.67(m, 3H), 7.36-7.33(m, 1H), 7.24(d, J =7.8Hz, 1H), 5.89(s, 2H), 4.83(s, 2H), 3.88(m, 2H), 3.65-3.58(m, 6H). MS (ESI +): 425.0. HPLC (max plot) 97.5%; rt 2.55 min.

Example 48: 1-butyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides Article of manufacture

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 1-bromobutane, the title compound was prepared according to the procedure AG: 1-butyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.02(d, J =7.8Hz, 1H), 7.95(d, J =7.7Hz, 1H), 7.88(t, J =7.7Hz, 1H), 7.89(t, J =7.8Hz, 1H), 4.79(s, 2H), 4.51(t, J =7.1Hz, 2H), 3.93(brs, 2H), 3.65-3.62(m, 6H), 1.97-1.81(m, 2H), 0.86(t, J =7.2Hz, 3H). MS (ESI +): 376.0. HPLC (max plot) 99.0%; rt 3.39 min.

Example 49: 1- (cyclopentylmethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and (bromomethyl) cyclopentane, the title compound was prepared according to the procedure of procedure AG: 1- (cyclopentylmethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400MHz) δ 8.01(dd, J =7.7Hz, J =2.1Hz, 1H), 7.88(t, J =7.4Hz, 1H), 7.70(t, J =7.7Hz, 1H), 4.78(m, 2H), 4.50(d, J =7.5Hz, 2H), 3.93(brs, 2H), 3.65-3.62(m, 6H), 2.42-2.35(m, 1H), 1.60-1.57(m, 4H), 1.54-1.50(m, 2H), 1.47-1.44(m, 2H). MS (ESI +): 376.0. HPLC (max plot) 982%; rt 4.29 min.

Example 50: 1-isobutyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-bis Oxide compound

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiobenzeneAnd pyrano [4,3-c ]]Starting from pyrazole 5, 5-dioxide and 1-bromo-2-methylpropane, the title compound was prepared according to the procedure of procedure AG: 1-isobutyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.00(d, J =7.9Hz, 2H), 7.88(t, J =7.6Hz, 1H), 7.70(t, J =7.7Hz, 1H), 4.78(s, 2H), 4.40(d, J =7.4Hz, 2H), 3.92(brs, 2H), 3.65-3.62(m, 6H), 2.15-2.08(m, 1H), 0.82(d, J =7.4Hz, 6H). MS (ESI +): 390.0. HPLC (max plot) 98.3%; rt 3.74 min.

Example 51: 1- (cyclohexylmethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and (bromomethyl) cyclohexane, the title compound was prepared according to the procedure AG: 1- (cyclohexylmethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹HNMR(DMSO-d₆400MHz) δ 8.02-7.98(m, 2H), 7.88(t, J =7.6Hz, 1H), 7.70(t, J =7.6Hz, 1H), 4.77(s, 2H), 4.42(d, J =7.3Hz, 2H), 3.92-3.89(m, 2H), 3.65-3.62(m, 6H), 1.86-1.80(m, 1H), 1.60-1.54(m, 6H), 1.50-1.47(m, 3H), 1.09-0.99(m, 2H). MS (ESI +): 430.0. HPLC (max plot) 97.4%; rt 4.56 min.

Example 52: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 4- (bromomethyl) tetrahydro-2H-pyran, the title compound was prepared according to the procedure AG: 3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-ylmethyl) -1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400MHz) δ 8.02-8.00(m, 2H), 7.90-7.86(m, 1H), 7.71(t, J =7.7Hz, 1H), 4.78(s, 2H), 4.48(d, J =7.3Hz, 2H), 3.90-3.89(m, 2H), 3.79-3.76(m, 2H), 3.65-3.63(m, 6H), 3.18(d, J =11.8Hz, 2H), 2.12-2.07(m, 1H), 1.47-1.40(m, 2H), 1.35-1.30(m, 3H). MS (ESI +): 432.0. HPLC (max plot) 97.1%; rt 3.04 min.

Example 53: 1- (2-methoxyethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyridine (II) Azole 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 1-bromo-2-methoxyethane, the title compound was prepared according to the procedure of procedure AG: 1- (2-methoxyethyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.14(d, J =7.9Hz, 1H), 8.01(d, J =7.8Hz, 1H), 7.87(t, J =7.6Hz, 1H), 7.71(t, J =7.6Hz, 1H), 4.78(s, 2H), 4.67(t, J =5.12Hz, 2H), 3.93-3.85(m, 4H), 3.66-3.64(m, 2H), 3.21(s, 3H). MS (ESI +): 392.0. HPLC (max plot) 94.2%; rt 2.97 min.

Example 54: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopy-ro-pylenePyrano [4,3-c ]]Pyrazol-1 (4H) -yl] Propan-1-ol

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 3-bromopropan-1-ol, the title compound was prepared according to the procedure of procedure AG: 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl]Propan-1-ol as a white solid.¹H NMR(DMSO-d₆400MHz) δ 8.03-8.01 (m, 2H), 7.88(t, J =7.9Hz, 1H), 7.71(t, J =7.8Hz, 1H), 4.78(s, 2H), 4.74(t, J =4.8Hz, 1H), 4.59(t, J =7.1Hz, 1H), 3.92(brs, 2H), 3.65-3.63(m, 6H), 3.49-3.48(m, 2H), 2.05-1.99(m, 2H). MS (ESI +): 392.0. HPLC (max plot) 99.0%; rt 2.45 min.

Example 55: 3- (morpholin-4-ylcarbonyl) -1- (2-pyridin-2-ylethyl) -1, 4-dihydrothiochromeno [4,3-c] Pyrazole 5, 5-dioxides

With 3- (morpholin-4-ylcarbonyl) -2, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and 2- (2-bromoethyl) pyridine, the title compound, 3- (morpholin-4-ylcarbonyl) -1- (2-pyridin-2-ylethyl) -1, 4-dihydrothiochromeno [4,3-c, was prepared according to the procedure AG ]Pyrazole 5, 5-dioxide, as a white solid.¹HNMR(DMSO-d₆，400MHz)δ8.50(d，J=4.6Hz，1H)，8.07(d，J=7.8Hz，1H)，8.02(d，J=7.7Hz，1H)，7.89(t，J=7.1Hz，1H)，7.75-7.70(m，2H)，7.30-7.22(m，2H)，4.98(t，J=6.7Hz，2H)，4.75(s，2H)，3.61-3.58(m，6H)，3.50-3.48(m，2H)，3.40-3.37(m，2H)。MS(ESI+)：439.0。HPLC (max plot) 98.7%; rt 2.12min.

The following compounds were obtained with reference to procedure AG:

procedure AH

Example 348: 3- (morpholin-4-ylcarbonyl) -1- [1- (2-morpholin-4-ylethyl) piperidin-3-yl]-1, 4-dihydrothioxobenzene Pyrano [4,3-c ]]Enantiomer A of pyrazole 5, 5-dioxide

1- [1- (2-chloroethyl) piperidin-3-yl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Enantiomer A of pyrazole 5, 5-dioxide (274 mg; 0.57 mmol; 1.00eq.), morpholine (199. mu.l; 2.29 mmol; 4.00eq.), sodium iodide (85 mg; 0.57 mmol; 1.00eq.) and K₂CO₃(237 mg; 1.72 mmol; 3.00eq.) in ACN (6 mL). The reaction mixture was stirred at 60 ℃ overnight. The reaction mixture was diluted with DCM, washed with water and MgSO₄Drying and evaporating. Purify by flash chromatography (DCM/MeOH: 0 to 5%) and redissolve in ACN: in water, after lyophilization the title compound was obtained as a white solid.¹H NMR(DMSO-d₆300 MHz): δ 8.05(dd, J =1.2, 7.8Hz, 1H), 7.94(td, J =1.3, 7.8Hz, 1H), 7.88-7.81(m, 1H), 7.80-7.70(m, 1H), 5.05-4.62(m, 3H), 4.05-3.79(m, 2H), 3.79-3.58(m, 6H), 3.56-3.42(m, 4H), 3.32-3.08(m, 3H), 2.91(d, J =10.8Hz, 1H), 2.46-2.22(m, 8H), 2.20-1.60(m, 6H). MS (ESI +): 530.46. HPLC (max plot) 99.4%; rt 1.56 min. [ alpha ] to ]25D+4.20(c 1.09，DCM)。

Reference procedure AH gave the following compounds:

procedure AJ

Example 360: 1- {3- [2- (1H-imidazo l-1-yl) ethoxy]Phenyl } -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrosulfide Substituted benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

To a suspension of 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] phenol (206.5 mg; 0.49 mmol; 1eq.) potassium carbonate (401.6 mg; 2.91 mmol; 5.99eq.) and sodium iodide (11.7 mg; 0.08 mmol; 0.16eq.) in DMF (4ml) was added N- (2-chloroethyl) -imidazole hydrochloride (158.4 mg; 0.95 mmol; 1.95 eq.). The suspension was stirred at 80 ℃ for 2 days and then at 120 ℃ for 30 minutes under microwave heating. The reaction mixture was diluted with water and the product was extracted with EtOAc. The organic layers were combined, washed sequentially with water and brine, MgSO, and the solvent was evaporated in vacuo to give a brown residue. Purification by flash chromatography (silica; DCM/MeOH 98/2-0/100) gave the title compound as a soft yellow powder. 1H NMR (DMSO-d 6): delta 8.07-7.98(m, 1H), 7.73-7.55(m, 3H), 7.55-7.44(m, 1H), 7.28-7.13(m, 3H), 7.09-7.00(m, 1H), 6.93-6.83(m, 2H), 4.10(s, 2H), 4.44-4.22(m, 4H), 4.00-3.87(m, 2H), 3.75-3.55(m, 6H). HPLC (max plot) 93.5%; rt 2.48min. MS (ESI +): 520.4.

Example 340: 3- (morpholin-4-ylcarbonyl) -1- {3- [2- (1H-pyrazol-1-yl) ethoxy]Phenyl } -1, 4-dihydrothio Benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

Starting from 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] phenol and 1- (2-bromoethyl) -1H-pyrazole, the title compound was prepared according to the procedure AJ: 3- (morpholin-4-ylcarbonyl) -1- {3- [2- (1H-pyrazol-1-yl) ethoxy ] phenyl } -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide as a yellow powder. 1H NMR (DMSO-d6) delta 8.07-7.97(m, 1H), 7.82-7.75(m, 1H), 7.70-7.54(m, 2H), 7.54-7.46(m, 1H), 7.46-7.41(m, 1H), 7.22-7.14(m, 1H), 7.14-7.08(m, 1H), 7.08-7.00(m, 1H), 6.92-6.84(m, 1H), 6.26-6.18(m, 1H), 4.90(s, 2H), 4.55-4.45(m, 2H), 4.45-4.34(m, 2H), 4.01-3.88(m, 2H), 3.76-3.56(m, 6H). HPLC (max plot) 96.2%; rt 4.14 min. MS (ESI +): 520.3.

example 341: 1- [3- (2-methoxyethoxy) phenyl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochroman And [4,3-c ]]Pyrazole 5, 5-dioxides

Starting from 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] pyrazol-1 (4H) -yl ] phenol and 2-bromoethyl methyl ether, the title compound was prepared according to the procedure AJ: 1- [3- (2-methoxyethoxy) phenyl ] -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide as a white solid. 1H NMR (DMSO-d6) delta 8.09-7.96(m, 1H), 7.71-7.56(m, 2H), 7.56-7.44(m, 1H), 7.29-7.11(m, 2H), 7.11-6.97(m, 1H), 6.97-6.82(m, 1H), 4.90(s, 2H), 4.25-4.08(m, 2H), 4.05-3.87(m, 2H), 3.79-3.53(m, 8H), 3.29(s, 3H). HPLC (max plot) 99.5%; rt 3.53 min. MS (ESI +): 484.3.m.p. = [ 142-.

Procedure AK:

example 168: 1- {4- [ (4-Methoxypiperidin-1-yl) methyl group]Phenyl } -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothio Benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

To 4- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl]Benzyl methanesulfonyl ester (230 mg; 0.44 mmol; 1eq.) in DMF (10mL) was added K₂CO₃(184 mg; 1.33 mmol; 3eq.) and 4-methoxypiperidine (102 mg; 0.89 mmol; 2 eq.). The reaction mixture was stirred at 85 ℃ for 30 min, diluted with water, extracted with EtOAc, washed with brine, MgSO₄And (5) drying. The solvent was evaporated and the residue was purified by MD-Autoprep chromatography to give the title compound as a white solid. 1H NMR (DMSO-d6) delta 8.07-8.04(m, 1H), 7.70-7.50(m, 6H), 6.88-6.85(m, 1H), 4.94(s, 2H), 4.01-3.98(m, 2H), 3.71-3.62(m, 8H), 3.27(s, 3H), 3.27-3.22(m, 1H), 2.76-2.70(m, 2H), 2.23-2.14(m, 2H), 1.92-1.84(m, 2H), 1.55-1.44(m, 2H). HPLC (max plot) 100%; rt 2.23 min. MS (ESI +): 537.0.

reference procedure AK gave the following compounds:

procedure AL

Example 357: 1- {4- [ (3-methylmorpholin-4-yl) methyl]Phenyl } -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiophenes And pyrano [4,3-c ]]Pyrazole 5, 5-dioxides

To {4- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-C ] at 0 ℃]Pyrazol-1 (4H) -yl]Phenyl } methanol (123 mg; 0.28 mmol; 1eq.) and DIEA (330. mu.l; 1.93 mmol; 2.56eq.) in DCM (13mL) was added methanesulfonyl chloride (75. mu.l; 0.97 mmol; 1.3 eq.). The solution was stirred for 30 minutes and the temperature was allowed to rise to room temperature. Then, sodium iodide (32 mg; 0.21 mmol; 0.28eq.), K₂CO₃A suspension of (336 mg; 2.43 mmol; 3.22eq.) and 3-methylmorpholine (166. mu.l; 1.51 mmol; 2eq.) in DMF (50mL) was added to the sulfonyl chloride mixture. The resulting suspension was stirred at 80 ℃ for 2 hours, and after warming to room temperature, water was added. The product was extracted with DCM, the organic layers combined, washed with brine, MgSO₄Dried, purified by MD-Autoprep chromatography and triturated in a mixture of DCM and pentane to give the title compound as an orange powder. 1H NMR (DMSO-d 6): δ 8.02-7.98(m, 1H), 7.69-7.43(m, 6H), 6.87-6.79(m, 1H), 4.91(s, 2H), 4.18-4.03(m, 1H), 4.03-3.88(m, 2H), 3.79-3.56(m, 8H), 3.56-3.41(m, 1H), 3.33-3.24(m, 2H), 3.24-3.10(m, 1H), 2.52-2.66(m, 1H), 2.50-2.36(m, 1H), 2.29-2.09(m, 1H), 1.03(d, J =6.3Hz, 3H). HPLC (max plot) 98.1%; rt 2.09 min. HPLC (max plot) 76.8%; rt 2.15 min. MS (ESI +): 523.4.

Reference procedure AL gave the following compound:

example 137: 3- (morpholin-4-ylcarbonyl) -1- [4- (morpholin-4-ylmethyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

1- [4- (hydroxymethyl) phenyl in 15 minutes at 0 ℃]-1, 4-dihydrothiochromeno [4,3-c]A suspension of pyrazole-3-carboxylic acid 5, 5-dioxide (5.29 g; 14.29 mmol; 1eq.) in DCE (212mL) was added dropwise to thionyl chloride (3.17 mL; 42.88 mmol; 3eq.) and DMF (2mL) was added. The reaction mixture was stirred at 40 ℃ for 6 hours and then at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in DCE (106 mL). The resulting solution was added dropwise to a solution of morpholine (26mL) in DCE (106mL) over 30 minutes at 0 ℃, then the temperature of the reaction mixture was allowed to rise to room temperature, then heated to 50 ℃ and held for 4.5 hours. Removing the solvent under reduced pressure to remove the residueThe residue was taken up in DCM, washed with water and brine, MgSO₄Drying and vacuum evaporating. The residue is triturated in ether and filtered off to give 5.77g (79%) of the title compound as a milky white solid.¹HNMR(DMSO-d₆) Delta 8.04-8.01(m, 1H), 7.66-7.48(m, 6H), 6.85-6.82(m, 1H), 4.91(s, 2H), 3.97-3.94(m, 2H), 3.68-3.60(m, 12H), 2.43-2.40(m, 4H). HPLC (max plot) 99.4%; rt 1.94 min; MS (ESI +): 509.0. CHN analysis: [ C26H28N4O5S ]And (3) correction: 61.40% of C, 5.55% of H and 11.02% of N; as a result: 61.27% of C, 5.62% of H and 10.95% of N.

Program AM

Example 56: 3- (morpholin-4-ylcarbonyl) -1- (piperidin-4-ylmethyl) -1, 4-dihydrothiochromeno [4,3-c]Pyridine (II) Azole 5, 5-dioxide

To 4- { [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl]Methyl } piperidine-1-carboxylic acid tert-butyl ester (0.1g, 0.21mmol) in DCM (2.0mL) was added TFA (0.119g, 1.05mmol, 5Eq) and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was washed with sodium bicarbonate followed by brine, MgSO₄And (5) drying. The crude residue was purified by flash chromatography to give the title compound as a light brown solid.¹H NMR(DMSO-d₆400MHz) δ 8.03-7.98(m, 2H), 7.88(t, J =7.5Hz, 1H), 7.73-7.70(m, 1H), 4.78(s, 2H), 4.47(t, J =7.1Hz, 2H), 3.91(s, 2H), 3.66-3.63(m, 6H), 2.98-2.95(m, 2H), 2.00(brs, 1H), 1.75-1.69(m, 1H), 1.48-1.40(m, 2H), 1.24-1.17(m, 3H). MS (ESI +): 431.0. HPLC (max plot) 97.2%; rt 2.16 min.

The following examples were obtained with reference to procedure AM:

procedure AN

Example 57: 4-benzyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ]Pyrazoles 5, 5-dioxide

To 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]A solution of pyrazole 5, 5-dioxide (100 mg; 0.24 mmol; 1.0Eq.) in THF (4.0mL) was added NaH (55% w/w in mineral oil) (12.79 mg; 0.29 mmol; 1.2 Eq.). After stirring for 15 min, benzyl bromide (34.81. mu.L; 0.29 mmol; 1.2eq.) was added and the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phases were combined, washed with brine, MgSO₄Drying, and concentrating under reduced pressure. The crude residue was recrystallized from ethanol and dried in vacuo to give the title compound as a cream solid.¹H NMR (DMSO-d₆300MHz) delta 8.01-7.98(m, 1H), 7.63-7.58(m, 4H), 7.53-7.46(m, 3H), 7.12-7.07(m, 3H), 6.89-6.86(m, 2H), 6.66-6.64(m, 1H), 5.29-5.25(m, 1H), 3.93-3.88(m, 1H), 3.63-3.53(m, 5H), 3.45-3.36(m, 2H), 3.26-3.20(m, 1H), 2.76-2.69(m, 1H). UPLC/MS: (ES +): 500.2, (ES-): 498.3. HPLC (max plot) 97.6%; rt 4.32min.

Example 58: 4- (cyclopropylmethyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3- c]Pyrazole 5, 5-dioxides

Starting from 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide and cyclopropylmethyl bromide, the title compound was prepared according to the procedure of a: 4- (cyclopropylmethyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide as a white solid. UPLC/MS: (ES +): 464.1. HPLC (max plot) 98.1%; rt 4.01 min.

Example 59: 4-Ethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Starting with pyrazole 5, 5-dioxide and iodoethane, the title compound was prepared according to the procedure of AN: 4-Ethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆300MHz) δ 8.03-8.00(m, 1H), 7.67-7.53(m, 7H), 6.84-6.81(m, 1H), 4.85-4.80(m, 1H), 3.99-3.95(m, 2H), 3.80-3.50(m, 6H), 2.08-1.95(m, 1H), 1.53-1.38(m, 1H), 0.82(t, J =7.4Hz, 3H). HPLC (max plot) 99.8%; rt 3.67 min.

Example 60: 4, 4-dimethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)] Pyrazole 5, 5-dioxides

With 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxidesStarting from material and methyl iodide, the title compound was prepared according to the procedure of AN: 4, 4-dimethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide, as a white solid. ¹HNMR(DMSO-d₆300MHz) delta 8.06-8.03(m, 1H), 7.67-7.56(m, 5H), 7.51-7.48(m, 2H), 6.83-6.80(m, 1H), 3.72-3.65(m, 4H), 3.59-3.50(m, 4H), 1.60(s, 6H). HPLC (max plot) 100%; rt 3.40 min.

Example 112: 4- (3-methoxypropyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

Starting from 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide and 1-bromo-3-methoxypropane, the title compound was prepared according to the procedure of a: 4- (3-methoxypropyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide as a white solid. HPLC (max plot) 98.4%; rt 3.64 min. MS (ESI +): 482.0.

example 111: 4-benzyl-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

With 1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Starting from pyrazole 5, 5-dioxide and benzyl bromide, the title compound was prepared according to the procedure of AN: 4-benzyl-1-methyl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c ]Pyrazole 5, 5-dioxide, as a white solid.¹H NMR(DMSO-d₆) δ 8.05-8.02(m, 1H), 7.96-7.93(m, 1H), 7.89-7.84(m, 1H), 7.76-7.70(m, 1H), 7.17-7.07(m, 3H), 6.88-6.85(m, 2H), 5.20(q, J =5.0Hz, 1H), 4.19(s, 3H), 3.84-3.79(m, 1H), 3.65-3.50(m, 5H), 3.39-3.18(m, 3H), 2.62-2.55(m, 1H). HPLC (max plot) 100.0%; rt 3.35 min. MS (ESI +): 438.2.

example 316: 4-fluoro-3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochroman And [4,3-c ]]Pyrazole 5, 5-dioxides

Starting from 3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromano [4,3-c ] pyrazole 5, 5-dioxide and N-fluoro-N' -chloromethyl-triethylenediamine-bis (tetrafluoroborate), the title compound was prepared according to the procedure of procedure AN: 4-fluoro-3- (morpholin-4-ylcarbonyl) -1- (tetrahydro-2H-pyran-4-yl) -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide as a white solid. HPLC (max plot) 90.0%; rt 3.12 min. MS (ESI +): 435.8.

program AO

Intermediate AO: {3- [3- (morpholin-4-ylcarbonyl) -5, 5-dioxido-1-phenyl-1, 4-dihydrothiochromeno [4,3- c]Pyrazol-4-yl ]Propyl } carbamic acid tert-butyl ester

To a solution of 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide (150 mg; 0.37 mmol; 1eq.) in THF (3mL) was added dropwise potassium bis (trimethylsilyl) amide (879.19. mu.l; 0.5M; 0.44 mmol; 1.2eq.) followed by 3- (boc-amino) propyl bromide (104.68 mg; 0.44 mmol; 1.20 eq.). The reaction mixture was stirred at room temperature for 2 days. The reaction was not complete even after 2eq.3- (boc-amino) propyl bromide was added. Water was added to terminate the reaction. The product was extracted with EtOAc, combined with organic phase, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give 217mg (quantitative) of the title compound. HPLC (max plot) 83.1%; rt 4.08 min. MS (ESI-): 565.5.

program AP

Example 123: 1- [1- (methylsulfonyl) piperidin-4-yl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochroman And [4,3-c ]]Pyrazole 5, 5-dioxides

To 3- (morpholin-4-ylcarbonyl) -1-piperidin-4-yl-1, 4-dihydrothiochromeno [4,3-c]A solution of pyrazole 5, 5-dioxide (30mg, 0.066mmol) in THF (10mL) was added triethylamine (40. mu.L, 0.26mmol), the reaction was cooled to 0 ℃ and then methanesulfonyl chloride (0.01mL, 0.099mmol) was added slowly. The temperature of the reaction mixture was slowly raised to room temperature and stirred for an additional 12 hours. Subsequently, water was added to the reaction mixture, and extracted with EtOAc. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The compound was purified by column chromatography over natural neutral alum (0.2% MeOH in chloroform) to give the title compound as a cream solid. ¹H NMR(DMSO-d₆400 MHz): δ 8.20-8.18(d, J =7.0Hz, 1H), 7.78-7.75(m, 1H), 7.67-7.64(m, 1H), 7.52-7.49(m, 1H), 4.70(m, 3H), 4.18(m, 2H), 4.05(m, 2H), 3.81(s, 6H), 2.99-2.94(t, J =11.4Hz, 2H), 2.80(s, 3H), 2.47-2.42(m, 2H), 2.24-2.18(m, 2H). MS (ESI +): 495.0. HPLC (max plot) 93.19%; rt 3.18 min.

Reference procedure AP gave the following compounds:

general procedure AQ

Example 152: n, N-dimethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)] Pyrazole-7-amine 5, 5-dioxides

Reacting 7-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (100mg, 0.20mmol, 1eq.) and sodium tert-butoxide (280mg, 0.29mmol, 1.4eq.) were placed in toluene in a sealed tube. Tris (dibenzylideneacetone) dipalladium (0) (5mg, 0.005mmol, 0.025eq.) and 2-di-tert-butylphosphino-2 ', 4 ', 6 ' -triisopropyldiphenyl (3.5mg, 0.008mmol, 0.04eq.) were added followed by dimethylamine in THF (3mL, 2M) and the reaction mixture was heated at 90 ℃ for 16 h. After this time, the reaction mixture was filtered through celite, evaporated and purified by flash chromatography on silica gel to give the title compound as a light brown solid. ¹H NMR(DMSO-d₆400 MHz): δ 7.61-7.59(m, 3H), 7.51-7.49(m, 2H), 7.10(s, 1H), 6.81-6.79(dd, J =2.6, 9.0Hz, 1H), 6.61-6.59(d, J =9.0Hz, 1H), 4.76(s, 2H), 3.96(m, 2H), 3.65(m, 4H), 3.59(m, 2H), 2.97(s, 6H). MS (ESI +): 453.0. HPLC (max plot) 91.39%; rt 4.20 min.

Reference procedure AQ gave the following compounds:

procedure AR

Example 129: 8-methyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

Reacting 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (160mg, 0.32mmol) was dissolved in 1, 4-dioxane: to water (4: 2), potassium methyltrifluoroborate (80mg, 0.65mmol) and K were added₂CO₃(90mg, 0.65 mmol). The reaction mixture was degassed for 5 min and then 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (6.5mg, 0.016mmol) and potassium acetate (3.6mg, 0.016mmol) were added. The reaction mixture was heated for 2 hours at 120 ℃ with microwave radiation. The reaction was then concentrated and purified by flash chromatography on silica gel to give the title compound as a cream solid.¹H NMR(DMSO-d₆400 MHz): δ 7.90-7.88(d, J =8.0Hz, 1H), 7.64-7.62(m, 3H), 7.54-7.52(m, 2H), 7.43-6.55(d, J =7.5Hz, 1H), 6.55(s, 1H), 4.85(s, 2H), 3.94(m, 2H), 3.66(m, 4H), 3.62(m, 2H), 2.11(s, 3H). MS (ESI +): 424.0. HPLC (max plot) 91.94%; rt 4.17min.

Reference procedure AR gave the following compounds:

procedure AS

Example 114: 8- [ (4-methylpiperazin-1-yl) carbonyl]-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrobenzothiophene Pyrano [4,3-c ]]Pyrazole 5, 5-dioxides

To 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]A solution of pyrazole 5, 5-dioxide (200mg, 0.4mmol) in toluene (10mL) was added Na₂CO₃(65mg, 0.6mmol) and N-methylpiperidine (961mg, 0.6 mmol). The reaction mixture was purged with nitrogen for 15 minutes and then with carbon monoxide, followed by addition of palladium acetate (4.4mg, 0.02mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (11mg, 0.02 mmol). Inverse directionThe mixture was heated at 110 ℃ and refluxed under carbon monoxide atmosphere for 12 hours. The solvent was then reduced to remove the solvent and the compound was purified by flash chromatography on silica gel to give the title compound as a cream solid.¹H NMR(DMSO-d₆400 MHz): δ 8.08-8.06(d, J =7.6Hz, 1H), 7.63-7.61(m, 4H), 7.57-7.55(m, 2H), 6.71(s, 1H), 4.93(s, 2H), 3.94(m, 2H), 3.66-3.60(m, 6H), 3.45(bs, 2H), 3.00(bs, 2H), 2.21(m, 2H), 2.16(s, 3H), 2.05(bs, 2H). MS (ESI +): 536.0. HPLC (max plot) 95.74%; rt 2.45 min.

Example 115: n, N-dimethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)] Pyrazole-8-carboxamide 5, 5-dioxide

With 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and N, N-dimethylamine, the title compound was prepared according to the procedure of procedure AS: n, N-dimethyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole-8-carboxamide 5, 5-dioxide as a milky white solid.¹H NMR(DMSO-d₆400 MHz): δ 8.08-8.06(d, J =8.0Hz, 1H), 7.65-7.54(m, 6H), 6.75(s, 1H), 4.94(s, 2H), 3.94(m, 2H), 3.66(m, 4H), 3.60(m, 2H), 2.84(s, 3H), 2.62(s, 3H). MS (ESI +): 481 HPLC (max plot) 95.16%; rt 3.19 min.

Example 116: 3, 8-bis (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5,5- Dioxide compounds

With 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Starting from pyrazole 5, 5-dioxide and morpholine, the title compound was prepared according to the procedure of procedure AS: 3, 8-bis (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4, 3-c) ]Pyrazole 5, 5-dioxide, as a milky white solid.¹HNMR(DMSO-d₆400 MHz): δ 8.09-8.07(d, J =8.0Hz, 1H), 7.67-7.64(m, 4H), 7.57-7.54(m, 2H), 6.75(s, 1H), 4.93(s, 2H), 3.94(m, 2H), 3.66(m, 4H), 3.61(m, 2H), 3.49(m, 4H), 3.3(m, 2H), 3.03(m, 2H). MS (ESI +): 523.0. HPLC (max plot) 95.86%; rt 3.17 min.

Example 117: 3- (morpholin-4-ylcarbonyl) -1-phenyl-8- (piperidin-1-ylcarbonyl) -1, 4-dihydrothiochromeno-a [4,3-c]Pyrazole 5, 5-dioxides

With 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Starting with pyrazole 5, 5-dioxide and piperidine, the title compound was prepared according to the procedure of procedure AS: 3- (morpholine-4-ylcarbonyl) -1-phenyl-8- (piperidin-1-ylcarbonyl) -1, 4-dihydrothiobenzene and pyran [4,3-c ] o]Pyrazole 5, 5-dioxide, as a milky white solid.¹H NMR(DMSO-d₆400 MHz): δ 8.07-8.05(d, J =8.0Hz, 1H), 7.63-7.53(m, 6H), 6.68(s, 1H), 4.93(s, 2H), 3.94(m, 2H), 3.66(m, 4H), 3.61(m, 2H), 3.42(m, 2H), 2.98(m, 2H), 1.54(m, 2H), 1.40(m, 2H), 1.22(m, 2H). MS (ESI +): 521.0. HPLC (max plot) 93.95%; rt 3.89 min.

Procedure AT

Example 157: 1-Diphenyl-3-yl-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazoles 5, 5-dioxide

Reacting 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (100mg, 0.20mmol), phenylboronic acid (37mg, 0.31mmol), cesium fluoride (124mg, 0.82 mmol) were placed in dioxane-water (2: 1), bubbled with nitrogen for 5 minutes, bis (triphenylphosphine) palladium (II) dichloride (21g, 0.03mmol) was added to the reaction, heated at 90 ℃ for 1 hour with microwave radiation, the reaction mixture was filtered through a pad of celite, concentrated under reduced pressure, and purified by flash chromatography to give the title compound as a pale yellow solid.¹HNMR(DMSO-d₆400 MHz): δ 8.03-8.01(m, 1H), 7.95-7.93(d, J =8.0Hz, 1H), 7.83(s, 1H), 7.72-7.70(m, 4H), 7.68-7.60(m, 2H), 7.59-7.47(m, 3H), 7.45-7.40(m, 1H), 4.91(s, 2H), 3.96(m, 4H), 3.62-3.61(m, 2H). MS (ESI +): 486.0. HPLC (max plot) 98.53%; rt 4.84 min.

Reference procedure AT gave the following compounds:

program AU

Example 164: {3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c]Pyrazol-1 (4H) -yl] Phenyl } amines

Reacting 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (150mg, 0.31mmol), copper acetate (6.1mg, 0.031mmol), cesium carbonate (200mg, 0.616mmol) and acetylacetone (13. mu.L, 0.123mmol) were placed in a sealed tube, DMF was added, and purged with ammonia gas. The reaction mixture was heated to 90 ℃ for 24 hours. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (100% EtOAc) to give the title compound as a light brown solid.¹H NMR(DMSO-d₆400 MHz): δ 7.99-7.97(m, 1H), 7.62-7.60(m, 1H), 7.24-7.20(t, J =7.8Hz, 1H), 6.98-6.95(m, 1H), 6.75-6.73(d, J =9.3Hz, 1H), 6.58-6.56(m, 2H), 5.57(s, 2H), 4.87(s, 2H), 3.95(m, 2H), 3.66(m, 6H). MS (ESI +): 425.0. HPLC (max plot) 94.69%; rt 2.65 min.

Example 165: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-7-amines 5, 5-dioxide

With 7-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Starting with pyrazole 5, 5-dioxide and ammonia, the title compound was prepared according to the procedure AU: 3- (morpholin-4-ylcarbonyl) ) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazol-7-amine 5, 5-dioxide, as a light brown solid.¹HNMR(DMSO-d₆400 MHz): δ 7.60-7.58(m, 3H), 7.49-7.47(m, 2H), 7.16(s, 1H), 6.54(m, 1H), 6.47(m, 1H), 6.15(s, 2H), 4.72(s, 2H), 3.95(m, 2H), 3.65(m, 4H), 3.59(m, 2H). MS (ESI +): 425.0. HPLC (max plot) 95.93%; rt 3.36min.

Example 65: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-8-amine 5,5- Dioxide compounds

Starting with 8-bromo-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide and ammonia, the title compound was prepared according to the procedure AU: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c ] pyrazol-8-amine 5, 5-dioxide as a light brown solid. 1HNMR (400MHz, DMSO-d6) δ =7.61-7.58(m, 4H), 7.50-7.48(m, 2H), 6.62(dd, J =8.6, 2.1Hz, 1H), 6.04(s, 2H), 6.00(d, J =1.9Hz, 1H), 4.65(s, 2H), 3.92(bs, 2H), 3.65-3.59(m, 6H). MS (ESI +): 425.0. HPLC (max plot) 94.64%; rt 3.11min.

The following examples were obtained with reference to procedure Z:

Program AX

Example 418: 1- [1- (3-furoyl) piperidin-3-yl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Enantiomer B of pyrazole 5, 5-dioxide

To a solution of 3- (morpholin-4-ylcarbonyl) -1- [ piperidin-3-yl ] -1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide enantiomer B (30 mg; 0.07 mmol; 1eq.) in DCM (0.45mL) was added N, N-diisopropylethylamine (25. mu.l; 0.14 mmol; 2eq.) followed by 3-furoyl chloride (14 mg; 0.11 mmol; 1.5eq.) and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated and the residue was purified by flash chromatography (eluent: MeOH/EtOAc 0 to 10%) to give 20mg (54%) of the title compound as a white powder. 1H NMR (DMSO-d 6): δ 8.04(d, J =7.7Hz, 2H), 7.86(s, 1H), 7.75(d, J =7.8Hz, 2H), 6.67(s, 1H), 4.85(s, 1H), 4.79(s, 2H), 3.91(s, 2H), 3.64(d, J =9.7Hz, 5H), 2.26(s, 2H), 1.95-1.61(m, 2H). HPLC (max plot) 99.4%; rt 3.02 min. MS (ESI +): 511.30.

reference to program AX gave the following compounds:

example 276: n-cyclohexyl-3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4, 3-c)]Pyrazole- 1(4H) -yl]Pyrrolidine-1-carboxamides

To a solution of 3- (morpholin-4-ylcarbonyl) -1-pyrrolidin-3-yl-1, 4-dihydrothiochromeno [4,3-c ] pyrazole 5, 5-dioxide hydrochloride (50 mg; 0.11 mmol; 1eq.) and NN-diisopropylethylamine (21.59. mu.l; 0.13 mmol; 1.10eq.) in DCM (0.5ml) was added cyclohexyl isocyanate (15.68 mg; 0.13 mmol; 1.1eq.) and the reaction mixture was stirred at room temperature for 20 min. The aminomethyl resin was added and the reaction mixture was stirred at room temperature overnight. The resin was filtered off and the solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (eluent: 0-10% EtOAc in MeOH) to afford, after concentration of the desired fraction, 45mg (75%) of the title compound as a white solid. HPLC (max plot) 99.7%; rt 3.68 min. MS (ESI +): 528.3.

example 189: 3- (morpholin-4-ylcarbonyl) -1- [3- (1, 3-thiazol-2-yl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxides

Reacting 1- (3-bromophenyl) -3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4, 3-c)]Pyrazole 5, 5-dioxide (100mg, 0.20mmol, 1eq.) was placed in THF and bubbled with nitrogen for 5 minutes. Thiazolyl zinc bromide (2mL), tetrakis (triphenylphosphine) palladium (0) (12mg, 0.010mmol, 0.05eq.) were added and the reaction mixture was heated under sealed conditions at 65 ℃ for 4 h. The reaction mixture was filtered through a pad of celite, concentrated under reduced pressure and purified by flash chromatography to give the title compound as a pink solid. ¹H NMR(DMSO-d₆400 MHz): δ 8.18-8.16(d, J =7.7Hz, 1H), 8.07(s, 1H), 8.04-8.02(d, J =7.7Hz, 1H), 7.96-7.95(d, J =3.2Hz, 1H), 7.87-7.86(d, J =3.2Hz, 1H), 7.76-7.72(t, J =7.9Hz, 1H), 7.65-7.56(m, 3H), 6.98-6.96(d, J =7.7Hz, 1H), 4.91(s, 2H), 3.93(m, 2H), 3.67(m, 4H), 3.62-3.61(m, 2H). MS (ESI +): 493.0. HPLC (max plot) 98.44%; rt 4.02 min.

Example 199: 1- [3- (5-ethyl-1, 2, 4-oxadiazol-3-yl) phenyl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothio Benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

To N' -hydroxy-3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] under nitrogen atmosphere]Pyrazol-1 (4H) -yl]To a solution of benzamidine (150mg, 0.32mmol) in dry EtOAc was added propionic acid (g13 μ L, 0.32mmol), and then TEA (0.13mL, 0.963mmol) and propanephosphonic acid cyclic anhydride (0.51mL, 0.80mmol) were added at 0 ℃ under a nitrogen atmosphere. The reaction mixture was heated to 80 ℃ under nitrogen and held for 12 hours and concentrated in vacuo. The solid residue was purified by silica gel column chromatography (1.2% MeOH in DCM) to give the title compound as a cream solid.¹H NMR(DMSO-d₆400 MHz): δ 8.24-8.22(d, J =7.4Hz, 1H), 8.05-8.02(m, 2H), 7.81-7.77(m, 2H), 7.64(m, 1H), 7.57(m, 1H), 6.93-6.91(d, J =7.9Hz, 1H), 4.91(s, 2H), 3.92-3.90(m, 2H), 3.67(m, 4H), 3.61-3.60(m, 2H), 3.02-3.0(m, 2H), 1.33-1.29(t, J =7.6Hz, 3H). MS (ESI +): 506.0. HPLC (max plot) 97.13%; rt 4.34 min.

Example 200: 1- [3- (5-methyl-1H-1, 2, 4-triazol-3-yl) phenyl]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothio Substituted benzopyrano [4,3-c]Pyrazole 5, 5-dioxides

To 3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4,3-c ] under nitrogen atmosphere]Pyrazol-1 (4H) -yl]A solution of benzonitrile (100mg, 0.23mmol) in dry toluene was added with acetyl azide (34mg, 0.46mmol) and K₂CO₃(158mg, 0.115 mmol). The reaction mixture was heated to 110 ℃ under nitrogen and held for 12 hours, then concentrated in vacuo. The solid residue was purified by preparative HPLC to give the title compound as a white solid.¹H NMR(DMSO-d₆400 MHz): δ 8.21-8.19(d, J =7.7Hz, 1H), 8.03-7.98(m, 2H), 7.73-7.69(m, 1H), 7.64-7.56(m, 3H), 6.92-6.90(d, J =7.8Hz, 1H), 4.91(s, 2H), 3.93(m, 2H), 3.75-3.67(m, 4H), 3.62-3.61(m, 2H), 2.37(s, 3H). MS (ESI +): 491.0. HPLC (max plot) 98.76%; rt 2.96 min.

Example 238: 1- [4- (morpholine-4)-ylmethyl) phenyl]-1, 4-dihydrothiochromeno [4,3-c]Pyrazole-3-carboxylic acids 5, 5-dioxide

To 1- [4- (hydroxymethyl) phenyl at 0 DEG C]-1, 4-dihydrothiochromeno [4,3-c ]A suspension of pyrazole-3-carboxylic acid 5, 5-dioxide (30 mg; 0.08 mmol; 1eq.) in DCE (2ml) was added thionyl chloride (15. mu.l; 0.2 mmol; 2.5 eq.). The reaction mixture was stirred for 15 minutes, the solvent was removed and a solution of morpholine (300. mu.l; 10V) in DCE (2mL) was added. After stirring overnight, the solvent was removed and the crude residue was purified by Autoprep chromatography to give the title compound as a white fluffy solid.¹H NMR(DMSO-d₆) δ 8.02(dd, J =1.3, 7.7Hz, 1H), 7.69-7.41(m, 5H), 6.93-6.72(m, 1H), 4.97(s, 2H), 3.76-3.53(m, 5H), 3.32-3.30(m, 2H), 2.46-2.32(m, 3H). HPLC (max plot) 91.4%; rt 2.26 min. MS (ESI +): 439.98.

example 212: n-methyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazole- 6-amine 5, 5-dioxides

To N-methyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydrothiochromeno [4,3-c]Pyrazol-6-amine (90mg, 0.22mmol) in THF: a solution in water (1: 1, 10mL) was added oxone (545mg, 0.88mmol) and the reaction mixture was stirred at room temperature for 3h, then EtOAc was added to the reaction mixture washed with water. Separating the organic layer, Na₂SO₄Drying, and concentrating under reduced pressure. The solid residue was purified by flash chromatography on silica gel (40% EtOAc in petroleum ether) to give the title compound as A white solid.¹HNMR(DMSO-d₆400 MHz): δ 7.59-7.56(m, 3H), 7.47-7.44(m, 2H), 7.26-7.22(t, J =8.1Hz, 1H), 6.80-6.74(m, 2H), 5.98-5.96(d, J =7.6Hz, 1H), 4.87(s, 2H), 3.95-3.94(m, 2H), 3.65(m, 4H), 3.61-3.59(m, 2H), 2.83-2.82(d, J =4.7Hz, 3H). MS (ESI +): 439.0. HPLC (max plot) 95.63%; rt 4.39 min.

Example 440: 1- (2- {3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4, 3-c)]Pyrazole- 1(4H) -yl]Enantiomer B of piperidin-1-yl } ethyl) pyrrolidin-2-one

A solution of 2-pyrrolidone (35 mg; 0.42 mmol; 2eq.) and NaH (10 mg; 0.42 mmol; 2eq.) in ACN was added to 1- [1- (2-chloroethyl) piperidin-3-yl at 0 ℃]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Pyrazole 5, 5-dioxide enantiomer B (100 mg; 0.21 mmol; 1eq.) and NaI (31 mg; 0.21 mmol; 1eq.) in ACN (2 mL). The reaction mixture was heated to 60 ℃ and held for 18 hours, then DCM was added and the organic phase was washed with water and brine. MgSO (MgSO)₄Drying and MD-Autoprep chromatography gave 11mg (9%) of the title compound as a white solid.¹H NMR(DMSO-d₆300 MHz): δ 8.05(d, J =7.7Hz, 1H), 8.00-7.82(m, 2H), 7.81-7.67(m, 1H), 4.89-4.64(m, 3H), 4.00-3.83(m, 2H), 3.83-3.56(m, 8H), 3.22-3.12(m, 1H), 2.99-2.82(m, 1H), 2.67-2.34(m, 4H), 2.29-2.15(m, 2H), 2.15-1.54(m, 8H). MS (ESI +): 528.5. HPLC (max plot) 97.6%; rt 1.86 min.

Example 454: 1- (1- {2- [ (1-methylpiperidin-4-yl) oxy)]Ethyl } piperidin-3-yl) -3- (morpholin-4-ylcarbonyl) -1,4- Dihydrothiochromeno [4,3-c ] s]Enantiomer B of pyrazole 5, 5-dioxide

1- [1- (2-chloroethyl) piperidin-3-yl at 0 ℃]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]A solution of enantiomer B of pyrazole 5, 5-dioxide (100 mg; 0.21 mmol; 1eq.) and NaH (18 mg; 0.42 mmol; 2eq.) in acetonitrile (2mL) was added to a solution of 1-methyl-4-piperidinol (49. mu.L; 0.42 mmol; 2eq.) and NaI (31 mg; 0.21 mmol; 1eq.) in ACN (2 mL). The reaction mixture was heated to 60 ℃ and held for 18 hours, then DCM was added and the organic phase was washed with water and brine. MgSO (MgSO)₄Drying and MD-Autoprep chromatography gave 11mg (9%) of the title compound as a yellow oil.¹H NMR(DMSO-d₆300 MHz): δ 8.06(d, J =7.9Hz, 1H), 7.98-7.87(m, 1H), 7.86-7.70(m, 2H), 4.87-4.70(m, 3H), 3.97-3.84(m, 2H), 3.84-3.76(m, 1H), 3.76-3.56(m, 6H), 3.55-3.47(m, 2H), 3.37-3.16(m, 3H), 3.15-2.93(m, 4H), 2.91-2.70(m, 3H), 2.63-2.54(m, 1H), 2.30-1.59(m, 10H). MS (ESI +): 558.3. HPLC (max plot) 75.1%; rt 1.74 min.

Example 452: 2- {3- [3- (morpholin-4-ylcarbonyl) -5, 5-thiobenzopyrano [4, 3-c)]Pyrazole-1 (4H) -substituted derivatives Base of]Enantiomer B of piperidin-1-yl } ethylamine

To 1- [1- (2-chloroethyl) piperidin-3-yl group]-3- (morpholin-4-ylcarbonyl) -1, 4-dihydrothiochromeno [4,3-c]Enantiomer B of pyrazole 5, 5-dioxide (90 mg; 0.19 mmol; 1.00eq.) in CH₃Ammonia (181.88. mu.l; 2.82 mmol; 15.00eq.) was added to a solution in CN (0.90 ml). The reaction was stirred for 15 minutes under heating by microwave radiation at 135 ℃ and then purified by MD-Autoprep chromatography to give the title compound as a white solid.¹HNMR(DMSO-d₆300 MHz): δ 8.05(d, J =7.8Hz, 1H), 7.96(t, J =7.1Hz, 1H), 7.87(d, J =7.6Hz, 1H), 7.75(t, J =7.4Hz, 1H), 4.79(q, J =16.2Hz, 3H), 3.90(s, 2H), 3.66(s, 6H), 3.15(d, J =9.7Hz, 2H), 2.90(q, J =13.0Hz, 3H), 2.73-2.53(m, 2H), 2.27-2.02(m, 2H), 2.00-1.59(m, 3H). MS (ESI +): 460.3. HPLC (max plot) 55.4%; rt 2.09 min.

Procedure AY

Example 487: 4- (methoxymethyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydropyrazolo [4,3-c][1，2]Benzene and its derivatives Azethizine 5, 5-dioxide

2-bromo-N- (methoxymethyl) -N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl ]Benzenesulfonamide (240 mg; 0.45 mmol; 1.00eq.), palladium acetate (20 mg; 0.09 mmol; 0.20eq.), triphenylphosphine (94 mg; 0.36 mmol; 0.80eq.), and Cs₂CO₃(584 mg; 1.79 mmol; 4.00eq.) of the mixture was purged with nitrogen for 10 minutes. Toluene (50mL) was added and the reaction mixture was refluxed for 2 hours. The reaction mixture was then filtered through a short plug of celite and washed with ethyl acetate. The organic phases are combined and successively NaHCO is used₃And brine, dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography to give the title compound as a white solid.¹H NMR(300MHz，DMSO-d₆): δ 8.03(dd, J =1.3, 7.5Hz, 1H), 7.88-7.46(m, 7H), 7.04-6.94(m, 1H), 5.15(s, 2H), 3.69(s, 6H), 3.64-3.54(m, 2H), 2.89(s, 3H). HPLC (max plot) 83.4%; rt 3.71 min. MS (ESI +) 423.2.

Example 488: 4-methyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydropyrazolo [4,3-c][1,2]Benzothiazine 5, 5-dioxide

Starting from 2-bromo-N-methyl-N- [3- (morpholin-4-ylcarbonyl) -1-phenyl-1H-pyrazol-4-yl ] benzenesulfonamide, the title compound was prepared according to the procedure AY: 4-methyl-3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydropyrazolo [4,3-c ] [1,2] benzothiazine 5, 5-dioxide as a white solid. 1H NMR (300MHz, DMSO-d 6): delta 8.04-7.98(m, 1H), 7.76-7.55(m, 7H), 7.00-6.92(m, 1H), 3.80-3.66(m, 6H), 3.66-3.57(m, 2H), 3.16(s, 3H). HPLC (max plot) 100.0%; rt 3.45 min. MS (ESI +) 425.3.

Example 489: 3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydropyrazolo [4,3-c][1,2]Benzothiazine 5, 5-dioxides Article of manufacture

To 4- (methoxymethyl) -3- (morpholin-4-ylcarbonyl) -1-phenyl-1, 4-dihydropyrazolo [4,3-c][1,2]A solution of benzothiazine 5, 5-dioxide (85 mg; 0.19 mmol; 1.00eq.) in 1, 4-dioxane (3mL) was added HCl (0.75 mL; 1M; 0.75 mmol; 4.00eq.) and the reaction mixture was stirred for 90 minutes with heating by microwave radiation (. multidot.2) at 100 ℃. DCM was added and the reaction mixture was washed with NaHCO₃Neutralized to pH 6, extracted with DCM and MgSO₄Drying and purification by MD-Autoprep chromatography gave 8mg (10%) of the title compound as a cream solid. 1H NMR (300MHz, DMSO-d 6): delta 10.94(s, 1H), 8.00-7.91(m, 1H), 7.71-7.50(m, 7H), 6.99-6.86(m, 1H), 3.83-3.55(m, 8H). HPLC (max plot) 97.4%; rt 3.27 min. MS (ESI +) 411.2.

Example 486: 3- (morpholin-4-ylcarbonyl) -1-phenyl-4H-imidazo [5,1-c][1,4]Benzothiazine 5, 5-dioxide Article (A)

Starting from 3- (morpholin-4-ylcarbonyl) -1-phenyl-4H-imidazo [5,1-c ] [1,4] benzothiazine, the title compound is prepared according to the procedure Q: 3- (morpholin-4-ylcarbonyl) -1-phenyl-4H-imidazo [5,1-c ] [1,4] benzothiazine 5, 5-dioxide. 1H NMR (DMSO-d6, 400MHz) Δ 8.04-8.02(m, 1H), 7.61-7.58(m, 2H), 7.55-7.52(m, 3H), 7.50-7.43(m, 2H), 6.99-6.97(m, 1H), 5.24(s, 2H), 4.15(m, 2H), 3.63(m, 6H). MS (ESI +): 410.0. HPLC (max plot) 94.7%; rt 3.73 min.

Example 600: biological assay

Pi3Kα

The effect of the compounds of the present invention in inhibiting PI 3K-induced lipid phosphorylation can be measured by the following binding assay. The assay combines scintillation proximity analysis (SPA, SAmersham) and neomycin (polycationic antibiotics) with high affinity and the ability to bind phospholipids specifically. Scintillation proximity assays are based on weakly radioactive isotopes (e.g.³H，¹²⁵I，³³P) of the substrate. After culturing the neomycin-coated SPA beads in the same well with PI3K recombinant and radioactive ATP, the phosphorylated phospholipid substrate was detected by capturing the radioactive phospholipid on the SPA beads through specific binding of the radioactive phospholipid to neomycin.

To a 384 well MTP containing 5 μ L of a test compound of formula (I) (dissolved in 2% DMSO to give final concentrations of 20, 5, 1.25, 0.3125, 0.0781, 0.0195, 0.0049, 0.0012, 0.0003 and 0.00075 μ M of test compound) the following experimental components were added: 1)5 μ L of lipid microbubbles; 2) 5. mu.L of a kinase buffer solution (,)³³P]γATP 30μM/200nCi，MgCl₂10mM，DTT 1mM，Na₃VO₄100 mu M, 0.1% of sodium cholate, beta glycerophosphateSalt 1mM, in Hepes, 40mM, pH 7.4); and 3) 5. mu.L (30ng) of human recombinant GST-PI3K (in Hepes, 40mM, pH 7.4). After incubation at 30 ℃ for 120 minutes with gentle agitation, the reaction was stopped by adding 60. mu.L of a PBS solution containing 75. mu.g of neomycin-coated PVT SPA beads, ATP 5mM and EDTA 5 mM. Gentle stirring was continued at 30 ℃ for 60 minutes to bind the phospholipid to the neomycin-SPA beads. The neomycin-coated PVT SPA beads were pelleted for 5 hours and then washed with Wallac Microeta ^TMThe radioactivity PtdIns (3) P obtained was quantitatively analyzed by scintillation counting in a plate counter.

Pi3Kβ

The effect of the compounds of the present invention in inhibiting PI 3K-induced lipid phosphorylation can be measured by the following binding assay. The assay combines scintillation proximity analysis (SPA, SAmersham) and neomycin (polycationic antibiotics) with high affinity and the ability to bind phospholipids specifically. Scintillation proximity assays are based on weakly radioactive isotopes (e.g.³H，¹²⁵I，³³P) of the substrate. After culturing the neomycin-coated SPA beads in the same well with PI3K recombinant and radioactive ATP, the phosphorylated phospholipid substrate was detected by capturing the radioactive phospholipid on the SPA beads through specific binding of the radioactive phospholipid to neomycin.

To a 384 well MTP containing 5 μ L of a test compound of formula (I) (dissolved in 2% DMSO to give final concentrations of 20, 5, 1.25, 0.3125, 0.0781, 0.0195, 0.0049, 0.0012, 0.0003 and 0.00075 μ M of test compound) the following experimental components were added: 1)5 μ L of lipid microbubbles; 2) 5. mu.L of a kinase buffer solution (,)³³P]γATP 70μM/300nCi，MgCl₂4mM，DTT 1mM，Na₃VO₄0.1 μ M, 0.2% cholanic acid sodium salt, in Hepes, 40mM, pH 7.4); and 3) 5. mu.L (12ng) of human recombinant GST-PI3K (in Hepes, 40mM, pH 7.4). After incubation at 30 ℃ for 120 minutes with gentle agitation, the reaction was stopped by adding 60. mu.L of a PBS solution containing 75. mu.g of neomycin-coated PVT SPA beads, ATP 5mM and EDTA 5 mM. Gentle stirring was continued at 30 ℃ for 60 minutes to bind the phospholipid to the neomycin-SPA beads. Will be coated with neomycin The PVT SPA beads of the elements were pelleted for 5 hours and then washed with Wallac Microeta^TMThe radioactivity PtdIns (3) P obtained was quantitatively analyzed by scintillation counting in a plate counter.

Pi3Kδ

The effect of the compounds of the present invention in inhibiting PI 3K-induced lipid phosphorylation can be measured by the following binding assay. The assay combines scintillation proximity analysis (SPA, SAmersham) and neomycin (polycationic antibiotics) with high affinity and the ability to bind phospholipids specifically. Scintillation proximity assays are based on weakly radioactive isotopes (e.g.³H，¹²⁵I，³³P) of the substrate. After culturing the neomycin-coated SPA beads in the same well with PI3K recombinant and radioactive ATP, the phosphorylated phospholipid substrate was detected by capturing the radioactive phospholipid on the SPA beads through specific binding of the radioactive phospholipid to neomycin.

To a 384 well MTP containing 5 μ L of a test compound of formula (I) (dissolved in 2% DMSO to give final concentrations of 20, 5, 1.25, 0.3125, 0.0781, 0.0195, 0.0049, 0.0012, 0.0003 and 0.00075 μ M of test compound) the following experimental components were added: 1)5 μ L of lipid microbubbles; 2) 5. mu.L of a kinase buffer solution (,)³³P]γATP 260μM/300nCi，MgCl₂4mM，DTT 4mM，Na₃VO₄0.4. mu.M in Hepes, 40mM, pH 7.4); and 3) 5. mu.L (50ng) of human recombinant GST-PI3K (in Hepes, 40mM, pH 7.4). After incubating at room temperature for 120 minutes with gentle stirring, the reaction was stopped by adding 60. mu.L of a PBS solution containing 75. mu.g of neomycin-coated PVTSPA beads, 6.5mM ATP and 6.5mM EDTA. Gentle stirring was continued at room temperature for 60 minutes to allow the phospholipid to bind to the neomycin-SPA beads. The neomycin-coated PVT SPA beads were pelleted for 5 hours and then washed with Wallac Microeta ^TMThe radioactivity PtdIns (3) P obtained was quantitatively analyzed by scintillation counting in a plate counter.

Pi3Kγ

The compounds of the invention inhibit PI 3K-induced lipid phosphorylationAs determined by the following binding assay test. The assay combines scintillation proximity analysis (SPA, SAmersham) and neomycin (polycationic antibiotics) with high affinity and the ability to bind phospholipids specifically. Scintillation proximity assays are based on weakly radioactive isotopes (e.g.³H，¹²⁵I，³³P) of the substrate. After culturing the neomycin-coated SPA beads in the same well with PI3K recombinant and radioactive ATP, the phosphorylated phospholipid substrate was detected by capturing the radioactive phospholipid on the SPA beads through specific binding of the radioactive phospholipid to neomycin.

To a 384 well MTP containing 5 μ L of a test compound of formula (I) (dissolved in 2% DMSO to give final concentrations of 20, 5, 1.25, 0.3125, 0.0781, 0.0195, 0.0049, 0.0012, 0.0003 and 0.00075 μ M of test compound) the following experimental components were added: 1)5 μ L of lipid microbubbles; 2) 5. mu.L of a kinase buffer solution (,)³³P]γATP 30μM/200nCi，MgCl₂ 10mM，DTT 1mM，Na₃VO₄1001 μ M, cholanic acid sodium salt 0.1%, beta glycerophosphate 1mM, in Hepes, 40mM, pH 7.4); and 3) 5. mu.L (30ng) of human recombinant GST-PI3K (in Hepes, 40mM, pH 7.4). After incubation at 30 ℃ for 120 minutes with gentle agitation, the reaction was stopped by adding 60. mu.L of a PBS solution containing 75. mu.g of neomycin-coated PVT SPA beads, ATP 5mM and EDTA 5 mM. Gentle stirring was continued at 30 ℃ for 60 minutes to bind the phospholipid to the neomycin-SPA beads. The neomycin-coated PVT SPA beads were pelleted for 5 hours and then washed with Wallac Microeta ^TMThe radioactivity PtdIns (3) P obtained was quantitatively analyzed by scintillation counting in a plate counter.

The values listed in Table I below are the best ICs obtained for the four isoforms of PI3K described above₅₀(μ M), i.e., the amount required to achieve 50% inhibition of the target.

Example 512: experiments on target cell mechanisms

The cellular activity of the example compounds of the invention on Ramos B lymphocyte cell line (ATCC # CRL-1923) was determined by flow cytometry experiments. These cells were incubated overnight in 5% serum and the next day the serum was removed and the cells were starved to reduce background AKT phosphorylation, preincubated with test compound for 20 min and stimulated with anti-human IGM antibody (jacksonno Research #109006129) (10ug/ml final) for 15 min. The reaction was stopped by fixing the cells with paraformaldehyde at 4% (final concentration) for 10 minutes at room temperature. Cells were washed once with Phosphate Buffered Saline (PBS), permeabilized in PBS-Triton X-1000.2% for 15 minutes at room temperature, washed twice with PBS, and once with PBS-4% serum. Cells were incubated with anti-p-AKT (Ser 473) (CellSignaling #4058L) (1/70dilution) in PBS-4% serum for 1 hour at room temperature. After washing twice with PBS-4% serum, cells were stained with a mixture of mouse anti-human IgM-APC (BD Pharmingen #551062) (1: 50), anti-rabbit IgG-Alexa 488(Invitrogen Ref.A-45558A) (1: 200) and goat IgG (5mg/ml, 10mg) (Zymed #02-6202) (1: 200) for 30 minutes at 4 ℃. The cells were washed twice with PBS and resuspended in PBS. The cell suspension was passed through an FC500 flow cytometer (Beckman Coulter), IGM positive cells were gated and AKT phosphorylation was measured.

Examples of inhibitory activity of the compounds of the present invention are listed in table I below.

TABLE I

Example 511: preparation of pharmaceutical formulations

Formulation 1-tablet

Dry powders of the compound of formula (I) are mixed with a dry gelatin binder in a ratio of about 1: 2 weight ratio. A small amount of magnesium stearate was added as a lubricant. The mixture is compressed into 240-270mg tablets (each containing 80-90mg of the active compound according to the invention) using a tablet press.

Preparation 2-capsule

Dry powders of the compound of formula (I) are mixed with a starch diluent at a ratio of about 1: 1 weight ratio. The mixture is filled into 250mg capsules (each containing 125mg of the active compound of the invention).

Formulation 3-liquid agent

The compound of formula (I) (1250mg), sucrose (1.75g) and xanthan gum (4mg) were mixed, passed through a 10 mesh U.S. sieve and then mixed with an aqueous solution of microcrystalline cellulose and carboxymethylcellulose (11: 89, 50mg) previously prepared. Sodium benzoate (10mg), flavours and colours were diluted with water and added with stirring. Sufficient water was then added to bring the total volume to 5 ml.

Formulation 4-tablet

Dry powders of the compound of formula (I) are mixed with a dry gelatin binder in a ratio of about 1: 2 weight ratio. A small amount of magnesium stearate was added as a lubricant. The mixture was compressed into 450-900mg tablets (150-300 mg of the active compound of the invention) using a tablet press.

Preparation 5-injection

The compound of formula (I) is dissolved in an injectable aqueous medium in buffered sterile saline at a concentration of about 5 mg/ml.

Claims (15)

1. General formula (I)^*) A compound shown in the formula (I):

in the formula (I), the compound is shown in the specification,

X₁represents a nitrogen atom or CR³，

X₂，X₅Each independently being a nitrogen or carbon atom,

u represents renAromatic 6-membered rings, having 1, 2 or 3 nitrogen atoms, including X₅Inside; or an unsaturated or aromatic 5-membered ring having 1 to 3 heteroatoms selected from N, S or O, including X₅The meaning of (a) is given,

z represents an unsaturated or aromatic 5-membered heterocyclic ring having 2 nitrogen atoms, including X₅The meaning of (a) is given,

t represents S, SO or SO₂，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，-NR⁶COAr，NR⁶COHet，COHet，-NR⁶SO₂R⁶，CO₂R⁶Comprising CO₂Y，

R²Represents H, Ar, Het, A, Cyc,

R³the structural formula (I) represents a group of H, Y,

R⁴represents H, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂Or if X₁Is CR³And also means Hal, in the name of Hal,

R⁵represents H, Y or Ar when R⁵When is Y and R is 2, two R⁵Groups may be linked together to provide a morpholino group in the bridge system with the two R⁵The groups are connected with each other,

R⁶is H, A, Cyc or Ar.

u is 0, 1, 2, 3, or 4, preferably 0 or 1,

r is a number of 0, 1 or 2,

g is a number of 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF ₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which finally contains SO₂Or a CO group, said heterocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_{1- q}A_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_{2- m}(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

Het²to represent

Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_{1- q}A_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched or unbranched alkane having from 1 to 12 carbon atomsIn which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y，CO₂H or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein₂The radicals being optionally substituted by O, NR⁶，CO，CONR⁶，NR⁶CO, OCO, and/or substituted by a-CH = CH-or-C ≡ C-group, or represents cycloalkyl or cycloalkylalkylene having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios,

with the following conditions: excluding compounds of formula (B1):

2. the compound of claim 1 of the formula (I)^*) A compound of the formula (I)^*) The following sections

Selected from the following groups:

in the formula, R¹，R²，R³，R⁴T is as aboveThe definition of the method is that,

and, U¹，U²，U³And U is⁴Represents CR¹Or U is¹，U²，U³And U⁴One or two of which are independently N, the remainder being CR¹Or U is¹And U⁴One of them is S, U²-U³Together form a group CR¹The balance being CR¹Or U is¹And U⁴One of them is S, U²-U³Together form a group CR¹And the remainder are N, or said moieties represent the following groups:

in the formula of U¹Represents N, U²-U³Together form a group CR¹，U⁴Is CR¹，X₅Is N, and Z, X¹，X²，R²And T is as defined above.

3. The general formula (I) as claimed in claim 1 or 2^*) A compound of formula (I) wherein R²Selected from H, branched or straight chain C₁-C₆-an alkyl group, or one of the following:

4. the compound of claim 1 of the formula (I)^*) A compound, wherein the compound is represented by the following general formula (I):

R²represents H, Ar, Het, A, Cyc,

R³，R⁴each independently represents H, Y, (CH) ₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，

R⁵Represents a group of H, Y or Ar,

U¹，U²，U³and U is⁴Represents CR¹Or U is¹，U²，U³And U⁴One or two of which are independently N, the remainder being CR¹，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，

T represents S, SO or SO₂.

r represents a number of 0, 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²(ii) a Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which heterocycle is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

cyc denotes a saturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_{1- q}A_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²Or- (CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein ₂The radicals being optionally substituted by O, NR⁶，CONR⁶-and/or substituted by a-CH = CH-or-C ≡ C-group, or represents a cycloalkyl or cycloalkylalkylene group having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

R⁶is H, A, Cyc or Ar,

hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4,

and pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios,

with the following conditions: excluding compounds of formula (B1):

5. the compound of claim 1 of the formula (I)^*) A compound selected from the group consisting of:

6. general formula (I)^*) A compound shown in the formula (I):

in the formula (I), the compound is shown in the specification,

X₁represents a nitrogen atom or CR³，

X₂，X₅Each independently being a nitrogen or carbon atom,

u represents an aromatic 6-membered ring optionally having 1, 2 or 3 nitrogen atoms, including X₅Inside; or an unsaturated or aromatic 5-membered ring having 1 to 3 heteroatoms selected from N, S or O, including X₅The meaning of (a) is given,

z represents an unsaturated or aromatic 5-membered heterocyclic ring having 2 nitrogen atoms, including X ₅The meaning of (a) is given,

t represents S, SO or SO₂，

R¹Denotes H, A, Hal, CN, NO₂，N(R⁶)₂，OR⁶，Ar，Het，Y，-NR⁶COR⁶，CON(R⁶)₂，-NR⁶COAr，NR⁶COHet，COHet，-NR⁶SO₂R⁶，CO₂R⁶Comprising CO₂Y，

R²Represents H, Ar, Het, A, Cyc,

R³the structural formula (I) represents a group of H, Y,

R⁴represents H, Y, (CH)₂)_nAr，(CH₂)_nCyc，(CH₂)_nHet，(CH₂)_nOY，(CH₂)_nNHY，(CH₂)_nNH₂Or if X₁Is CR³And also means Hal, in the name of Hal,

R⁵represents H, Y or Ar when R⁵When is Y and R is 2, two R⁵Groups may be linked together to provide a morpholino group in the bridge system with the two R⁵The groups are connected with each other,

R⁶is H, A, Cyc or Ar.

u is 0, 1, 2, 3, or 4, preferably 0 or 1,

r is a number of 0, 1 or 2,

g is a number of 1 or 2,

ar represents a monocyclic or fused bicyclic unsaturated or aromatic carbocycle having 6 to 14 carbon atoms, said carbocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，COHet，-NHCOR⁶，-NHSO₂A，-NHSO₂Ar，-NHSO₂-N(R⁶)₂，N(H)_1-qA_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_{1- q}A_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_n-N(R⁶)₂，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1, 2, 3 or 4N, O and/or S atoms, which finally contains SO₂Or a CO group, said heterocycle being unsubstituted or substituted by Hal, OCF₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，-CO₂R⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_1-qA_qCOR⁶，N(H)_{1- q}A_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-SO₂A，-SO₂Ar，-SO₂N(H)_{2- m}(A)_m，COHet，-SO₂Het，-(CH₂)_n-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

Het²to represent

Cyc denotes a saturated or unsaturated carbocyclic ring having 3 to 8 carbon atoms, which is unsubstituted or substituted by Hal, OCF ₃，NO₂CN, perfluoroalkyl, A, OR⁶，N(R⁶)₂，COR⁶，CON(R⁶)₂，-NHCOR⁶，-NHSO₂A，-NHSO₂R⁶，-NHSO₂-N(H)_2-m(A)_m，N(H)_{1- q}A_qCOR⁶，N(H)_1-qA_qSO₂-N(H)_2-m(A)_m，-N(H)_1-qA_qCON(H)_2-m(A)_m，-COOR⁶，-SO₂A，-SO₂Ar，-SO₂N(H)_2-m(A)_m，-SO₂Het，-(CH₂)_p-N(H)_2-m(A)_m，-(CH₂)_n-OR⁶，-(CH₂)_n-N(R⁶)SO₂A，-(CH₂)_n-N(R⁶)SO₂R⁶，Het²，-(CH₂)_n-Het²，-(CHY)_n-Het²Mono-, di-, or tri-substituted;

a is a branched OR unbranched alkyl radical having 1 to 12 carbon atoms, in which one OR more, preferably 1 to 7, hydrogen atoms may be replaced by Hal, Ar, Het, Cyc, OR⁶，-CN，-CO₂Y，CO₂H or N (R)⁶)₂A substitution, and one or more, preferably 1 to 7, non-adjacent CH's therein₂The radicals being optionally substituted by O, NR⁶，CO，CONR⁶，NR⁶CO, OCO, and/or substituted by a-CH = CH-or-C ≡ C-group, or represents cycloalkyl or cycloalkylalkylene having 3 to 7 ring carbon atoms;

y represents a branched or straight-chain alkyl group having 1 to 8 carbon atoms,

hal represents F, Cl, Br or I,

q is a number of 0 or 1,

m is a number of 0, 1 or 2,

n is 1, 2, 3, or 4

And pharmaceutically acceptable derivatives, solvates, tautomers, salts, hydrates and stereoisomers thereof, including mixtures thereof in various ratios,

for use as a medicament.

7. The general formula (I) as claimed in claim 1^*) Compounds for use in the prevention and/or treatment of diseases associated with abnormalities of phosphoinositide 3-kinase.

8. The compound of claim 7, wherein the disease is an inflammatory disease, an autoimmune disease, cancer, or multiple sclerosis and related diseases.

9. The compound of claim 8, wherein the autoimmune disease is selected from the group consisting of: asthma, rheumatoid arthritis, Acute Disseminated Encephalomyelitis (ADEM), Addison's disease, alopecia areata, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid, Behcet's disease, celiac disease, anti-transglutaminase, Chagas's disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, pulmonary hemorrhage-nephritis syndrome, Graves ' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki's disease, glomerulonephritis type A, immune thrombocytopenic purpura, interstitial cystitis, lupus erythematosus, mixed connective tissue disease, scleroderma, Multiple Sclerosis (MS), myasthenia gravis, sudden pyemia, neuromuscular sclerosis, ankylosing spondylitis, neuro-type, chronic myelopathy including chronic myelopathy, chronic myelopathy, Pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, schizophrenia, scleroderma, xerophthalmia, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, Wegener's granuloma.

10. A kit consisting of the following individual packages:

(a) an effective amount of a compound of the formula (I)^*) The compounds shown and/or their pharmaceutically usable derivatives, solvates, salts, hydrates and stereoisomers, including mixtures thereof in various ratios, and

(b) an effective amount of another pharmaceutically active ingredient.

11. A pharmaceutical composition comprising at least one compound of the general formula (I) according to any one of claims 1 to 5^*) A compound is provided.

12. The pharmaceutical composition of claim 11, wherein formula (I)^*) The compound is used in combination with at least one other drug for the treatment of inflammatory or immune diseases.

13. The pharmaceutical composition of claim 12, wherein formula (I)^*) The compound is used in combination with at least one additional immunomodulatory agent.

14. A process for preparing the compounds of the general formula (I) as claimed in claims 1 to 5^*) Chemical combinationA process comprising reacting a compound of formula (II)^*) A compound of the formula, wherein X₁，X₂，X₅，R¹，R²，R⁴T, U, Z and U are as defined in claim 1, V is H or Y,

with compounds D^*Reaction:

wherein R is⁵G and r are as defined in claim 1.

15. A process for preparing the compounds of the general formula (I) as claimed in claims 1 to 5^*) A process for the preparation of compounds of the general formula (I)^*) A compound of formula (I) wherein T is S, is oxidized to form ^*) A compound of the formula, wherein T is SO₂。