CN104211692B

CN104211692B - Derivative as Ou Ruola kinase inhibitor

Info

Publication number: CN104211692B
Application number: CN201410245663.XA
Authority: CN
Inventors: 刘兵; 张英俊; 张吉泉; 李燕平; 杨学绮; 张健存; 郑常春
Original assignee: Guangdong HEC Pharmaceutical
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2013-06-04
Filing date: 2014-06-04
Publication date: 2019-05-24
Anticipated expiration: 2034-06-04
Also published as: CN104211692A

Abstract

The present invention relates to for inhibiting the substituted pyrazole derivatives as shown in formula (I) or formula (Ia) of Ou Ruola kinases, or its stereoisomer, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, with contain pharmaceutical composition of these compounds as active constituent, and the compound and its pharmaceutical composition are prepared for protecting, and are handled, treatment or mitigate patient's proliferative diseases drug purposes.

Description

Derivatives as inhibitors of aurora kinase

Technical Field

The present invention relates to certain novel compounds useful for the treatment of certain diseases, particularly proliferative diseases such as cancer, and for the preparation of medicaments useful for the treatment of proliferative diseases, processes for their preparation, and pharmaceutical compositions containing them as active ingredient.

Background

Cancer and other hyperproliferative diseases are characterized by uncontrolled cellular proliferation. Loss of normal regulation of cell proliferation usually occurs due to damage to genes that regulate cellular pathways that progress through the cell cycle.

Studies have shown that in eukaryotic cells, an ordered cascade of protein phosphorylation controls the cell cycle. Several families of proteases have now been identified which play an important role in this cascade. The activity of many of the above kinases is significantly increased in human tumors compared to normal tissues. This may be due to increased levels of protein expression or to changes in the expression of co-activator or repressor proteins.

The first identified and extensively studied cell cycle regulators are Cyclin Dependent Kinases (CDKs), the activity of specific CDKs at specific times being essential for initiating and assisting the progression through the cell cycle. For example, the CDK4 protein appears to control entry into the cell cycle by phosphorylating the retinoblastoma oncogene product pRb (G0-G1-S switch). This stimulation of the release of the transcription factor E2F from pRb, followed by the action of E2F, increases the transcription of genes necessary for entry into S phase. CDK4 stimulates its catalytic activity by binding to the companion protein cyclin D. One of the first evidences of a direct link between cancer and cells was the observation that the cyclin D1 gene was amplified and that cyclin D concentrations were increased in many human tumors (see Science,1996,274,1672-1677, Sherr et al). Other studies (see Nature Medicine,1997,3,231-234, Loda et al) have also demonstrated that down-regulators of CDK function are often down-regulated or absent in human tumors, leading to inappropriate activation of these kinases.

Recently protein kinases have been identified which are structurally distinct from the CDK family, which have a key role in regulating the cell cycle and appear to be important for tumor formation. These kinases include the newly identified human homologs of Drosophila aurora (Drosophila aurora) and Saccharomyces cerevisiae (S.cerevisiae) Ipl1 proteins. The three human homologues of these genes, orula-A, orula-B and orula-C (Aurora-A, Aurora-B and Aurora-C), encode serine-threonine protein kinases that regulate the Cell cycle (see Trends in Cell Biology,2001,11,49-54, Adams et al). They show a peak in expression and kinase activity at G2 and mitotic stages, and several observations suggest that human orula protein is associated with cancer. The Euler-A gene is located on chromosome 20q13, a region that is frequently amplified in human tumors. It was found that while Eulerian-A was probably the major target gene for this amplification, Eulerian-A DNA was amplified and mRNA was overexpressed in more than 50% of primary human colorectal cancers. There was a significant increase in the level of orula-a protein in these tumors compared to adjacent normal tissue. Studies (see Nature Genetics,1998,20,189-93, Zhou et al) have demonstrated that human overexpression of Eulera-A results in a significant increase in the number of centrosomes, a known process of carcinogenesis. A further study (see Chromsa, 2001,110,65-74, Adams et al) demonstrated that the expression of Eulera-B was also significantly increased in tumor cells compared to normal cells.

Existing studies have demonstrated that: treatment of human tumor cell lines with antisense oligonucleotides abrogates the expression and function of orula-a (WO1997022702 and WO1999037788), resulting in cell cycle arrest and anti-proliferative effects in these tumor cells. In addition, small molecule inhibitors of Eulerian-A and Eulerian-B have been shown to have antiproliferative effects in human tumor cells, with siRNA treatment alone selectively eliminating Eulerian-B expression. This suggests that inhibition of the function of orula-a and orula-B will produce an antiproliferative effect, which is useful in the treatment of human tumors and other hyperproliferative diseases. Furthermore, inhibition of Aurora kinase has significant advantages as a treatment for these diseases compared to targeting the signaling pathway upstream of the cell cycle. Since the cell cycle is most downstream of all these different signaling activities, cell cycle directed therapies will be effective on all proliferating tumor cells, while approaches directed to specific signaling molecules such as epidermal growth factor receptors will only be effective on tumor cells expressing these receptors.

A number of pyrimidine derivatives are disclosed for use in inhibiting orula kinase, WO2002057259, WO2002059111, WO2004000833, WO2008115973 describe certain substituted pyrimidine compounds, but there are still more compounds with orula kinase inhibitory properties.

Summary of the invention

The present invention provides a novel class of derivatives having an inhibitory effect on aurora kinase, in particular, aurora-A kinase and/or aurora-B kinase. The compound of the present invention or its stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or its prodrug, and pharmaceutical composition containing the above compound can be used for treating proliferative diseases. In particular, the compounds of the invention are useful in the treatment of proliferative diseases known for their Aurora kinase action, such as cancer, whether in the form of solid or haematological tumours, in particular, such as colorectal, gastric, breast, lung, liver, prostate, pancreatic, thyroid, bladder, renal, brain, neck, central nervous system, glioblastoma, myeloproliferative disorders, atherosclerosis, pulmonary fibrosis, leukaemia, lymphoid, rheumatic diseases, chronic inflammation, cryoglobulinemia, non-lymphoid reticulum, mucoid deposition disease, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukaemia, primary macroglobulinemia, hemiarthropathy, monocytic leukaemia, primary macroglobulinemia purpura, secondary benign monoclonal gammopathy, an osteolytic lesion, myeloma, acute lymphocytic leukemia, lymphoblastoma, partial non-hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid cancer, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis of the liver, ovarian cancer, cholecystitis, head and neck squamous carcinoma, digestive tract malignancy, non-small cell lung cancer, cervical cancer, testicular tumor, bladder cancer or myeloma.

The invention provides a substituted pyrazole derivative which has a structure shown as a formula (I) or a formula (Ia) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof of the structure shown as the formula (I) or the formula (Ia),

wherein:

q is-NH-, or-O-

R¹Is morpholinyl, C_5-12Bridged bicyclic radical, C_5-12Bridged bicyclic radical, C_5-12Spiro bicyclic radical, C_5-12Spiro heterobicyclic radical, C_5-12Condensed bicyclic group, or C_5-12A fused heterobicyclic group;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-6An alkyl group;

or R²And R³Together with the carbon atom to which they are attached form a five-membered heterocyclic ring; wherein the five-membered heterocyclic ring may be substituted by R⁷NH-C(＝O)-，C_6-10Aryl radical C_1-6Alkyl, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

wherein R is⁴Is H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_1-9Heteroaryl, or C_6-10An aryl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_1-9Heteroaryl or C_6-10An aryl group; or, R⁴And R^4aTogether with the N atom to which they are attached form C_2-9A heterocyclic group;

each R⁵And R^5aIndependently is H, or C_3-6A cycloalkyl group; or, R⁵And R^5aTogether with the carbon atom to which they are attached form C_3-6A carbocyclic group;

R⁶is C_1-6Alkyl or C_6-10An aryl group;

wherein R is⁷Is C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl radical, C_1-9Heteroaryl, or C_6-10An aryl group;

wherein each R is⁸And R^8aIndependently of one another is hydrogen, C_6-10Aryl radical, C_1-6Alkoxy, or C_3-6A cycloalkyl group; or, R⁸And R^8aTogether with the carbon atom to which they are attached form C_3-6A carbocyclic group;

1) wherein, when Q is NH, and R¹Is morpholinyl, R³Is H, or C_1-6When the alkyl group is used, the alkyl group,

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl, or C_1-9A heteroaryl group; or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

R⁵and R^5aTogether with the carbon atom to which it is attached form cyclohexyl or cyclopentyl;

R⁶is C_1-4An alkyl group;

wherein, R is¹，R²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe bridged heterobicyclic group, bridged bicyclic group, fused heterobicyclic group, spiro bicyclic group, spiro heterobicyclic group, carbocyclic group, alkyl group, cycloalkyl group, cycloalkylalkyl group, arylalkyl group, heteroarylalkyl group, heteroaryl group, aryl group, heterocyclic group, carbocyclic group and alkoxy group described in (1) may be independently substituted with F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

In some of these embodiments, the first and second light sources are,

q is-NH-;

R¹is morpholinyl, or the subformula:

wherein each Q¹And X³Independently is N, or CH;

each X¹，X²，X⁴，X⁵，X⁶And X⁷Independently is-CH₂-，-O-，-NR^9a-, or-S-;

each of q, m, p, r and s is independently 0,1, 2,3, or 4;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

or R²And R³Together with the carbon atom to which they are attached form the following subformula:

wherein, R is²And R³The sub-formula formed together with the carbon atom to which it is attached may be represented by R⁷NH-C(＝O)-，C_6-10Aryl radical C_1-6Alkyl, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

wherein R is⁴Is H, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl, or C_6-10An aryl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl, or C_6-10An aryl group; or, R⁴And R^4aTogether with the N atom to which they are attached form a 5-6 membered heterocyclyl;

R⁶is C_1-4Alkyl or C_6-10An aryl group;

wherein R is⁷Is C_3-6Cycloalkyl radicals, or C_6-10Aryl radical C_1-4An alkyl group;

wherein each R is⁸And R^8aIndependently of one another is hydrogen, C_1-4Alkoxy radical, C_6-10Aryl, or C_3-6A cycloalkyl group; or, R⁸And R^8aTogether with the carbon atom to which they are attached form C_3-6A carbocyclic group;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, carbocyclyl, cycloalkylalkyl group recited in (1), and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently;

1) wherein, when Q is NH, and R¹Is morpholinyl, R³Is H, or C_1-4When the alkyl group is used, the alkyl group,

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

R^4ais C_1-6Alkyl, or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

R⁶is C_1-4An alkyl group.

In yet other embodiments, the method may further comprise,

R¹is morpholinyl, or the subformula:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

orWherein, R is²And R³The sub-formula formed together with the carbon atom to which it is attached may be represented by R⁷NH-C (═ O) -, phenylmethylene, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

wherein R is⁴Is H, methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, 2-fluoro-phenyl or 3-fluoro-phenyl;

R^4ais methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, 2-fluoro-phenyl or 3-fluoro-phenyl; or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

each R⁵And R^5aIndependently is H, cyclopropyl, cyclopentyl, or cyclohexyl; or, R⁵And R^5aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl group;

R⁶is methyl, ethyl, propyl, isopropyl, 2-fluoro-phenyl or 3-fluoro-phenyl;

wherein R is⁷Is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein each R is⁸And R^8aIndependently hydrogen, methoxy, ethoxy, phenyl, cyclopentyl, cyclohexyl, 2-fluoro-phenyl or 3-fluoro-phenyl; or, R⁸And R^8aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclopentyl, cyclobutyl, or cyclohexyl group;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe methyl group, ethyl group, propyl group, isopropyl group, 1-ethyl-propyl group, cyclopropyl group, cyclopentyl group, cyclobutyl group, cyclohexyl group, cyclopropylmethylene group, phenylmethylene group, heterocyclic group, phenyl group and the R group¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently;

1) wherein, when Q is NH, and R¹Is morpholinyl, R³When H, methyl, ethyl, or propyl,

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

R^4ais methyl, ethyl, isopropyl, butyl, 1-ethyl-propyl or pentyl, or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

R⁵and R^5aTogether with the carbon atom to which it is attached form a cyclopentyl or cyclohexyl group;

R⁶is methyl, ethyl, isopropyl, propyl or butyl.

In some embodiments, the present invention provides a substituted pyrazole derivative, which is a substituted pyrazole derivative represented by formula (II) or formula (IIa), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof,

wherein:

R¹is of the sub-structure:

wherein each Q¹And X³Independently is N, or CH;

each of q, m, p, r and s is independently 0,1, 2,3, or 4;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

R⁶is C_1-4Alkyl or C_6-10An aryl group;

wherein each R is⁷Independently is C_3-6Cycloalkyl radicals, or C_6-10Aryl radical C_1-4An alkyl group;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe alkyl, cycloalkyl, aryl, heterocyclic, cycloalkylalkyl, arylalkyl, carbocyclyl and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

In some of these examples, R is¹Is of the sub-structure:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

wherein, R is²And R³The sub-formula formed together with the carbon atom to which it is attached may be represented by R⁷NH-C (═ O) -, phenylmethylene, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

each R⁵And R^5aIndependently is H, cyclopropyl, cyclopentyl, or cyclohexyl; or, R⁵And R^5aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group;

R⁶is methyl, ethyl, propyl, isopropyl, 2-fluoro-phenyl or 3-fluoro-phenyl;

wherein R is⁷Is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein each R is⁸And R^8aIndependently hydrogen, methoxy, ethoxy, phenyl, cyclopentyl, cyclohexyl, 2-fluoro-phenyl or 3-fluoro-phenyl; or, R⁸And R^8aTogether with the carbon atom to which it is attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

In some embodiments, the present invention provides a substituted pyrazole derivative represented by formula (IIb) or formula (IIab), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,

wherein:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

wherein R is⁴Is C_2-6An alkyl group;

R⁵and R^5aTogether with the carbon atom to which they are attached form a 5-6 membered carbocyclic group;

R⁶is C_1-4An alkyl group;

In some of these embodiments, the first and second light sources are,

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

R^4ais methyl, ethyl, isopropyl, butyl, 1-ethyl-propyl or pentyl, or, R⁴And R^4aAnd itThe attached N atoms together form the following subformula:

R⁶is methyl, ethyl, isopropyl, propyl or butyl;

R³is H, methyl, ethyl, or propyl;

wherein each R is⁷Independently is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein each R is⁸And R^8aIndependently hydrogen, methoxy, ethoxy, phenyl, cyclopentyl or cyclohexyl; or, R⁸And R^8aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe methyl group, ethyl group, propyl group, isopropyl group, butyl group, 1-ethyl-propyl group, pentyl group, cyclopropyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethylene group as described in (1),carbocyclyl, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

In one aspect, the present invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or (Ia), formula (II) or (IIa) of the present invention or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent that is at least one of a chemotherapeutic agent, an antiproliferative agent, an immunosuppressive agent, an immunostimulatory agent, an agent useful for treating atherosclerosis, and an agent useful for treating pulmonary fibrosis.

In some embodiments, the pharmaceutical composition, wherein the additional therapeutic agent is chlorambucil (chlomambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busufan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozotocin), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), oxaliplatin (oxerlotinin), dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methtropine), fluorouracil (fluouracil), fluuridine (fluazurin), paclitaxel (ritoridine), paclitaxel (rituximab), paclitaxel (rituximab), paclitaxel (morphine), paclitaxel (morphine (gent), paclitaxel (gent (morphine (gent), paclitaxel (gent (morphine (gent), paclitaxel (gent (morphine (gent), paclitaxel (gent), or (gent), paclitaxel), dox (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent), or (gent.

In another aspect, the invention also provides a compound of formula (I) or (Ia), formula (II) or (IIa) or a pharmaceutical composition according to the invention for use in protecting, managing, treating or ameliorating a condition mediated by aurora kinase in a subject.

In some embodiments, the use of the invention, wherein the aurora kinase is an aurora-a kinase or an aurora-B kinase.

In one aspect, the invention also provides a use of a compound of formula (I) or (Ia), formula (II) or (IIa) or a pharmaceutical composition according to the invention for the preparation of a medicament for the prevention, treatment or alleviation of a proliferative disease in a patient.

In some embodiments, medicaments containing compounds of the invention are useful for the treatment of proliferative diseases, such as, inter alia, colorectal, gastric, breast, lung, liver, prostate, pancreatic, thyroid, bladder, kidney, brain, neck, central nervous system, glioblastoma, or myeloproliferative disorders, atherosclerosis, pulmonary fibrosis, leukemia, lymphoma, rheumatic diseases, chronic inflammation, cryoglobulinemia, non-lymphoid reticulosis, papular mucinous deposition, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, semimolecularly, monocytic leukemia, primary macroglobulinemic purpura, secondary benign monoclonal gammopathy, osteolytic lesions, myeloma, acute lymphocytic leukemia, lymphoblastoma, partial non-hodgkin's lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, hodgkin's lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumors, islet cell tumors, medullary thyroid cancer, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis of the liver, ovarian cancer, cholecystitis, head and neck squamous carcinoma, digestive tract malignancies, non-small cell lung cancer, cervical cancer, testicular tumors, bladder cancer or myeloma.

The foregoing has outlined only certain aspects of the present invention but is not limited in that these and other aspects will be more fully described in the following detailed description.

Detailed description of the invention

Definitions and general terms

The invention will be described in detail in the literature corresponding to the identified embodiments, and the examples are accompanied by the graphic illustrations of structural formulae and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the present invention as defined by the appended claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein which can be used in the practice of the present invention. The present invention is in no way limited to the description of methods and materials. There are many documents and similar materials that may be used to distinguish or contradict the present application, including, but in no way limited to, the definition of terms, their usage, the techniques described, or the scope as controlled by the present application.

The following definitions shall apply unless otherwise indicated. For the purposes of the present invention, the chemical elements are described in the periodic table of elements, CAS version and handbook of chemicals, 75,^thed, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausaltio: 1999, and "March's Advanced Organic Chemistry," by Michael B.Smith and Jerry March, John Wiley Chemistry&Sons, New York, 2007, all of which are hereby incorporated by reference.

Like the inventionAs described, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the present invention within the examples. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally," whether preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to: f, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The terms "halogen", "halogen atom" or "halogen atom" as used herein include fluorine, chlorine, bromine, iodine.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1 to 10 carbon atoms, in other embodiments, the alkyl group contains 1 to 8 carbon atoms, in other embodiments, the alkyl group contains 1 to 6 carbon atoms, and in yet other embodiments, the alkyl group contains 1 to 4 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂)，Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) Pentyl group (-CH)₂CH₂CH₂CH₂CH₃) 1-Ethyl-propyl (-CH (CH)₂CH₃)₂) And so on. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains.

The term "alkoxy", as used herein, relates to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom. Such examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.

The term "haloalkyl" or "haloalkoxy" denotes a situation where an alkyl or alkoxy group may be substituted by one or more of the same or different halogen atoms. Wherein alkyl and alkoxy groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, chloromethyl, chloromethoxy and the like.

The terms "hydroxyalkyl", "hydroxy-substituted alkyl" or "hydroxyalkoxy" refer to the situation where an alkyl or alkoxy group may be substituted with one or more hydroxy groups. Wherein alkyl and alkoxy groups have the meaning as described herein, examples include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, hydroxypropyl, 1, 2-dihydroxypropyl, hydroxymethoxy, 1-hydroxyethoxy, and the like.

The term "alkoxyalkyl" denotes a condition in which an alkyl group may be substituted with one or more alkoxy groups. Wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, methoxymethyl, ethoxyethyl, and the like.

The term "aryl" used alone or as a majority of "aralkyl", "aralkoxy", or "aryloxyalkyl" refers to monocyclic, bicyclic, and tricyclic carbon ring systems containing a total of 6-14 ring members, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 ring members, andonly one attachment point is attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl, and anthracene. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The term "arylalkyl" refers to a condition where an alkyl group may be substituted with one or more aryl groups. Wherein the alkyl group and the aryl group have the meanings as described herein, and such examples include, but are not limited to, phenylmethyl, phenylethyl, and the like.

The term "heteroaryl" may be used alone or as part of a "heteroarylalkyl" or "heteroarylalkoxy" and denotes monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings and only one attachment point is attached to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

In other embodiments, the heteroaromatic ring includes, but is not limited to, the following monocyclic rings: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 4-methylisoxazol-5-yl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, pyrimidin-5-yl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group and 5-triazolyl group), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), and isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), and the like.

The term "heteroarylalkyl" denotes a moiety wherein an alkyl group may be substituted with one or more heteroaryl groups. Wherein alkyl groups and heteroaryl groups have the meaning as described herein, examples include, but are not limited to, imidazolylmethyl, thiazolylethyl, and the like.

The terms "carbocyclyl" or "cyclic aliphatic", "carbocycle", "cycloalkyl" refer to a mono-or polyvalent, non-aromatic, saturated or partially unsaturated ring, and contain no heteroatoms, including monocyclic rings of 3 to 12 carbon atoms or bicyclic or tricyclic rings of 7 to 12 carbon atoms. The carbocycle having 7 to 12 atoms may be bicyclo [4,5]]，[5,5]，[5,6]Or [6,6 ]]The system, the carbocycle having 9 or 10 atoms at the same time, may be bicyclo [5,6 ]]Or [6,6 ]]And (4) preparing the system. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl. Examples of cyclic aliphatic groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like. And said "carbocyclyl" or "cycloaliphatic"The "carbocycle" and "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The term "cycloalkylalkyl" denotes a situation where an alkyl group may be substituted by one or more cycloalkyl groups. Wherein the alkyl group and cycloalkyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclohexylethyl, cyclohexylmethyl and the like.

The terms "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" are used interchangeably herein and all refer to monocyclic, bicyclic, or tricyclic ring systems in which one or more atoms in the ring is independently optionally substituted with a heteroatom, the ring may be fully saturated or contain one or more degrees of unsaturation, but is by no means aromatic, having only one point of attachment to another molecule. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some of the examples are "heterocyclyl", "heterocycle", "heteroalicyclic" or "heterocyclic" groups which are 3-7 membered rings of a monocyclic ring (1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted with one or more oxygen atoms to give a ring system like SO, SO₂，PO，PO₂When said ring is a three-membered ring, in which there is only one heteroatom), or 7-to 10-membered bicyclic rings (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give the group like SO, SO₂，PO，PO₂The group of (1).

"heterocyclyl" may be a carbon or heteroatom radical. "Heterocyclyl" also includes heterocyclic groups fused to saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranylTetrahydrothiopyranyl, piperidinyl, thialkyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepinyl, oxepinyl, thietanyl, N-morpholinyl, 2-morpholinyl, 3-morpholinyl, thiomorpholinyl, N-piperazinyl, 2-piperazinyl, 3-piperazinyl, homopiperazinyl, 4-methoxy-piperidin-1-yl, 1,2,3, 6-tetrahydropyridin-1-yl, oxazepinyl, diazepinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1, 3-dioxolyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, quinolizinyl and N-pyridylurea. And said heterocyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The terms "fused bicyclic", "fused ring", "fused bicyclic group" or "fused ring group" mean a fused ring system, saturated or unsaturated, and refers to a non-aromatic bicyclic ring system, at least one of the rings being non-aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). Each ring in the fused bicyclic ring is either a carbocyclic or a heteroalicyclic, examples of which include, but are not limited to, hexahydro-furo [3,2-b ]]Furyl, 2,3,3a,4,7,7 a-hexahydro-1H-indenyl, 7-azabicyclo [2.2.1] groups]Heptylalkyl, fused bicyclo [3.3.0]Octyl, fused bicyclo [3.1.0]Hexane, 1,2,3,4,4a,5,8,8 a-octahydronaphthyl, which are all contained within a fused bicyclic ring system. And said fused bicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo(═ O), acetyl, trifluoromethyl, nitro, or the like.

The term "fused heterobicyclic group" refers to a saturated or unsaturated fused ring system, involving a non-aromatic bicyclic ring system, at least one of the rings being non-aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give a structure like SO, SO₂，PO，PO₂Examples of such include, but are not limited to hexahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrolyl, 3-azabicyclo [3.3.0]Octyl 3-methyl-3, 7-diazabicyclo [3.3.0]Octyl, 8-azabicyclo [4.3.0 ] groups]Nonanyl, 8-azabicyclo [4.3.0]Nonane 3-yl, 3-azabicyclo [4.3.0]Nonan-3-yl, 1, 5-dioxo-8-azabicyclo [4.3.0]Nonyl, (1R,6S) -2, 5-dioxo-8-azabicyclo [4.3.0]Nonyl, (1R,6R) -2, 5-dioxo-8-azabicyclo [4.3.0]Nonanyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolinyl, (1S,5S) -1-hydroxy-3-azabicyclo [3.1.0]Hexane radical, (1R,5S) -1-hydroxy-3-azabicyclo [3.1.0]Hexane radical, (1R,5S) -1-N, N-dimethylamino-3-azabicyclo [3.1.0]Hexane radical, (1S,5R,6R) -1-methyl-6-ol-3-azabicyclo [3.2.0]Heptenyl, 3-nitrogen-7-oxabicyclo [3.3.0]Octyl 3, 7-diazabicyclo [3.3.0 ]]Octyl, 2, 6-diazabicyclo [3.3.0 ]]Octyl, 2, 7-diazabicyclo [3.3.0 ]]Octyl 3-ethyl-3, 7-diazabicyclo [3.3.0]Octyl, 2, 7-diazabicyclo [3.3.0 ]]Octyl, 7-acetyl-2, 7-diazabicyclo [3.3.0]Octyl, 2, 8-diazabicyclo [4.3.0 ]]Nonanyl, 3, 8-diazabicyclo [4.3.0]Nonanyl, 2-methyl-2, 8-diazabicyclo [4.3.0]Nonanyl, 3-oxo-8-azabicyclo [4.3.0]Nonanyl, 2-oxo-8-azabicyclo [4.3.0]Nonanyl, 2, 8-diaza-5-oxabicyclo [4.3.0]Nonyl, (1S,6R) -2-methyl-2, 8-diaza-5-oxabicyclo [4.3.0]Nonanyl, 3-ethyl-3, 9-diazabicyclo [4.3.0]Nonanyl, 4, 9-diazabicyclo [4.3 ].0]Nonanyl, 2, 9-diazabicyclo [4.3.0]Nonanyl, 3-methyl-3, 9-diazabicyclo [4.3.0]Nonanyl, 3-ethyl-3, 7-diazabicyclo [4.3.0]Nonanyl, 3-methyl-3, 7-diazabicyclo [4.3.0]Nonanyl, 2-ethyl-2, 8-diazabicyclo [4.3.0]Nonanyl, 2-oxo-3-oxo-8-azabicyclo [4.3.0]Nonanyl, 3-oxo-2, 4, 8-triazabicyclo [4.3.0]Nonanyl, 3-oxo-4-oxo-2, 8-diazabicyclo [4.3.0]Nonanyl, 3-oxo-2, 8-diazabicyclo [4.3.0]Nonanyl, 3, 8-diazabicyclo [4.3.0]Nonanyl, 8-methyl-2, 8-diazabicyclo [4.3.0]Nonanyl, 3, 7-diazabicyclo [4.3.0]Nonanyl, 3, 9-diazabicyclo [4.3.0]Nonanyl, 3-oxo-8-azabicyclo [4.3.0]Nonanyl, 3-thio-8-azabicyclo [4.3.0]Nonanyl, 9-methyl-3, 9-diazabicyclo [4.3.0]Nonanyl, 7-methyl-3, 7-diazabicyclo [4.3.0]Nonanyl, 9-ethyl-3, 9-diazabicyclo [4.3.0]Nonanyl, 7-ethyl-3, 7-diazabicyclo [4.3.0]Nonanyl, 8-ethyl-2, 8-diazabicyclo [4.3.0]Nonanyl, 5, 6-dihydro-4H-pyrrolo [3, 4-c)]Isoxazolyl, 3-ethyl- [1,2, 4]]Triazole [4,3-a ]]And is piperidinyl, [1,2, 4]]Triazole [4,3-a ]]Piperidinyl, 3-methyl-isoxazolo [4, 3-c)]Piperidinyl, 3-methyl-5, 6-dihydro-4H-pyrrolo [3, 4-c)]Isoxazolyl, 2-methyl-4, 5,6, 7-tetrahydro-1H-imidazo [4,5-c]Pyridyl, 2-methyl-4, 5,6, 7-tetrahydrooxazolo [4, 5-c)]Pyridyl, 2-methyl-4, 5,6, 7-tetrahydro-1H-thiazolo [4,5-c]Pyridyl, isoxazolo [4,3-c]Piperidinyl, 4,5,6, 7-tetrahydroisooxazolo [3, 4-c)]Pyridyl, [1,2, 4] or a salt thereof]Triazole [4,3-a ]]Piperazinyl, 3-trifluoromethyl- [1,2, 4%]Triazole [4,3-a ]]Piperazinyl, 3-methyl- [1,2, 4]]Triazole [4,3-a ]]Piperazinyl, 2-oxo-3-oxo-8-azabicyclo [4.3.0]Nonanyl, 1, 3-dimethyl-4, 5,6, 7-tetrahydro-1H-pyrazolo [4,3-c]Pyridin-yl, 2-oxo-7-azabicyclo [4.4.0]Decyl, 1, 5-dioxo-9-azabicyclo [4.4.0]Decyl, 2, 3-dimethyl-4, 5,6, 7-tetrahydro-2H-pyrazolo [4,3-c]Pyridin-yl, 3-azabicyclo [4.4.0]Decyl, 2, 7-diazanaphthyl or 2-oxo-8-azabicyclo [4.4.0]Decyl, and the like.

The term "bridged heterobicyclic group" denotes a saturated or unsaturated bridged ring system, involving a bicyclic system that is not aromatic. Such a system may beTo contain independent or conjugated unsaturation but whose core structure does not contain aromatic or heteroaromatic rings (although aromatics may be substituents thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give a structure like SO, SO₂，PO，PO₂Examples of such include, but are not limited to, 2-oxo-5-azabicyclo [2.2.1]]Heptylalkyl, 7-oxo-2-azabicyclo [2.2.1]Heptylalkyl, 2-oxo-5-azabicyclo [2.2.2]Octyl, 8-oxo-3-azabicyclo [3.2.1]Octyl, 2-thio-5-azabicyclo [2.2.1]Heptadecyl, and the like. And said bridged heterobicyclic group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The term "bridged bicyclic group" denotes a saturated or unsaturated bridged ring system, involving a bicyclic system that is not aromatic. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or aromatic rings (although aromatics may be substituents thereon). Wherein each ring system comprises 3-7 membered rings, examples of which include, but are not limited to, bicyclo [2.2.1]Heptylalkyl, 2-methyl-heterobicyclo [2.2.1]Heptadecyl, and the like. And said bridged bicyclic group can be substituted or unsubstituted, wherein the substituents can be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The terms "spirocyclic", "spiro", "spirobicyclic group", "spirobicyclic ring" indicate that one ring originates from a particular cyclic carbon on the other ring. For example, as depicted in formula a below, a saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas ring A and ring B are shared in two saturated ring systemsSharing a single carbon atom, are referred to as "spiro rings". Each ring within the spiro ring is either a carbocyclic or a heteroalicyclic. Examples of such include, but are not limited to, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, spiro [2.4 ]]Heptylalkyl, spiro [4.4 ]]Nonanyl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, and the like. And said spirobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

The term "spiroheterobicyclic group" means that one ring originates from a specific cyclic carbon on the other ring. For example, as depicted in formula a above, a saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas ring a and ring B share a carbon atom in two saturated ring systems, is referred to as a "spiro ring". And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, whereby S or P is optionally substituted by one or more oxygen atoms to give a structure like SO, SO₂，PO，PO₂Examples of such include, but are not limited to, 4-azaspiro [2.4 ]]Heptane-5-yl, 4-oxaspiro [2.4 ]]Heptane-5-yl, 5-azaspiro [2.4 ]]Heptane-5-yl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, 2-azaspiro [4.5 ]]Decyl, 2-azaspiro [3.3]Heptylalkyl, 2-azaspiro [4.4]Nonanyl, 2-methyl-2, 6-diazaspiro [4.5 ]]Decyl, and the like. And said spiroheterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl, nitro or the like.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to denote the absolute configuration of the chiral center of the molecule. The prefix d, l or (+), (-) is used to designate the sign of the plane-polarized light rotation of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.

The term "tautomer" or "tautomeric form" means that isomers of different energies may be converted to one another by a lower energy barrier. Examples of such include, but are not limited to, proton tautomers (i.e., proton transmutations) including interconversion by proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include recombinant interconversion of some of the bonding electrons.

The "hydrate" of the present invention means an association of solvent molecules with water.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

By "ester" herein is meant a compound of formula (I) containing a hydroxyl group which forms an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolysed in the human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compound of formula (I) containing a hydroxy group includes, but is not limited to, phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, benzoylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl, etc.

"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

The compounds may exist in a number of different geometric isomers and tautomers and the compounds of formula (I) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is apparent that all other forms are encompassed in formula (I).

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14of the A.C.S.Sympossium Series, Edward B.Roche, ed., BioversibleCarriers in Drug Design, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrugs: Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al,Prodrugs ofPhosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51，2328-2345。

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, and barbiturateSulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

The term "protecting group" or "Pg" refers to a substituent that when reacted with another functional group, is typically used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrickand J.C.Boylan,1988-1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, indicates that different carriers can be used In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Substances which may serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The compositions of the invention may be administered orally, by injection, topically, buccally, or via an implantable kit. The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial (luminal), intrasternal, intramembranous, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferred compositions are administered orally, intraperitoneally or intravenously. The compositions of the invention may be injected in sterile form as aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing, wetting and suspending agents.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral use in tablets, carriers generally include lactose and corn starch. Lubricating agents, such as magnesium stearate, are typically added. For oral administration in capsules, suitable diluents include lactose and dried corn starch. When the oral administration is an aqueous suspension, the active ingredient thereof consists of an emulsifying agent and a suspending agent. Certain sweetening, flavoring or coloring agents may also be added if such dosage forms are desired.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain conventional inert diluents, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, fats and oils (in particular, cottonseed, groundnut, corn, microorganisms, olive, castor, and sesame oils), glycerol, 2-tetrahydrofuryl alcohol, polyethylene glycols, sorbitan fatty acid esters, and mixtures thereof. Besides inert diluents, the oral compositions can also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening, flavoring, and perfuming agents.

Injectables, such as sterile injectable solutions or oleaginous suspensions, may be prepared according to the known art using appropriate dispersing, wetting and suspending agents in the formulation. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Acceptable excipients and solvents may be water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, nonvolatile oils are conventionally employed as a solvent or suspending medium. Any bland non-volatile oil for this purpose may comprise synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The injectable formulations can be sterile, e.g., filtered through a bacterial-defense filter, or have incorporated therein a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of the compounds of the invention, it is generally necessary to slow the absorption of the compounds by subcutaneous or intramuscular injection. This allows the use of liquid suspensions to solve the problem of poor water solubility of crystalline or amorphous materials. The absorption rate of a compound depends on its dissolution rate, which in turn depends on the grain size and crystal shape. In addition, delayed absorption of the compound for administration by injection may be accomplished by dissolving or dispersing the compound in an oily vehicle.

The depot form of the injection is accomplished by a microcapsule matrix of a biodegradable polymer, such as a polylactic-polyglycolide-forming compound. The controlled release rate of the compound depends on the rate at which the compound forms a polymer and the nature of the particular polymer. Other biodegradable polymers include poly (n-esters) and poly (anhydrides). Injectable depot forms can also be prepared by embedding the compounds in liposomes or microemulsions which are compatible with body tissues.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or fillers or a) fillers such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary amines, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, these dosage forms may contain buffering agents.

Solid compositions of a similar type may be filled with soft or hard capsules filled with fillers, lactose and high molecular weight polyethylene glycols and the like. Solid dosage forms like tablets, dragees, capsules, pills and granules can be prepared by coating, encrustation such as enteric coating and other well known coating methods on pharmaceutical preparations. They may optionally contain opacifying agents or, preferably, release the only active ingredient in the composition in a certain part of the intestinal tract, optionally, in a delayed manner. For example, the implant composition may include polymeric materials and waxes.

The active compound may be formulated in a microencapsulated form with one or more of the excipients described herein. Solid dosage forms like tablets, troches, capsules, pills and granules can be coated or shelled, such as enteric coatings, controlled release coatings and other well-known pharmaceutical formulation methods. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, as a general matter of application, additional substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. For capsules, tablets and pills, these dosage forms may contain buffering agents. They may optionally contain a sedative or, preferably, release the only active ingredient in the composition in any delayed manner in a certain part of the intestinal tract. Applicable implant compositions can include, but are not limited to, polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or necessary buffers. Ophthalmic pharmaceutical preparations, ear drops and eye drops are all contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches which provide further advantages in controlling the delivery of the compounds to the body, and such dosage forms may be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can increase the flux of the compound across the skin, controlling its rate by a rate controlling film or dispersing the compound in a polymer matrix or gelatin.

The compounds of the present invention are preferably formulated in unit dosage form to reduce the dosage and uniformity of dosage. It will be appreciated that the total daily usage of a compound or composition of the invention will be determined by the attending physician, within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition, the activity of the specific compound, the specific composition employed, the age, body weight, health, sex and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the specific compound employed, the duration of the treatment, the drug employed in combination or with the specific compound, and other factors well known in the pharmaceutical arts.

Description of the Compounds of the invention

wherein:

q is-NH-, or-O-;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-6An alkyl group;

or R²And R³Together with the carbon atom to which they are attached form a five-membered heterocyclic ring which may be substituted by R⁷NH-C(＝O)-，C_6-10Aryl radical C_1-6Alkyl, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

R⁶is C_1-6Alkyl or C_6-10An aryl group;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-6Alkyl radical, C_1-9Heteroaryl C_1-6Alkyl, or C_1-9A heteroaryl group; or,

R⁴and R^4aTogether with the N atom to which they are attached form the following subformula:

R⁶is C_1-4An alkyl group;

In some of these embodiments, the first and second light sources are,

q is-NH-, or-O-;

R¹is morpholinyl, or the subformula:

wherein each Q¹，X³，X⁸And X⁹Independently is N, or CH;

each of q, m, p, r and s is independently 0,1, 2,3, or 4;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

R⁶is C_1-4Alkyl or C_6-10An aryl group;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

R⁶is C_1-4An alkyl group.

In yet other embodiments, the method may further comprise,

q is-NH-, or-O-;

R¹is morpholinyl, or the subformula:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

wherein R is⁴Is H, methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl;

R^4ais methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, or phenyl; or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

R⁶is methyl, ethyl, propyl, isopropyl or phenyl;

wherein R is⁷Is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein each R is⁸And R^8aIndependently hydrogen, methoxy, ethoxy, phenyl, cyclopentyl or cyclohexyl; or, R⁸And R^8aTogether with the carbon atom to which they are attached form cyclopropyl, cyclopentyl, cyclobutylOr cyclohexyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

R⁶is methyl, ethyl, isopropyl, propyl or butyl.

wherein:

R¹is of the sub-structure:

wherein each Q¹，X³，X⁸And X⁹Independently is N, or CH;

each of q, m, p, r and s is independently 0,1, 2,3, or 4;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

R⁶is C_1-4Alkyl or C_6-10An aryl group;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe alkyl group, cycloalkane, etc. described in (1)Aryl, heterocyclyl, cycloalkylalkyl, arylalkyl, carbocyclyl and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

In some of these examples, R is¹Is of the sub-structure:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

R⁶is methyl, ethyl, propyl, isopropyl or phenyl;

wherein R is⁷Is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein, R is²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aSaid methyl, ethyl, propyl, isopropyl, butyl, 1-ethyl-propyl, pentyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocyclyl, cyclopropyl, cyclopentyl, phenyl, cyclohexyl, phenylmethylene and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

wherein:

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

wherein R is⁴Is C_2-6An alkyl group;

R⁶is C_1-4An alkyl group;

In some of these embodiments, the first and second light sources are,

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

R⁶is methyl, ethyl, isopropyl, propyl or butyl;

R³is H, methyl, ethyl, or propyl;

In some embodiments, the invention provides a substituted pyrazole derivative having a structure represented by formula (III), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein:

R¹is morpholinyl, or the subformula:

wherein each Q¹，X³，X⁸And X⁹Independently is N, or CH;

each of q, m, p, r and s is independently 0,1, 2,3, or 4;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

wherein, R is²And R³The sub-formula formed together with the carbon atom to which it is attached may be represented by R⁷NH-C(＝O)-，C_6-10Aryl radical C_1-4Alkyl, or R⁸R^8aCH-C (═ O) -, monosubstituted or polysubstituted, which are identical or different;

R⁶is C_1-4Alkyl or C_6-10An aryl group;

wherein each R is⁸And R^8aIndependently of one another is hydrogen, C_1-4Alkoxy radical, C_6-10Aryl, or C_3-6A cycloalkyl group; or, R⁸And R^8aTo carbon atoms to which they are attachedTogether form C_3-6A carbocyclic group;

In some of these embodiments, the first and second light sources are,

R¹is morpholinyl, or the subformula:

said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

Wherein, in some embodiments, R is²Is R⁴R^4aN-C(＝O)-NH-，R⁵R^5aCH-C (═ O) -NH-or R⁶O-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

or R²And R³Together with the carbon atom to which they are attachedHas the following sub-structural formula:

each R⁵And R^5aIndependently is H, cyclopropyl, cyclopentyl, or cyclohexyl; or, R⁵And R^5aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclopentyl, or cyclohexyl group;

R⁶is methyl, ethyl, propyl, isopropyl or phenyl;

wherein R is⁷Is cyclopropyl, cyclopentyl, cyclohexyl, or phenylmethylene;

wherein each R is⁸And R^8aIndependently hydrogen, methoxy, ethoxy, phenyl, cyclopentyl or cyclohexyl; or, R⁸And R^8aTogether with the carbon atom to which it is attached form a cyclopropyl, cyclopentyl, or cyclohexyl group;

wherein,said R²，R³，R⁴，R^4a，R⁵，R^5a，R⁶，R⁷，R⁸And R^8aThe methyl, ethyl, propyl, isopropyl, butyl, 1-ethyl-propyl, pentyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, carbocyclyl, cyclopropyl, cyclopentyl, phenyl, cyclohexyl and phenylmethylene mentioned in (1) may be independently substituted by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

In some embodiments, the compounds of formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or formula (III) of the present invention comprise a structure of one of the following:

or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof.

In one aspect, the present invention also provides a pharmaceutical composition comprising at least one compound represented by formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or formula (III) of the present invention or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof.

In another aspect, the invention also provides the use of a compound of formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or formula (III) or a pharmaceutical composition according to the invention for protecting, managing, treating or ameliorating a condition mediated by Eulerian kinase in a subject.

In one aspect, the invention also provides a use of a compound of formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or formula (III) or a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention, treatment, or amelioration of a proliferative disease in a subject.

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts of the compounds of the invention or prodrugs thereof are within the scope of the invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions which must be compatible with chemical or toxicological considerations, in connection with the other ingredients comprising the formulation and the mammal being treated. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic or organic acids such as fumaric acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, phosphoric acid, sulfuric acid, and the like. Pharmaceutically acceptable non-toxic base forming salts include, but are not limited to, inorganic or organic bases such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, lithium and the like.

Compositions, formulations and administration of the compounds of the invention

According to another aspect, a pharmaceutical composition of the invention is characterized by comprising a compound of formula (I) or (Ia), a compound listed in the present invention, or a compound of examples 1-31, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the invention is effective to detectably inhibit protein kinases in a biological sample or patient.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrickand J.C.Boylan, 1988. Annua 1999, Marcel Dekker, New York, taken together with The disclosure of The references herein, suggests that different carriers may be employed In The preparation of pharmaceutically acceptable compositions and their well known methods of preparation. Except insofar as any conventional carrier vehicle is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated by the present invention.

Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; aluminum; alumina; aluminum stearate; lecithin; serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate; salts such as sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The composition of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit. The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial (luminal), intrasternal, intramembranous, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferred compositions are administered orally, intraperitoneally or intravenously. The compositions of the invention may be injected in sterile form as aqueous or oleaginous suspensions. These suspensions may be formulated according to the known art using suitable dispersing, wetting and suspending agents. Sterile injectable preparations can be sterile injectable solutions or suspensions, in the form of non-toxic acceptable diluents or solvents, such as solutions in 1, 3-butanediol. These acceptable excipients and solvents may be water, ringer's solution and isotonic sodium chloride solution. Further, sterile, nonvolatile oils may conventionally be employed as a solvent or suspending medium.

For this purpose, any bland non-volatile oil may be a synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, and pharmaceutical preparations typically used in pharmaceutically acceptable dosage forms include emulsions and suspensions. Other commonly used surfactants, such as tweens, spans and other emulsifiers or enhancers of bioavailability, are commonly used in pharmaceutically acceptable solid, liquid, or other dosage forms, and may be used in the preparation of targeted pharmaceutical formulations.

In addition, the pharmaceutically acceptable compositions of the present invention may be administered rectally in the form of suppositories. These may be prepared by mixing the agent with a suitable non-infusion adjuvant which is solid at room temperature but liquid at the rectal temperature, so as to melt in the rectum and release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, particularly topically, where the therapeutic target is readily achieved in relation to an area or organ, such as an ocular, dermal or lower intestinal tract disorder. Suitable topical formulations can be prepared and applied to these areas or organs.

Rectal suppositories (see above) or suitable enemas can be applied for topical application in the lower intestinal tract. Topical skin patches may also be applied as such. For topical administration, pharmaceutically acceptable compositions may be formulated in a suitable ointment comprising the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration according to the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. In addition, pharmaceutically acceptable compositions can be prepared in a suitable lotion or emulsion comprising the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, span-60 (sorbitan monostearate), tween 60 (polysorbate 60), cetyl esters wax, palmitic alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as isotonic micronised suspensions, pH adjusted sterile saline or other aqueous solutions, preferably isotonic and pH adjusted sterile saline or other aqueous solutions, to which may be added a sterile preservative such as benzalkonium chloride. In addition, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum. The pharmaceutically acceptable compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to well known techniques for formulation, or may be prepared as salt solutions using benzyl alcohol or other suitable preservatives, absorption promoters, fluorocarbons or other conventional solubilizing or dispersing agents to enhance bioavailability.

In some embodiments, the compositions for rectal or vaginal administration are suppositories which can be prepared by mixing the compounds of the invention with suitable non-perfusing excipients or carriers, such as cocoa butter, polyethylene glycol, or suppository waxes which are solid at room temperature but liquid at body temperature and therefore melt in the vagina or the sheath lumen to release the active compound.

The compounds of the present invention are preferably formulated in unit dosage form to reduce the dosage and uniformity of dosage. The term "dosage unit form" as used herein refers to physically discrete units of a drug required for proper treatment of a patient. However, it will be appreciated that the total daily usage of the compounds or compositions of the invention will be determined by the attending physician, according to sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the condition being treated and the severity of the condition, the activity of the specific compound, the specific composition employed, the age, body weight, health, sex and dietary habits of the patient, the time of administration, the route of administration and rate of excretion of the specific compound employed, the duration of the treatment, the drug employed in combination or with the specific compound, and other factors well known in the pharmaceutical arts.

The amount of a compound of the present invention that may be combined with a carrier material to produce a single dosage composition will vary depending upon the indication and the particular mode of administration. In some embodiments, the composition can be formulated to provide a dosage of the inhibitor of 0.01 to 200mg/kg body weight/day for administration by the patient in an amount to receive the composition.

The compounds of the invention may be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combined administration results in an acceptable adverse effect, which is of particular interest for the treatment of hyperproliferative diseases such as cancer. In such cases, the compounds of the present invention may bind to known cytotoxic agents, single transduction inhibitors or other anti-cancer agents, as well as mixtures and combinations thereof. As used herein, the normal administration of an additional therapeutic agent to treat a particular disease is known as "treating the disease appropriately". As used herein, "additional therapeutic agents" including chemotherapeutic or other anti-proliferative agents may be combined with the compounds of the present invention to treat proliferative diseases or cancer.

Chemotherapeutic or other antiproliferative agents include Histone Deacetylase (HDAC) inhibitors, including, but not limited to, SAHA, MS-275, MGO103, and those described in: WO2006/010264, WO03/024448, WO2004/069823, US2006/0058298, US2005/0288282, WO00/71703, WO01/38322, WO01/70675, WO03/006652, WO2004/035525, WO2005/030705, WO2005/092899, and demethylating agents include, but are not limited to, 5-aza-2' -deoxycytidine (5-aza-dC), azacitidine (Vidaza), Decitabine (Decitabine) and compounds described in: US6,268137, US5,578,716, US5,919,772, US6,054,439, US6,184,211, US6,020,318, US6,066,625, US6,506,735, US6,221,849, US6,953,783, US11/393,380.

In other embodiments, chemotherapeutic or other antiproliferative agents may be combined with the compounds of the invention to treat proliferative diseases and cancer. Known chemotherapeutic agents include, but are not limited to, other therapies or anticancer agents that may be used in combination with the anticancer agents of the present invention including surgery, radiation therapy (a few examples are gamma radiation, neutron beam radiation, electron beam radiation, proton therapy, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (paclitaxel, docetaxel, etc.), platinum derivatives, biological response modifiers (interferons, interleukins, Tumor Necrosis Factor (TNF), TRAIL receptor targeting and mediators), hyperthermia and cryotherapy, agents to dilute any adverse reactions (e.g., antiemetics), and other recognized chemotherapeutic agents including, but not limited to, alkylating drugs (nitrogen mustards, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate, pemetrexed (Pemetrexed), etc.), purine antagonists and pyrimidine antagonists (6-Mercaptopurine), 5-fluorouracil, Cytarabile, Gemcitabine (Gemcitabine)), spindle inhibitors (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxin (etoposide, Irinotecan (Irinotecan), Topotecan (Topotecan)), antibiotics (Doxorubicin), Bleomycin (Bleomycin), Mitomycin (Mitomycin)), nitrosoureas (Carmustine), Lomustine (Lomustine), inorganic ions (cisplatin, carboplatin), cell division cycle inhibitors (p by kinesin inhibitors, CENP-E and CDK inhibitors), enzymes (asparaginase), hormones (Tamoxifen, tamoxin), Leuprolide (Leuprolide), Flutamide (flugestimatide), progesterone (fludroxide, progesterone), progesterone (fludroxyne, Leuprolide, fludroxyne, Leuprolide (Megestrol, Leuprolide (Leuprolide, leucinolone, Mitomycin (Mitomycin, mito, gleevec (Gleevec), doxorubicin (Adriamycin), Dexamethasone (Dexamethasone), and cyclophosphamide. Anti-angiogenic factors (Avastin and others), kinase inhibitors (Imatinib), sunitinib (Sutent), sorafenib (Nexavar), cetuximab (Erbitux), Herceptin (Herceptin), Tarceva (Tarceva), Iressa (Iressa) and others). Drugs inhibit or activate cancer pathways such as mTOR, the HIF (hypoxia inducible factor) pathway, and others. A more extensive forum for cancer treatment is http:// www.nci.nih.gov/, a list of oncology drugs approved by FAD is http:// www.fda.gov/cd/cancer/drug-random. htm, and the Merck Manual, eighteenth edition 2006, all incorporated herein by reference.

In other embodiments, the compounds of the invention may bind to cytotoxic anticancer agents. Such anti-cancer agents can be found in the merck index of the thirteenth edition (2001). These anti-cancer agents include, but are in no way limited to, Asparaginase (Asparaginase), Bleomycin (Bleomycin), carboplatin, Carmustine (Carmustine), Chlorambucil (Chlorambucil), cisplatin, L-Asparaginase (Colaspase), cyclophosphamide, Cytarabine (Cytarabine), Dacarbazine (Dacarbazine), actinomycin D (Dactinomycin), Daunorubicin (Daunorubicin), doxorubicin (doxorubicin), Epirubicin (Epirubicin), Etoposide (Etoposide), 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, nitrogen mustard, 6-mercaptopurine, Mesna (Mesna), Methotrexate (Methhoextrytrate), mitomycin C (mitomycin C), Mitoxantrone (Mitoxanthone), Prednisolone (Prelonone), Prednisolone (Preclonixazine), streptozocine (Profenone), streptozocine (Prezoxin), tamoxifen (Tamoxifen), Thioguanine (Thioguanine), topotecan, vinblastine, vincristine, vindesine.

Other suitable cytotoxic agents for use in combination with the compounds of the present invention include, but are not limited to, those compounds which are generally recognized for use in the treatment of neoplastic diseases, as described in: goodman and Gilman's the Pharmacological Basis of Therapeutics (Ninth Edition,1996, McGraw-Hill.); such anti-cancer agents include, but are in no way limited to, Aminoglutethimide (Aminoglutethimide), L-asparaginase, azathioprine, 5-azacytidine, Cladribine (Cladribine), Busulfan (Busulfan), diethylstilbestrol, 2', 2' -difluorodeoxycytidylcholine, docetaxel, erythrohydroxynonanyladenine (Erythroxynonylene), ethinylestradiol, 5-fluorouracil deoxynucleoside, 5-fluorodeoxyuridine monophosphate, Fludarabine phosphate (Fludarabine diphosphate), Fluoxymesterone (Fluoxymestrerone), Flutamide (Fluutamide), hydroxyprogesterone caproate, Idarubicin (Idaruluubicin), interferon, medroxyprogesterone acetate, megestrol acetate, Mellanpha (Mellanpha), Mitotane (Mitotane), paclitaxel, Pentostatin (N-acetyl-L), pennystatin (Palmethylakyl-L), pennystatin (P-L-phosphate (Palmycin), teniposide (Teniposide), testosterone propionate, Thiotepa (Thiotepa), trimethylmelamine, uridine and vinorelbine.

Other suitable cytotoxic anticancer agents for use in combination with the compounds of the present invention include newly discovered cytotoxic substances including, but not limited to, Oxaliplatin (Oxaliplatin), Gemcitabine (Gemcitabine), Capecitabine (Capecitabine), macrolide antineoplastics and natural or synthetic derivatives thereof, Temozolomide (Temozolomide) (Quinn et al, j.clin. Oncology,2003,21(4), 646-.

In other embodiments, the compounds of the invention may be combined with other signal transduction inhibitors. Interestingly, signal transduction inhibitors target the EGFR family, such as EGFR, HER-2 and HER-4(Raymond et al, Drugs,2000,60 (supply. l), 15-23; Harari et al, Oncogene,2000,19(53),6102-6114) and their respective ligands. Such agents include, but are in no way limited to, antibody therapies such as herceptin (trastuzumab), cetuximab (Erbitux), and Pertuzumab (Pertuzumab). Such therapies also include, but are in no way limited to, small molecule kinase inhibitors such as Iressa (Gefitinib), which is Erlotinib, Tykerb (Lapatinib), CANERTINIB (CI1033), AEE788(Traxler et al, Cancer Research,2004,64, 4931-.

In still other embodiments, the compounds of the invention target receptor kinases of the family of the division kinase domain (VEGFR, FGFR, PDGFR, flt-3, c-kit, c-fins, Abl, Jak, Aurora-A, or Aurora-B, etc.), and their respective ligands, in combination with other signal transduction inhibitors. Such agents include, but are not limited to, antibodies such as bevacizumab (Avastin). Such agents include, but are in no way limited to, small molecule inhibitors such as Gleevec/Imanitib, Sprycel (Dasatinib), Taigna/Nilotinib, Nexavar (Vandernib), Vatalanib (PTK787/ZK222584) (Wood et al, Cancer Res.2000,60(8), Tatina 8 2189), Telatinib/BAY-57-9352, BMS-690514, BMS-540215, Axitinib/AG-013736, Motesanib/AMG706, Sutent/Suniniatib/SU-48, ZD-6474(Hennequin et al, 92nd AACR meetings, New Orleanans 2004, Marab.24-28,2001, Stract3152), KRN-951(Taguchi et al, AACR 95, Oracter AAR nett-3163, Mar.11, Marabe.3152, Mar.11, Marek.35, Marek.11, Marek.32, Marek, Marc.7363, Marc.11, proceedings of the American Association of Cancer Research,2004,45, abstrate 2130), MLN-518(Shen et al, Blood,2003,102,11, abstrate 476).

In other embodiments, the compounds of the present invention may bind to histone deacetylase inhibitors. Such agents include, but are in no way limited to, suberoylanilide hydroxamic acid (SAHA), LAQ-824(Ottmann et al, Proceedings of the American Society for Clinical Oncology,2004,23, abstract3024), LBH-589(Beck et al, Proceedings of the American Society for Clinical Oncology,2004,23, abstract3025), MS-275(Ryan et al, Proceedings of the American Society for Clinical Oncology,2004, 45, abstract2452), FR-901228(Piekarz et al, Proceedings of the American Society for Clinical Oncology, 23, abstract3028 and 8584).

In other embodiments, the compounds of the present invention may be combined with other anti-cancer agents such as proteasome inhibitors and m-TOR inhibitors. These include, but are in no way limited to, Bortezomib (Bortezomib) (Mackay et al, Proceedings of the American Society for Clinical Oncology,2004,23, Abstract3109), and CCI-779(Wu et al, Proceedings of the American Association of Cancer Research,2004,45, Abstract 3849). The compounds of the invention may also be combined with other anti-cancer agents such as topoisomerase inhibitors, including but in no way limited to camptothecin.

Those additional therapeutic agents may be administered separately from the compositions comprising the compounds of the present invention as part of a multiple dosing regimen. Alternatively, those therapeutic agents may be part of a single dosage form, mixed together with the compounds of the present invention to form a single composition. If administered as part of a multiple dosing regimen, the two active agents can be delivered to each other simultaneously, sequentially or over a period of time, to achieve the desired agent activity.

The amount of compound and additional therapeutic agent that can be combined with the carrier material to produce a single dosage form (those compositions containing an additional therapeutic agent like those described herein) will vary depending on the indication and the particular mode of administration. Normally, the amount of additional therapeutic agent in a composition of the invention will not exceed the amount normally administered for compositions comprising the therapeutic agent as the only active agent. In another aspect, the amount of additional therapeutic agent of the presently disclosed compositions ranges from about 50% to 100% of the normal amount of the presently disclosed compositions, including the agent as the sole active therapeutic agent. In those compositions that include an additional therapeutic agent, the additional therapeutic agent will act synergistically with the compounds of the present invention.

Detailed Description

In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I) or (Ia), formula (II) or (IIa), formula (IIb) or (IIab), or formula (III). The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The column used silica gel column, silica gel (200-300 mesh) purchased from Qingdao oceanic plant. Nuclear magnetic resonance spectroscopy with CDC1₃,d₆-DMSO,CD₃OD or d₆Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets, quartet), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were measured by an Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

Low resolution Mass Spectral (MS) data were determined by Agilent6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Compound purification was assessed by Agilent1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The compounds of the invention inhibit serine-threonine kinase activity of aurora kinases, particularly aurora-B, thereby inhibiting cell cycle and cell proliferation. Inhibition of aurora kinase by this class of compounds was evaluated by the calipers mobility Shify Assay method described below.

In vitro aurora-A and aurora-B kinase inhibition assay

The ability of a test compound to inhibit serine-threonine kinase activity is determined in this assay. The Caliper mobility Shify Assay is used for testing, the technology is to apply the basic concept of capillary electrophoresis to a microfluid environment, and an enzymology experiment is detected under the condition of not adding a stopping reagent. The substrate used for the experiment is polypeptide with fluorescent label, the substrate is converted into a product under the action of enzyme in a reaction system, the charge of the substrate is correspondingly changed, and the Mobility-Shift Assay separates the substrate and the product by utilizing the difference of the charges of the substrate and the product and respectively detects the substrate and the product. The forces for separating samples in microfluidic chips arise from two different aspects, electrodynamics and fluid pressure. In operation, the reaction system in the 96 or 384-well plate is sucked into the pipeline inside the chip through the sample sucking needle at the bottom of the chip under the action of negative pressure. Due to the voltage applied to the separation channel in the chip, the polypeptide substrate with fluorescent label and the reaction product are separated due to the difference of electric charges, and then the excitation and detection of signal are performed in the detection window. The amount of Product was evaluated by calculating the Conversion value, i.e., the height of the Product peak over the sum of the Substrate peak and Product peak heights (Product peak height/(Substrate + Product peak height)).

The following acronyms are used throughout the invention:

DCM,CH₂Cl₂methylene dichloride

EtOAc, EA ethyl acetate

PE Petroleum Ether

MeOH,CH₃OH methanol

EtOH,CH₃CH₂OH ethanol

HCl hydrochloric acid

AcOH acetic acid, acetic acid

Et₃N, TEA Triethylamine

K₂CO₃Potassium carbonate

NaHCO₃Sodium bicarbonate

Na₂CO₃Sodium carbonate

NaH sodium hydride

NaOH sodium hydroxide

KOH potassium hydroxide

Na₂SO₄Sodium sulfate

DMF N, N-dimethylformamide

HOBt 1-hydroxybenzotriazole

TBTU O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate

HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate

THF tetrahydrofuran

4-DMAP 4-dimethylaminopyridine

DMAC Dimethylacetamide

DMSO dimethyl sulfoxide

DMSO-d₆Hexahydro-dimethyl sulfoxide

EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

m-CPBA m-chloroperoxybenzoic acid

Pd/C palladium on carbon

SOCl₂Thionyl chloride

SnCl₂Tin dichloride

TLC thin layer chromatography

TsCl tosyl chloride

CDI N, N' -carbonyldiimidazole

(Boc)₂Di-tert-butyl O dicarbonate

H₂O water

mL of

RT, RT Room temperature

Rt Retention time

The following schemes illustrate general methods for preparing the compounds of the present invention.

General synthetic methods

Synthesis method of intermediate

Intermediate 1

Acylating a compound A1 to obtain an ester A2, reacting to obtain a compound A3, reacting the compound A3 with a compound A5 to obtain a compound A4, reducing to obtain a compound A6, reacting with TsCl to obtain A8, cyclizing to obtain A9 under alkaline conditions, and deprotecting to obtain a compound A10.

Intermediate 2

Acylating compound A12 to obtain ester A13, reacting to obtain compound A14, reducing compound A14 to obtain compound A15, reacting with MsCl to obtain A16, and reacting with Na₂And (3) carrying out cyclization on the S reaction to obtain A17, and carrying out deprotection to obtain a compound A18.

Intermediate 3

Compound A19 is reduced to produce compound A20.

Intermediate 4

Reacting the compound A21 with m-CPBA to generate a compound A22, reacting the compound A23 to generate a compound A24, performing ring closure under alkaline conditions to generate a compound A25, and performing reduction deprotection to generate a compound A26.

Synthesis scheme 1

Reacting compound 1 with compound 2 under alkaline condition to obtain compound 3, reacting compound 3 with hydrazine to obtain compound 4, hydrolyzing compound 4 under alkaline condition to obtain compound 5, and reacting with compound 6 to obtain compoundReducing and deprotecting the compound 7 to produce a compound 8, a compound 8 and R⁷NH₂The reaction produces the final product 9.

Synthesis scheme 2

Compound R¹Reacting H with a compound 11 to generate a compound 13, carrying out a reduction reaction on the compound 13 to generate a compound 6, carrying out a two-step acidic condition on the compound 6 and the compound 14 to generate a compound 15, carrying out the reduction reaction to generate a compound 16, then reacting with CDI to generate a compound 17, and reacting the compound 17 with a compound 19 to generate a final product 18.

Synthesis scheme 3

The compound 4 reacts under the alkaline condition to generate a compound 41, and the compound 41 and the compound 6 react in two steps to generate a compound 42.

Synthesis scheme 4

Compound 16 is reacted with CDI, compound 19, respectively, to produce final product 18.

Synthesis scheme 5

Compound 16 is reacted with compound 34 to produce compound 35.

Synthesis scheme 6

Compound 15 with (Boc)₂The reaction of O gives compound 36, which is reduced to give compound 37, which is reacted with compound 39 to give compound 38, which is deprotected to give compound 40.

Synthesis scheme 7

Compound 4 is reduced and deprotected to produce compound 21, which is reacted with compound 22 to produce compound 23, compound 24 under basic conditions, and compound 24 is reacted with compound 6 to produce compound 25.

Synthesis scheme 8

Compound R¹Reaction of H with compound 26 produces compound 27, which is reduced to produce compound 28, which is further reduced to produce compound 29, reaction of compound 29 with compound 14 to produce compound 30, reaction of compound 30 with TsOH to form ring to produce compound 31, reduction of compound 31 to produce compound 32, which is further reduced to produce compound 33 with compound 19.

Wherein R is¹，R^4a，R⁴，R⁷，R⁶，R^8a，R⁸，R^5a，R⁵Having the definitions set out herein.

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Examples

Example 1

N-cyclopropyl-3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4, 6-dihydropyrrolo [3,4-c ] pyrazole-5 (1H) -carboxamide

Step one 2- (1-benzyl-4-oxopyrrol-3-yl) -glyoxylic acid ethyl ester

Sodium was added to absolute ethanol (60mL) under ice-bath, stirred for 1.5 h, then brought to-10 ℃ diethyl oxalate (7.72g,52.8mmol) was added dropwise, followed by N-benzyl-3-pyrrolidone (9.24g,52.8mmol) dissolved in absolute ethanol (60mL), added over 1h, followed by warming to room temperature to react overnight, suction filtered to give a pale yellow solid, which was washed with ethanol (5mL), dried under reduced pressure to give the product (9.3g, 63%).

LC-MS：276.1[M+1]⁺.

Step two 5-benzyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid ethyl ester

Ethyl 2- (1-benzyl-4-oxopyrrol-3-yl) -glyoxylate (9.3g,33.8mmol) was dissolved in acetic acid (50mL), cooled to zero, hydrazine hydrate (1.7g,34.1mmol) was added dropwise, and then heated under reflux for 3 hours, cooled to room temperature, water (50mL) was added, ethyl acetate was extracted (3 × 50mL), washed with saturated aqueous sodium bicarbonate (50mL), dried over anhydrous sodium sulfate (10g), and after removal of the solvent under reduced pressure, purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (6.3g, 69%).

LC-MS：272.2[M+1]⁺.

Step three 5-benzyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid

Dissolving 5-benzyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-ethyl formate (6.3g,23.2mmol) in tetrahydrofuran (40mL), adding an aqueous solution of sodium hydroxide (10mol/L,40mL), heating and refluxing for 2 hours, concentrating the mixture after the reaction is finished to remove the organic solvent, adjusting the pH value to 5-6, separating out a white solid, performing suction filtration to collect the product, washing with a small amount of cold water (10mL), and performing vacuum drying to obtain a white solid product (5g, 89%).

LC-MS：244.3[M+1]⁺.

Step four 4- ((2- (5-benzyl-1, 4,5, 6-tetrahydropyrrole [3,4-c ] pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) morpholine

The compound 5-benzyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid (2.8g,11.52mmol) and 4- (morpholinomethyl) benzene-1, 2-diamine (2.3g,11.52mmol) were dissolved in DMF (25mL), EDCI (2.64g,13.8mmol) and HOBt (1.71g,12.6mmol) were added, reacted at room temperature for 24 hours, the solvent was removed under reduced pressure, acetic acid (40mL) was then added, heated under reflux for 3 hours, cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (V) ═ 15/1) to give the product (3g, 63%).

LC-MS：414.3[M+1]⁺.

Step five 4- ((2- (1,4,5, 6-tetrahydropyrrole [3,4-c ] pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) morpholine

The compound 4- ((2- (5-benzyl-1, 4,5, 6-tetrahydropyrrole [3,4-c ] pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) morpholine (3g,7.24mmol) was dissolved in methanol (60mL), and palladium on carbon (500mg) hydroxide was added, followed by replacement of hydrogen gas and reaction at room temperature for 24 hours. After completion of the reaction, the solid was removed by filtration, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol (V/V) ═ 5/1) to give the product (2g, 86%).

LC-MS：325.1[M+1]⁺.

Step six N-cyclopropyl-3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4, 6-dihydropyrrolo [3,4-c ] pyrazole-5 (1H) -carboxamide

Compound 4- ((2- (1,4,5, 6-tetrahydropyrrole [3, 4-c)]Pyrazol-3-yl) -1H-benzo [ d]Imidazol-5-yl) methyl) morpholine (200mg,0.62mmol) and carbonyldiimidazole (150mg,0.92mmol) were dissolved in DMAC (5mL) and the reaction was heated to 80 ℃ and stirred overnight. Cyclopropylamine (1mL) was added thereto at room temperature, the mixture was heated to 60 ℃ for 5 hours, and after the solvent was removed under reduced pressure, the product was purified by preparative chromatography (120mg, 40.7%).¹H NMR(400MHz,DMSO-d₆):δ12.31(s,1H),10.18(s,1H),7.46-7.50(m,2H),7.15(d,J＝3.4Hz,1H),6.53(s,1H),4.53(d,J＝5.3Hz,4H),3.56-3.58(m,4H),2.55-2.68(m,1H),2.36(s,4H),1.22-1.27(m,2H),0.55-0.60(m,2H),0.44-0.47(m,2H).

LC-MS：408.1[M+1]⁺.

Example 2

1-cyclopropyl-3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

Step one hexahydro-2H 1,4 Dioxin 2,3-c pyrrole

Benzyl tetrahydro-2H- [1,4] dioxin [2,3-C ] pyrrole-6 (3H) carbonate (10.3g,39.12mmol) was dissolved in tetrahydrofuran (100mL), 10% Pd/C (1.03g) was added, and the mixture was heated to 50 ℃ and stirred overnight. After Pd/C was removed by filtration, the solvent was removed under reduced pressure to give a pale yellow liquid (7.32g), which was directly subjected to the next reaction.

Step two: (3, 4-dinitrophenyl) (tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methanone

3, 4-dinitrobenzoic acid (4.74g,22.35mmol) and DMF (0.05mL) were dissolved in THF (50mL) and SOCl was added₂(2.14mL,29.5mmol) was heated backFlow 2.5 hours. The mixture was then cooled to 0 deg.C, triethylamine (4.7mL,33.75mmol) was added, followed by hexahydro-2H- [1,4]]Dioxin [2,3-c ]]Pyrrole (5.05g,39.12mmol) and the mixture allowed to return to room temperature and stirring continued overnight. After removing the solvent under reduced pressure, dichloromethane (50mL) and water (50mL) were added, extraction was performed, the organic layer was dried over anhydrous sodium sulfate (10g), concentration was performed, and column chromatography was performed (dichloromethane/methanol (V/V) ═ 5/1) to give a pale yellow solid (5.67g, 78.5%).

LC-MS：324[M+1]⁺.

Step III 6- (3, 4-dinitrobenzyl) hexahydro-2H- [1,4] Dioxin [2,3-c ] pyrrole

Sodium borohydride (1.44g,37.18mmol) was dissolved in THF (200mL), the mixture was cooled to 0 deg.C, boron trifluoride diethyl ether (4.8mL,37.18mmol) was added dropwise, followed by (3, 4-dinitrophenyl) (tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methanone (5.67g,17.54 mmol). The ice bath was removed and the mixture was stirred at room temperature for 3.5 hours, TLC showed the reaction of the starting materials was complete, the mixture was cooled to 0 ℃ again, methanol was slowly added until no gas was produced and then heated under reflux for 1 hour. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate (50mL) and water (50mL), dried over anhydrous sodium sulfate (10g), and concentrated to give a pale yellow liquid (7.9g, > 100%).

LC-MS：310[M+1]⁺.

Step four 4- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) benzene-1, 2-diamine

6- (3, 4-dinitrobenzyl) hexahydro-2H- [1,4] dioxin [2,3-C ] pyrrole (5.42g,17.54mmol) was dissolved in methanol (200mL), 10% Pd/C (0.5g) was added, and the mixture was stirred under hydrogen at room temperature overnight. Pd/C was removed by filtration, the filtrate was concentrated under reduced pressure, and column chromatography (dichloromethane/methanol (v/v) ═ 10/1) gave the product (2.19g, 50%).

LC-MS：250[M+1]⁺.

Step five 6- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) hexahydro-2H- [1,4] Dioxin [2,3-c ] pyrrole

4- ((tetrahydro-2H- [1,4] Dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) benzene-1, 2-diamine (2.19g,8.78mmol), 4-nitro-1H-pyrrole-3-carboxylic acid (1.24g,7.91mmol), EDCl (1.68g,8.78mmol) and HOBt (1.19g,8.78mmol) were dissolved in DMF (22mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure and AcOH (35mL) was added to the residue and heated under reflux for 3.5 h. The solvent was removed under reduced pressure and column chromatography (dichloromethane/methanol (v/v) ═ 10/1) gave the product (1.65g, 51%).

LC-MS：371[M+1]⁺.

Step six 3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine

6- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) hexahydro-2H- [1,4] dioxin [2,3-C ] pyrrole (1.65g,4.46mmol) was dissolved in DMF (50mL), and 10% Pd/C (0.17g) was added to the mixture, followed by stirring overnight at room temperature under hydrogen. Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure to give the product (1.52g, 100%).

LC-MS：341[M+1]⁺.

Step seven 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one

3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.68g,2mmol) and CDI (0.64g,3.9mmol) were dissolved in DMF (10mL), heated to 80 ℃ and stirred for 10 hours, TLC indicated that the starting material was reacted completely, and the next reaction was directly carried out.

LC-MS：438[M+1]⁺.

Step eight 1-cyclopropyl-3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.73g,2mmol) and cyclopropylamine (0.9mL) were dissolved in DMF (10mL), heated at 50 ℃ and stirred overnight. After removing the solvent under reduced pressure, column chromatography (dichloromethane/methanol (v/v) ═ 10/1) was performed to give the product (150mg, 18%).

¹H NMR(400MHz,DMSO-d₆):δ13.00(s,1H),12.80(s,1H),9.64(s,1H),8.05(s,1H),7.54(d,J＝8.4Hz,1H),7.40(d,J＝5.6Hz,1H),7.11-7.20(m,2H),4.00(s,2H),3.74(s,2H),3.69(t,J＝5.2Hz,2H),3.44-3.50(m,2H),2.78-2.82(m,2H),2.68-2.72(m,2H),2.60(s,1H),0.84(t,J＝2.8Hz,2H),0.54(s,2H)；

LC-MS：424[M+1]⁺.

Example 3

1- (3- (5- (2-oxa-5-heterobicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) -3-cyclopropylurea

Step one cis-4-hydroxyproline methyl ester hydrochloride

Cis-4-hydroxyproline hydrochloride (20g,150mmol) was dissolved in methanol (200mL) and SOCl was added at 0 deg.C₂(13.1mL,180mmol) and heated to 75 deg.C reflux for 7 h. After cooling to room temperature, the solid was removed by filtration, and the solvent was removed under reduced pressure to directly carry out the next reaction.

Step two (2S,4S) -1-tert-butyl-2-methyl-4-hydroxytetrahydropyrrole-1, 2-dicarbonate

Cis-4-hydroxyproline methyl ester hydrochloride (54.03g,372mmol) and sodium carbonate (102.57g,968mmol) were dissolved in THF/H₂O (2/1,600mL), added at 0 deg.C (Boc)₂O (107.75g,484mmol), then stirred at room temperature overnight. Dichloromethane (500mL) and water (500mL) were added to the mixture, extracted, anhydrousThe organic layer was dried over sodium sulfate (10g), concentrated and directly subjected to the next reaction.

Step three (2S,4S) -1-tert-butyl-2-methyl-4- ((tert-butyldimethylsilyl) oxo) tetrahydropyrrole-1, 2-dicarbonate

(2S,4S) -1-tert-butyl-2-methyl-4-hydroxytetrahydropyrrole-1, 2-dicarbonate (55g,225mmol) is dissolved in dichloromethane (450mL), diisopropylethylamine (86mL,495mmol) is added, then cooled to-40 degrees, and tert-butyldimethylsilyl trifluoromethanesulfonate (58.3mL,270mmol) is added dropwise with stirring for 1 hour. Water (100mL) was added to extract the reaction, dichloromethane (500mL) was added to extract, the organic layer was dried over anhydrous sodium sulfate (10g), concentrated, and separated by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a yellow liquid (56.5g, 69.8%).

Step four (2S,4S) -tert-butyl-4- ((tert-butyldimethylsilyl) oxo) -2- (hydroxymethyl) tetrahydropyrrole-1-carbonate

(2S,4S) -1-tert-butyl-2-methyl-4- ((tert-butyldimethylsilyl) oxo) tetrahydropyrrole-1, 2-dicarbonate (56.17g,156.23mmol) is dissolved in the removed THF (400mL), cooled to-10 ℃ and, after addition of lithium borohydride (8.95g,390.58mmol) in portions, stirred overnight at room temperature. Methanol (10mL) was added slowly at 0 ℃ to quench the reaction, then filtered, the filtrate was concentrated and purified on a column (dichloromethane/methanol (v/v) ═ 10/1) to give a yellow liquid (30g, 56%).

Step five (2S,4S) -tert-butyl-4- ((tert-butyldimethylsilyl) oxo) -2- ((benzenesulfonyloxy) methyl) tetrahydropyrrole-1-carbonate

(2S,4S) -tert-butyl-4- ((tert-butyldimethylsilyl) oxo) -2- (hydroxymethyl) tetrahydropyrrole-1-carbonate (29.96g,86.7mmol) was dissolved in THF (200mL), cooled to 0 ℃ after addition of 4mol/L NaOH (208mL,832mmol), and TsCl (52.89g,277mmol) was added in portions to the mixture, which was then allowed to stir overnight at room temperature. Dichloromethane (500mL) and water (500mL) were added to the mixture, extracted, and the organic layer was dried over anhydrous sodium sulfate (10g), concentrated, and directly subjected to the next step.

Step six (2S,4S) -tert-butyl-4-hydroxy-2- ((benzenesulfonyloxy) methyl) tetrahydropyrrole-1-carbonate

(2S,4S) -tert-butyl-4- ((tert-butyldimethylsilyl) oxo) -2- ((benzenesulfonyloxy) methyl) tetrahydropyrrole-1-carbonate (34.92g,71.89mmol) was dissolved in THF (200mL), tetrabutylammonium fluoride (24.44g,93.46mmol) was added, and after stirring at room temperature for 1 hour, ethyl acetate (500mL) and water (500mL) were added for extraction, and the organic layer was dried over anhydrous sodium sulfate (10g), concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a white solid (12.3g, 46%).

Step heptatert-butyl-2-oxa-5-heterobicyclo [2.2.1] -heptane-5-carbonate

(2S,4S) -tert-butyl-4-hydroxy-2- ((benzenesulfonyloxy) methyl) tetrahydropyrrole-1-carbonate (12.3g,33.1mmol) was dissolved in dehydrated THF (150mL), cooled to-15 degrees, NaH (3.97g,99.34mmol) was added, then stirred at room temperature for 5 hours, after the mixture was cooled to 0 degrees, water (50mL) was slowly added to quench the reaction, ethyl acetate (50mL) was added to conduct extraction, the organic layer was dried over anhydrous sodium sulfate (10g), concentrated, and column-purified (dichloromethane/methanol (v/v) ═ 10/1) to give a white solid (5.52g, 84%).

Step eight 2-oxa-5-heterobicyclo [2.2.1] -heptane

Tert-butyl-2-oxa-5-heterobicyclo [2.2.1] heptane-5-carbonate (5.52g,27.7mmol) was dissolved in ethyl acetate (10mL), a saturated solution of hydrogen chloride in ethyl acetate (20mL) was added, the mixture was stirred at room temperature for 5 hours, and filtered to give a white solid, and the solid was added to ethyl acetate (100mL), followed by dropwise addition of a small amount of aqueous ammonia (5mL) until the solid was completely dissolved, drying over anhydrous sodium sulfate (10g), filtration, and concentration of the filtrate to give a colorless liquid (2.7g, 98%).

Step nine 2-oxa-5-heterobicyclo [2.2.1] -heptan-5-yl (3, 4-dinitrophenyl) methanone

2-oxa-5-heterobicyclo [2.2.1] -heptane (2.64g,26.63mmol), 3, 4-dinitrobenzoic acid (6.78g,31.96mmol), HATU (15.19g,39.95mmol) and diisopropylethylamine (14mL,79.9mmol) were dissolved in THF (100mL) and stirred at room temperature overnight. To the mixture was added dichloromethane (50mL) and water (50mL), extracted, and the organic layer was dried over anhydrous sodium sulfate (10g), concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a white solid (2.8g, 36%).

LC-MS：294[M+1]⁺.

Step deca 5- (3, 4-dinitrophenyl) -2-oxa-5-heterobicyclo [2.2.1] -heptane

Sodium borohydride (0.9g,23.33mmol) was dissolved in THF (90mL), the mixture was cooled to 0 deg.C, boron trifluoride diethyl ether (2.94mL,23.33mmol) was added dropwise, followed by 2-oxa-5-heterobicyclo [2.2.1] -heptan-5-yl (3, 4-dinitrophenyl) methanone (2.28g,7.78 mmol). The ice bath was removed and the mixture was allowed to return to room temperature and stirred overnight, TLC showed the starting material to react completely, the mixture was cooled to 0 ℃ again, methanol was slowly added until no gas was produced and heated to reflux for 1 hour. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate (50mL) and water (50mL), dried over anhydrous sodium sulfate (10g), concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (1.64g, 76%).

LC-MS：280[M+1]⁺.

Step eleven 4- (2-oxa-5-heterobicyclo [2.2.1] -heptan-5-ylmethyl) phenyl-1, 2-diamine

5- (3, 4-dinitrophenyl) -2-oxa-5-heterobicyclo [2.2.1]-heptane (1.23g,4.4mmol) was dissolved in ethanol (50mL) and SnCl was added₂(9.95g,44.09mmol) was stirred at room temperature for 3.5 hours. Saturated NaHCO₃The mixture was added (50mL), the solid was removed by filtration, the filtrate was concentrated under reduced pressure, and column-purified (dichloromethane/methanol (v/v) ═ 10/1) to give a yellow solid (0.85g, 89%).

LC-MS：220[M+1]⁺.

Step twelve 5- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) -2-oxa-5-heterobicyclo [2.2.1] -heptane

4- (2-oxa-5-heterobicyclo [2.2.1] -heptan-5-ylmethyl) phenyl-1, 2-diamine (0.85g,3.88mmol), 4-nitro-1H-pyrrole-3-carboxylic acid (0.58g,3.69mmol), EDCl (0.78g,4.06mmol) and HOBt (0.55g,4.06mmol) were dissolved in DMF (10mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure and AcOH (16mL) was added to the residue and heated under reflux for 3.5 h. The solvent was removed under reduced pressure and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a yellow solid (0.79g, 63%).

LC-MS：341.1[M+1]⁺.

Step thirteen 3- (5- (2-oxa-5-heterobicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine

5- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) -2-oxa-5-heterobicyclo [2.2.1] -heptane (0.74g,2.17mmol) was dissolved in DMF (20mL), and 10% Pd/C (0.1g) was added and stirred under hydrogen at room temperature overnight. Pd/C was removed by filtration, and the filtrate was concentrated under reduced pressure and directly subjected to the next reaction.

LC-MS：311[M+1]⁺.

Step fourteen 8- (2-oxo-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one

3- (5- (2-oxa-5-heterobicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.67g,2.17mmol) and CDI (0.69g,4.25mmol) were dissolved in DMF (7mL), heated to 80 ℃ and stirred overnight, TLC showed the starting material to react completely, and the next reaction was carried out directly.

Step fifteen 1- (3- (5- (2-oxa-5-heterobicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) -3-cyclopropylurea

The compound 8- (2-oxo-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.73g,2.17mmol) and cyclopropylamine (1.0mL) were dissolved in DMF (8mL) and heated 80 ℃ overnight with stirring. After removal of the solvent under reduced pressure, purification by column (dichloromethane/methanol (v/v) ═ 10/1) gave a yellow solid (105mg, 12%).

1H NMR(400MHz,DMSO-d6):δ12.83(s,1H),9.57(s,1H),8.03(s,1H),7.50(s,2H),7.35(s,1H),7.18(d,J＝8.0Hz,2H),4.34(s,2H),3.94(d,J＝7.2Hz,1H),3.80(d,J＝8.0Hz,2H),3.16(s,2H),2.73(d,J＝8.8Hz,1H),2.59(s,1H),1.81(d,J＝8.0Hz,1H),1.58(d,J＝9.2Hz,1H),0.84(d,J＝6.8Hz,2H),0.54(s,2H).

LC-MS：394.3[M+1]⁺.

Example 4

1- (3- (5- (2-thio-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzimidazol-2-yl) -1H-pyrazol-4-yl) -3-cyclopropylurea

Step one trans-4-hydroxy-L-proline methyl ester

Hydroxyproline (1.0g,7.63mmol) was dissolved in methanol (10mL) and SOCl was added at room temperature₂(0.66mL,9.15mmol) was added dropwise to the mixture, stirred for 15 minutes, and then the mixture was heated to reflux for 4 hours. Removing the solvent and SOCl under pressure₂And obtaining white solid which is directly used for the next reaction.

Step two (2S,4R) -N- (tert-butoxycarbonyl) hydroxyproline methyl ester

trans-4-hydroxy-L-proline methyl ester (1.38g,9.51mmol) and triethylamine (1.6mL,14.26mmol) were dissolved in dichloromethane (20mL), the mixture was cooled to 0 deg.C, (Boc)₂O (1.84mL,9.99mmol) was added dropwise to the mixture and stirring was continued overnight at room temperature until the starting material was completed. The solvent was removed under reduced pressure and the reaction was carried out as it was. .

Step three (2S,4R) -N- (tert-butoxycarbonyl) hydroxyprolinol

(2S,4R) -N- (tert-Butoxycarbonyl) hydroxyproline methyl ester (1.87g,7.62mmol) was dissolved in THF (30mL) and cooled to 0 deg.C, lithium aluminum hydride (0.29g,7.62mmol) was added in portions and stirring was continued at 0 deg.C overnight. After completion of the reaction, 10% sodium hydroxide and water (1/1,2mL) were added at 0 ℃, the solids were removed by filtration, the filtrate was concentrated, and the product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (1.44g, 87%).

LC-MS：239[M+23].

Step four (2S,4R) -4- ((methylsulfonyl) oxy) -2- (((methylsulfonyl) oxy) methyl) pyrrole-1-carboxylic acid tert-butyl ester

(2S,4R) -N- (tert-Butoxycarbonyl) hydroxyprolinol (2.4g,15.5mmol) and triethylamine (5.30mL,53.59mmol) were dissolved in dichloromethane (40mL) and cooled to 0 deg.C, methanesulfonyl chloride (2.86mL,53.17mmol) was added dropwise to the mixture and stirring continued at 0 deg.C for 3 hours. After the reaction was completed, the reaction was quenched with 1mol/L hydrochloric acid (5.30mL), the organic layer was separated, the aqueous phase was extracted with dichloromethane (50mL), the combined organic layers were washed with saturated brine (50mL) and dried, and concentrated to give the crude product, which was used directly in the next reaction.

Step five 2-thio-5-azabicyclo [2.2.1] heptane-5-carboxylic acid tert-butyl ester

Sodium sulfide nonahydrate (6.64g,33.17mmol) was dissolved in DMSO (30mL) and added dropwise to a solution of tert-butyl (2S,4R) -4- ((methanesulfonyl) oxy) -2- (((methanesulfonyl) oxy) methyl) pyrrole-1-carboxylate (3.44g,11.06mmol) in DMSO (20mL) at room temperature and stirring continued at room temperature for 45 minutes under nitrogen. Water (35mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50mL), the organic layers were combined, washed with saturated brine (50mL), dried, concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (1.28g, 65%).

Step six 2-thio-5-azabicyclo [2.2.1] heptane hydrochloride

Tert-butyl 2-thio-5-azabicyclo [2.2.1] heptane-5-carboxylate (0.65g,3.0mmol) was dissolved in dichloromethane (2mL), a saturated solution of hydrogen chloride in ethyl acetate (10mL) was added, the mixture was stirred at room temperature for 2 hours, and the solvent was removed and used directly in the next step.

Step hepta-2-thio-5-azabicyclo [2.2.1] heptan-5-yl (3, 4-dinitrophenyl) methanone

3, 4-Dinitrobenzoic acid (1.84g,8.7mmol) was dissolved in thionyl chloride (1mL), two drops of DMF were added and heated under reflux for 2.5 h. Cooled to room temperature, tetrahydrofuran (20mL), triethylamine (1mL) was added, cooled to zero degrees, and 2-thio-5-azabicyclo [2.2.1] heptane (1g,8.7mmol) was added, followed by warming to room temperature and reaction overnight. Water (5mL) was added to the reaction solution, the reaction solution was extracted by spin-drying, the mixture was extracted with ethyl acetate (50mL), the organic layers were combined, washed with saturated brine (50mL), dried, concentrated, and separated by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (1.7g, 65%).

LC-MS：310[M+1].

Step eight 5- (3, 4-dinitrobenzyl) -2-thio-5-azabicyclo [2.2.1] heptane

Sodium borohydride (0.938g,11.55mmol) was added to tetrahydrofuran (40mL) under nitrogen, cooled to zero, boron trifluoride in diethyl ether (1.64g,11.55mmol) was added followed by 2-thio-5-azabicyclo [2.2.1] heptan-5-yl (3, 4-dinitrophenyl) methanone (1.7g,5.5mmol) added in one portion, the reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with methanol (10mL), heated to reflux for half an hour, the solvent removed under reduced pressure, the mixture extracted with ethyl acetate (50mL), the organic layers combined, washed with saturated brine (50mL) and dried, and concentrated to give the product (1.2g, 75%).

LC-MS：296[M+1].

Step nine 4- (2-thio-5-azabicyclo [2.2.1] heptan-5-ylmethyl) benzene-1, 2-diamine

5- (3, 4-dinitrobenzyl) -2-thio-5-azabicyclo [2.2.1] heptane (1.2g,4mmol) was dissolved in ethanol (30mL), and palladium on carbon hydroxide (200mg) was added, followed by reaction for replacement of hydrogen gas under a hydrogen atmosphere at room temperature overnight. The solid was filtered off with suction and the filtrate was spin-dried to give the product (0.8g, 84%).

LC-MS：236[M+1].

Step ten 5- ((2- (4-1H-pyrazol-3-yl) -1H-benzimidazol-6-yl) -methyl) -2-thioxo-5-azabicyclo [2.2.1] heptane

4- (2-thio-5-azabicyclo [2.2.1] heptan-5-ylmethyl) benzene-1, 2-diamine (0.7g,3mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (0.47g,3mmol) were dissolved in DMF (15mL) followed by EDCI (0.63g,3.3mmol) and HOBt (0.45g,3.3mmol) and the reaction stirred at room temperature for 24 h. The solvent was removed under reduced pressure, acetic acid (20mL) was added, and the mixture was refluxed for 3 hours. After the reaction was completed, the reaction mixture was concentrated and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a product (0.5g, 50%).

LC-MS：357[M+1].

Step eleven 3- (5- (2-thio-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzimidazol-2-yl) -1H-pyrazol-4-amine

5- ((2- (4-1H-pyrazol-3-yl) -1H-benzimidazol-6-yl) -methyl) -2-thioxo-5-azabicyclo [2.2.1] heptane (0.5g,1.4mmol) was dissolved in methanol (30mL), palladium on carbon (50mg) was added, followed by reaction under hydrogen atmosphere, and room temperature overnight. The solid was filtered off with suction and the filtrate was spin-dried to give the product (0.3g, 66%).

LC-MS：327[M+1].

Step dodeca-1- (3- (6- (2-thioxo-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzimidazol-2-yl) -1H-pyrazol-4-yl) -3-cyclopropylurea

3- (6- (2-thio-5-azabicyclo [2.2.1] heptan-5-ylmethyl) -1H-benzimidazol-2-yl) -1H-pyrazol-4-amine (0.3g,0.92mmol), N-N' -carbonyldiimidazole (0.3g,1.84mmol) were dissolved in DMF (6mL) and heated to 80 ℃ for 8 hours, followed by addition of cyclopropylamine (2mL) and heating to 60 ℃ for 5 hours. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by preparative chromatography to give the product (0.12g, 32%).

LC-MS：410[M+1]；

¹H NMR(400MHz,DMSO-d₆):δ12.81(d,J＝78.8Hz,2H),9.61(s,1H),8.05(s,1H),7.53(d,J＝43.4Hz,2H),7.17(s,2H),3.80(s,2H),3.47(s,2H),3.03-3.08(m,2H),2.74-2.83(m,2H),2.61(s,1H),2.16(d,J＝9.8Hz,1H),11.65-1.68(m,1H),0.84(s,2H),0.55(s,2H).

Example 5

1-cyclopropyl-3- (3- (5- (morpholinomethyl) benzooxazol-2-yl) -1H-pyrazol-4-yl) urea

Step one (4-hydroxy-3-nitrophenyl) (morpholinyl) methanone

4-hydroxy-3-nitrobenzoic acid (14g,76.5mmol) was dissolved in tetrahydrofuran (150mL) at room temperature, morpholine (6.7g,84.1mmol), HATU (31g,84.1mmol) were added to the solution, and the mixture was stirred at room temperature overnight. After the reaction was complete, the solvent was dried by evaporation, extracted with ethyl acetate (3X 60mL), washed with water (50mL), dried over anhydrous sodium sulfate (10g), and evaporated to give the crude product as a yellow solid (12g) which was used directly in the next reaction.

Step two 4- (morpholinomethyl) -2-nitrophenol

Sodium borohydride (3.36g,89mmol) was added to anhydrous tetrahydrofuran (30mL) at zero degrees, N₂Boron trifluoride in ether (11.3mL,89mmol) was added dropwise with protection, followed by the addition of the compound (4-hydroxy-3-nitrophenyl) - (morpholino) methanone (11.93g,42mmol) in one portion, warmed to room temperature and stirred overnight. Methanol (50mL) was added under ice-bath and the reaction mixture was stirred under reflux for 30 min. The solvent was dried by evaporation and extracted with ethyl acetate (3X 60mL), washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and evaporated to give a yellow solid (9.54g, 83%).

LC-MS：253.1[M+1]⁺.

Step three 2-amino-4- (morpholinomethyl) phenol

To a solution of compound 4- (morpholinomethyl) -2-nitrophenol (11g,41.2mmol) in ethanol (150mL) was added 10% palladium on carbon (1g), hydrogen was replaced, the reaction was carried out at room temperature for 24 hours, the solid was removed by suction filtration, and the filtrate was spin-dried to give the product (8g, 94%).

LC-MS：209.1[M+1]⁺.

Step four N- (2-hydroxy-5- (morpholinomethyl) phenyl) -4-nitro-1H-pyrazole-3-carboxamide

The compound 2-amino-4- (morpholinomethyl) phenol (2.54g,16mmol) was dissolved in DMF (15mL), and 4-nitro-1-hydro-pyrazole-3-carboxylic acid (3.4g,16mmol) and HATU (7.4g,19.6mmol) were added, respectively, and reacted at room temperature overnight, after completion of the reaction, the solvent was dried by spinning, extracted with ethyl acetate (3X 50mL), washed with water (2X 50mL), dried over anhydrous sodium sulfate (10g), and spun to give the crude product (1.5g) which was used directly in the next step. LC-MS: 348.1[ M + 1]]⁺.

Step five 5- (Morpholinylmethyl) -2- (4-nitro-1H-pyrazol-3-yl) benzoxazole

The compound N- (2-hydroxy-5- (morpholinomethyl) phenyl) -4-nitro-1H-pyrazole-3-carboxamide (1g,2.89mmol) and p-toluenesulfonic acid (0.5g,2.89mmol) were added to toluene (50mL) and heated at reflux overnight. After the reaction is finished, the temperature is reduced to room temperature, the solvent is removed under reduced pressure, and the residue is purified by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 20/1), yielding the product (0.6g, 75%).

LC-MS：330.3[M+1]⁺.

Step six 3- (5- (morpholinomethyl) benzooxazol-2-yl) -1H-pyrazol-4-amine

To a solution of compound 5- (morpholinomethyl) -2- (4-nitro-1 h-pyrazol-3-yl) benzoxazole (0.6g,1.82mmol) in methanol (30mL) was added 10% palladium on carbon (10mg) to replace hydrogen, the mixture was reacted at room temperature for 24 hours, and the solid was removed by suction filtration, and the filtrate was dried by spin-drying to give the product (0.5g, 93%). LC-MS: 300.1[ M + 1]]⁺.

Step hepta 1-cyclopropyl-3- (3- (5- (morpholinomethyl) benzooxazol-2-yl) -1H-pyrazol-4-yl) urea

Compound 3- (5- (morpholinomethyl) benzooxazol-2-yl) -1 h-pyrazol-4-amine (500mg,1.67mmol) and carbonyldiimidazole (400mg,2.5mmol) were dissolved in DMF (10mL), and the reaction was heated to 80 ℃ and stirred overnight. Cooling to room temperature, adding cyclopropylamine (2mL), heating to 60 deg.C for 5 h, removing the solvent under reduced pressure, and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 20/1), yielding the product (120mg, 17%).¹H NMR(400MHz,DMSO-d₆):δ12.34(s,1H),10.18(s,1H),8.49(s,1H),7.60-7.63(d,1H),7.31-7.36(m,1H),7.15(s,1H),6.77(s,1H),3.75(s,1H),3.51(s,4H),3.39-3.43(m,2H),2.43-2,47(m,2H),1.91-2.01(m,4H),1.76-1.81(m,2H).

LC-MS：383.1[M+1]⁺.

Example 6

1-cyclopropyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

Step one 6-oxo-3-azabicyclo [3.1.0] hexane-3-carboxylic acid benzyl ester

Benzyl 2, 5-dihydropyrrolidine-1-carboxylate (10g,49.24mmol) was dissolved in dichloromethane (30mL), added slowly dropwise to a mixture of m-chloroperoxybenzoic acid (10.55g,61.14mmol) in dichloromethane (70mL), and the reaction was stirred at room temperature for 16 hours. The filtrate was filtered, and the filtrate was washed once with saturated sodium thiosulfate (100mL) and once with saturated sodium bicarbonate (100mL), anhydrous Na₂SO₄(10g) And (5) drying. The solvent was evaporated under reduced pressure and the residue was directly subjected to column chromatography (ethyl acetate/petroleum ether (V/V) ═ 1/3) to give the product (7.39g, 68.49%).

LC-MS:220(M+1).

Step two (3R,4R) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylic acid benzyl ester

Benzyl 6-oxo-3-azabicyclo [3.1.0] hexane-3-carboxylate (6.0g,27.37mmol) was dissolved in dry dichloromethane (100mL), 2-bromoethanol (3.73g,30.13mmol) was added, then a solution of boron trifluoride in diethyl ether (0.39g,2.74mmol) was slowly added at room temperature and stirred at room temperature overnight. The solvent is distilled off under pressure to obtain a crude product which is directly used for the next reaction.

LC-MS:344(M+1).

Step three (4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrole-6 (3H) -carboxylic acid benzyl ester

Benzyl (3R,4R) -3- (2-bromoethoxy) -4-hydroxypyrrolidine-1-carboxylate (crude) was dissolved in absolute ethanol (80mL), and an ethanol solution of potassium hydroxide (1.54g,27.39mmol) was added, followed by heating and refluxing for 6 hours. Filtration, rinsing of the filter cake with ethyl acetate (50mL), combining the filtrates, evaporation to dryness under reduced pressure, and column chromatography of the residue (ethyl acetate/petroleum ether (V/V) ═ 1/1) gave the product (0.60g, 8.40%).

LC-MS:264(M+1)；

¹H NMR(400MHz,CDCl₃):δ7.30-7.36(m,5H),5.17(s,2H),3.81-3.87(m,5H),3.59-3.77(m,2H),3.12-3.18(m,2H),1.24-1.27(m,1H).

Step four (4aR,7aR) -hexahydro-2H- [1,4] Dioxin [2,3-c ] pyrrole

Benzyl (4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-C ] pyrrole-6 (3H) -carboxylate (0.60g,2.28mmol) was dissolved in dry THF (10mL), 10% Pd/C (0.30g) was added, hydrogen was substituted twice, and then heated to 50 ℃ for hydrogenolysis for 6 hours. Filtering, evaporating the filtrate to dryness to obtain the product, and directly using the product in the next reaction.

Step five (3, 4-dinitrophenyl) (4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methanone

3, 4-Dinitrobenzoic acid (0.58g,2.74mmol) was dissolved in THF (20mL), DMF (2 drops), SOCl was added₂(0.24mL,3.62mmol) and heated at reflux for 2 h. The mixture was then cooled to 0 ℃ and triethylamine (0.59mL,4.14mmol) was added followed by (4aR,7aR) -hexahydro-2H- [1, 4aR ]]Dioxin [2,3-c ]]Pyrrole in THF (5mL) and the mixture warmed to room temperature and stirred for an additional 24 h. After removing the solvent under reduced pressure, dichloromethane (50mL) and water (50mL) were added, extraction was performed, the organic layer was dried over anhydrous sodium sulfate (10g), concentration was performed, and column chromatography separation was performed (EtOAc/PE (V/V) ═ 1/1) to give a pale yellow solid (365mg, 41.29%).

LC-MS：324[M+1]⁺.

¹H NMR(400MHz,DMSO-d₆):δ8.10(d,1H),7.99(d,1H),7.89-7.91(m,1H),4.00-4.03(m,1H),3.87-3.98(m,5H),3.85-3.86(m,1H),3.73-3.79(m,2H),3.38-3.44(m,2H).

Step Hexa (4aR,7aR) -6- (3, 4-dinitrobenzyl) hexahydro-2H- [1,4] Dioxin [2,3-c ] pyrrole

Sodium borohydride (0.23g,6.13mmol) was suspended in dry THF (20mL), the mixture was cooled to 0 deg.C, boron trifluoride diethyl ether (0.77mL,6.13mmol) was added dropwise, followed by (3, 4-dinitrophenyl) (4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methanone (0.90g,2.79mmol), slowly warmed to room temperature and stirred overnight. The mixture was again cooled to 0 ℃ and methanol (5mL) was added slowly until no gas was produced and heated at reflux for 1 hour. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate (50mL) and water (50mL), dried over anhydrous sodium sulfate (10g), and concentrated to give a pale yellow liquid (0.60g, 71.69%).

LC-MS：333[M+23]⁺.

Step hepta-4- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) benzene-1, 2-diamine

(4aR,7aR) -6- (3, 4-dinitrobenzyl) hexahydro-2H- [1,4] dioxin [2,3-C ] pyrrole (1.40g,4.53mmol) was dissolved in DMF (20mL) and 10% Pd/C (0.3g) was added under hydrogen stirring at room temperature overnight. Pd/C was removed by filtration, and the filtrate was used directly in the next reaction.

LC-MS：250[M+1]⁺.

Step eight (4aR,7aR) -6- ((2- (4-nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) hexahydro-2H- [1,4] Dioxin [2,3-c ] pyrrole

To the reaction solution obtained in the above step were added 4-nitro-1H-pyrrole-3-carboxylic acid (0.65g,4.12mmol), EDCI (0.87g,4.53mmol) and HOBt (0.61g,4.53mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and AcOH (20mL) was added to the residue, followed by heating and refluxing for 3 hours. The solvent was removed under reduced pressure and purified on column (dichloromethane/methanol (v/v) ═ 10/1) to give the product (2.10g, > 100%).

LC-MS：371[M+1]⁺.

Step nine 3- (6- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine

(4aR,7aR) -6- ((2- (4-nitro-1H-pyrazol-3-yl) -1H-benzo [ d)]Imidazol-5-yl) methyl) hexahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrole (2.10g,5.7mmol) was dissolved in DMF (20mL) and 10% Pd/C (0.5g) was added and stirred under hydrogen at room temperature overnight. Filtering to remove Pd/C, concentrating the filtrate under reduced pressure, and separating by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 20/1) yielded the product (0.37g, 19.17%).

LC-MS：341[M+1]⁺.

Step Ten 1-cyclopropyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

3- (6- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.37g,1.08mmol) and CDI (0.35g,2.17mmol) were dissolved in DMF (15mL) and heated to 75 ℃ with stirring for 12 hours, TLC showed the starting material to react completely, and the next reaction was carried out directly.

Cyclopropylamine (0.52mL) was added to the reaction mixture obtained in the above step, and the mixture was heated to 75 ℃ and reacted for 12 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a pure product (60mg, 13.13%).

LC-MS：424[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.09(s,1H),12.83(s,1H),9.64(s,1H),8.04(s,1H),7.53-7.56(m,1H),7.39-7.41(m,1H),7.11-7.21(m,1H),3.81-3.90(m,1H),3.62-3.68(m,2H),3.17(d,J＝7.2Hz,1H),2.86-2.90(m,2H),2.50-2.52(m,3H),1.10-1.20(m,4H),0.78-0.80(m,3H),0.50(s,2H).

Example 7

1, 1-diethyl-3- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

3- (5- (morpholinomethyl) -1H-benzo [ d)]Imidazol-2-yl) -1H-pyrazol-4-amine (0.27g,0.91mmol) and CDI (0.29g,1.82mmol) were dissolved in DMF (15mL) and heated to 75 ℃ for reaction for 12 hours. The mixture was cooled to room temperature, diethylamine (3mL) was added, and the reaction was continued by heating to 75 ℃ for 12 hours. Cooling to room temperature, evaporating the reaction solution to dryness, and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give a pure product (57mg, 15.79%).

LC-MS：398[M+1]⁺.

¹H NMR(400MHz,DMSO-d₆):13.02(s,1H),12.92(s,1H),9.95(d,J＝9.3Hz,1H),8.00(s,1H),7.57-7.47(m,1H),7.43(d,J＝8.1Hz,1H),7.18(dd,J＝15.2,8.1Hz,1H),3.57(s,6H),2.38(s,4H),1.28-1.23(m,10H).

Example 8

Isopropyl-3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.55g,1.5mmol) and isopropylamine (1.3mL) were dissolved in DMF (8mL) and heated at 60 degrees overnight with stirring. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a product (160mg, 25%).

LC-MS：426[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.97(s,1H),12.75(s,1H),8.95(s,1H),8.86(s,1H),8.04(d,J＝2.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.40(d,J＝8.0Hz,1H),7.15(t,J＝8.8Hz,1H),4.02(s,2H),3.79(d,J＝6.4Hz,3H),3.68-3.72(m,2H),3.46-3.49(m,2H),2.84(s,2H),2.75(s,2H),1.13(d,J＝6.4Hz,6H).

Example 9

1- (pentan-3-yl) -3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.55g,1.5mmol) and 3-aminopentane (0.71mL) were dissolved in DMF (7mL) and heated at 80 ℃ overnight with stirring. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a product (133mg, 32%).

LC-MS：454.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.72(s,1H),8.92(brs,1H),8.04-8.07(m,2H),7.72(s,1H),7.61(d,J＝8.4Hz,1H),7.39(d,J＝6.4Hz,1H),7.14(t,J＝7.6Hz,1H),3.99(s,2H),3.74(s,2H),3.69-3.71(m,2H),3.45-3.48(m,1H),3.38-3.44(m,2H),2.80-2.81(s,2H),2.69-2.73(m,2H),1.26-1.44(m,10H).

Example 10

Cyclopentyl-3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.55g,1.5mmol) and cyclopentylamine (0.6mL) were dissolved in DMF (7mL) and heated at 80 ℃ overnight with stirring. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (110mg, 27%).

LC-MS：452.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.69(s,1H),8.93(brs,1H),8.04(s,2H),7.60(s,1H),7.39(s,1H),7.28(s,1H),7.12(d,J＝7.2Hz,1H),3.98-4.02(m,2H),3.74(s,1H),3.67-3.70(m,2H),3.46-3.47(m,2H),2.79-2.83(m,2H),2.69-2.73(m,2H),1.85-1.88(m,2H),1.68-1.69(m,2H),1.52-1.56(m,2H),1.44-1.47(m,2H),0.83-0.85(m,2H).

Example 11

1- (2-fluorophenyl) -3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.34g,1.0mmol) and 2-fluorophenyl isocyanate (0.17mL) were dissolved in DMAC (20mL) and stirred overnight at room temperature. 1mol/L KOH (30mL) was added to the mixture and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (253mg, 53%).

LC-MS：478.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.13(s,1H),12.77(s,1H),9.63(s,1H),9.47(s,1H),8.14(s,1H),7.95-8.00(m,1H),7.61(s,1H),7.41(s,1H),7.08-7.27(m,4H),4.00-4.05(m,2H),3.75(s,2H),3.68-3.70(m,2H),2.81(s,2H),2.73(s,2H),1.98(s,2H).

Example 12

1-cyclohexyl-3- (3- (5- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

The compound 9- ((tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [3,4-e ] pyrazol-5 (4H) -one (0.55g,1.5mmol) and cyclohexylamine (1.7mL) were dissolved in DMF (8mL) and heated at 80 degrees overnight with stirring. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a product (92mg, 13%).

LC-MS：466[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.79(s,1H),8.97(s,1H),8.87(s,1H),8.03(d,J＝2.0Hz,1H),7.59(d,J＝7.6Hz,1H),7.39(d,J＝4.8Hz,1H),7.23(s,1H),7.14(d,J＝6.8Hz,1H),4.00(s,2H),3.74(d,J＝3.2Hz,2H),3.67-3.71(m,2H),3.58-3.60(m,1H),3.42-3.45(m,2H),2.79-2.82(m,2H),2.69-2.72(m,2H),1.85(d,J＝9.6Hz,2H),1.64-1.73(m,4H),1.13-1.29(m,4H).

Example 13

(R) -2-methoxy-1- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl-) pyrrolo [3,4-c ] pyrazol-5- (1H,4H,6H) -yl) -2-acetophenone

Step one 2- (1-benzyl-4-oxopyrrol-3-yl) -glyoxylic acid ethyl ester

Sodium was added to absolute ethanol (60mL) under ice bath, stirred for 1.5 hours, then brought to-10 ℃, diethyl oxalate (7.72g,52.8mmol) was added dropwise, then N-benzyl-3-pyrrolidone (9.24g,52.8mmol) was dissolved in absolute ethanol (60mL), added over 1 hour, then warmed to room temperature to react overnight, suction filtered to give a pale yellow solid, washed with a small amount of ethanol, and dried under reduced pressure to give the product (9.3g, 63%).

LC-MS：276.1[M+1]⁺；

Step two 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid ethyl ester

Ethyl 2- (1-benzyl-4-oxopyrrol-3-yl) -glyoxylate (9.3g,33.8mmol) was dissolved in acetic acid (50mL), cooled to zero, hydrazine hydrate (1.7g,34.1mmol) was added dropwise, and then heated under reflux for 3 hours, cooled to room temperature, added with water (50mL), extracted with ethyl acetate (3 × 50mL), washed with saturated sodium bicarbonate (50mL), dried over anhydrous sodium sulfate (10g), and after removal of the solvent under reduced pressure, purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (6.3g, 69%).

LC-MS：272.2[M+1]⁺.

Step three Ethyl 1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylate

To a solution of the compound 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid ethyl ester (6.3g,23.2mmol) in ethanol (80mL) was added palladium hydroxide on carbon (600mg), hydrogen was substituted, the reaction was carried out at room temperature for 12 hours, the solid was removed by suction filtration, the filtrate was dried by spinning, and column chromatography was carried out for purification (dichloromethane/methanol (v/v) ═ 10/1), whereby the product (4.0g, 95%) was obtained.

LC-MS：182.2[M+1]⁺.

Step four (R) -5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid ethyl ester

(R) -2-methoxy-2-phenylacetic acid (0.734g,4.4mmol) and ethyl 1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -3-carboxylate (0.8g,4.4mmol) were added to DMF (10mL), followed by addition of TBTU (1.7g,5.3mmol), reaction overnight at room temperature, addition of ethyl acetate (100mL), washing with water (2 × 30mL), drying over anhydrous sodium sulfate (10g), removal of the solvent under reduced pressure, and purification of the crude product by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (0.75g, 53%).

Step five (R) -5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid

Ethyl (R) -5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -3-carboxylate (0.75g,2.13mmol) was dissolved in tetrahydrofuran (20mL), followed by addition of an aqueous solution of sodium hydroxide (10mol/L,20mL), heating under reflux for 2 hours, after completion of the reaction, the mixture was concentrated to remove the organic solvent, the pH was adjusted to 5, a white solid precipitated, which was collected by suction filtration, washed with cold water (50mL), and dried in vacuo to give a white solid product (380mg, 59%).

LC-MS：302.1[M+1]⁺.

Step six (R) -2-methoxy-1- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl-) pyrrolo [3,4-c ] pyrazol-5- (1H,4H,6H) -yl) -2-acetophenone

The compound (R) -5- (2-methoxy-2-phenylacetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid (0.38g,1.28mmol) and 4- (morpholinomethyl) benzene-1, 2-diamine (0.317g,1.53mmol) were dissolved in DMF (10mL), EDCI (0.27g,1.4mmol) and HOBt (0.19g,1.4mmol) were added, reaction was carried out at room temperature for 24 hours, the solvent was removed under reduced pressure, acetic acid (20mL) was added, heating and refluxing were carried out for three hours, cooling to room temperature, the solvent was removed under reduced pressure, and the residue was chromatographed to give the product (50mg, 21%).

LC-MS：491.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.31(s,1H),12.69(s,1H),7.17-7.54(m,8H),5.74(s,5H),4.43-4.65(m,2H),4.08(s,1H),3.56-3.58(m,4H),3.17-3.19(m,4H),2.36(s,2H).

Example 14

4- ((2- (5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazol-3-yl) -1H-benzimidazol-6-yl) methyl) morpholine

Step one 2- (1-benzyl-4-oxopyrrol-3-yl) -glyoxylic acid ethyl ester

Sodium was added to absolute ethanol (60mL) under ice bath, stirred for 1.5 hours, then brought to-10 ℃, diethyl oxalate (7.72g,52.8mmol) was added dropwise, then N-benzyl-3-pyrrolidone (9.24g,52.8mmol) was dissolved in absolute ethanol (60mL), added over one hour, then warmed to room temperature to react overnight, suction filtered to give a pale yellow solid, washed with a small amount of ethanol, and dried under reduced pressure to give the product (9.3g, 63%).

LC-MS：276.1[M+1]⁺.

Step two Ethyl 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylate

LC-MS：272.2[M+1]⁺.

Step three 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid

Dissolving 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid ethyl ester (6.3g,23.2mmol) in tetrahydrofuran (40mL), adding aqueous sodium hydroxide (10mol/L,40mL), heating and refluxing for 2 hours, concentrating the mixture after the reaction is finished to remove the organic solvent, adjusting the pH value to 5-6, precipitating a white solid, filtering by suction to collect the product, washing with a small amount of cold water (50mL), and drying in vacuum to obtain a white solid product (5g, 89%).

LC-MS：244.3[M+1]⁺.

Step four 4- ((2- (5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazol-3-yl) -1H-benzimidazol-6-yl) methyl) morpholine

The compound 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) yl-3-carboxylic acid (0.5g,2mmol) and 4- (morpholinomethyl) benzene-1, 2-diamine (0.51g,2.46mmol) were dissolved in DMF (15mL), EDCI (0.3g,2.26mmol) and HOBt (0.43g,2.26mmol) were added and reacted at room temperature for 24 hours, the solvent was removed under reduced pressure, acetic acid (30mL) was then added, the mixture was heated under reflux for 3 hours, cooled to room temperature, the solvent was removed under reduced pressure, and the residue was chromatographed using preparative chromatography to give the product (50mg, 21%).

LC-MS：454.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.31(s,1H),10.42(s,1H),10.18(s,1H),8.60(s,1H),8.05(s,1H),7.61(d,J＝12.3Hz,2H),7.30-7.37(m,2H),6.85-6.89(m,1H),6.27(s,1H),4.16(s,2H),3.79-3.82(m,2H),3.60-3.68(m,4H),3.51(s,3H),3.4-3.47(m,4H).

Example 15

2- (3-fluorophenyl) -1- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl-) pyrrolo [3,4-c ] pyrazol-5- (1H,4H,6H) -yl) ethanone

Step one Ethyl 1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylate

To a solution of the compound 5-phenyl-1, 4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid ethyl ester (6.3g,23.2mmol) in ethanol (80mL) was added palladium hydroxide on carbon (600mg), hydrogen was substituted, the reaction was carried out at room temperature for 12 hours, the solid was removed by suction filtration, the filtrate was dried by spinning, and column chromatography was carried out for purification (dichloromethane/methanol (v/v) ═ 10/1), whereby the product (4g, 95%) was obtained.

LC-MS：182.2[M+1]⁺.

Step bis 5- (2- (3-fluorophenyl) acetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid ethyl ester

2- (3-fluorophenyl) acetic acid (1.0g,5.52mmol) and ethyl 1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylate (0.8g,4.4mmol) were added to DMF (20mL), then HATU (2.3g,6.07mmol) was added, reacted overnight at room temperature, ethyl acetate (100mL) was added, washed with water (2 × 30mL), dried over anhydrous sodium sulfate (10g), the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (1.5g, 86%).

Step three 5- (2- (3-fluorophenyl) acetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid

Ethyl 5- (2- (3-fluorophenyl) acetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylate (1.5g,4.73mmol) was dissolved in tetrahydrofuran (30mL), followed by addition of aqueous sodium hydroxide (10mol/L,30mL), heating under reflux for 2 hours, after completion of the reaction, the mixture was concentrated to remove the organic solvent, pH was adjusted to 5 with concentrated hydrochloric acid (60mL), a white solid was precipitated, which was collected by suction filtration, washed with a small amount of cold water (50mL), and dried in vacuo to give the product as a white solid (600mg, 46%).

LC-MS：300.1[M+1]⁺.

Step tetrakis 2- (3-fluorophenyl) -1- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl-) pyrrolo [3,4-c ] pyrazol-5- (1H,4H,6H) -yl) ethanone

The compound 5- (2- (3-fluorophenyl) acetyl) -1,4,5, 6-tetrahydropyrrole (3, 4-pyrazole) -yl-3-carboxylic acid (0.6g,2mmol) and 4- (morpholinomethyl) benzene-1, 2-diamine (0.43g,2mmol) were dissolved in DMF (15mL), EDCI (0.44g,2.3mmol) and HOBt (0.31g,2.3mmol) were added and reacted at room temperature for 24 hours, the solvent was removed under reduced pressure, acetic acid (20mL) was added and heated under reflux for 3 hours, cooled to room temperature, the solvent was removed under reduced pressure, and the residue was chromatographed using preparative chromatography to give the product (50mg, 21%).

LC-MS：461.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.31(s,1H),10.42(s,1H),7.49(s,2H),7.35-7.39(m,1H),7.09-7.17(m,1H),7.05-7.09(m,3H),4.56-4.94(m,4H),3.85(d,J＝19.9Hz,2H),3.55-3.58(m,4H),2.49-2.50(m,2H),2.29(s,4H).

Example 16

1-ethyl-1-methyl-3- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

Step one (3, 4-dinitrophenyl) (morpholino) methanone

3, 4-dinitrobenzoic acid (10.0g,47mmol) and DMF (0.1mL) were dissolved in THF (100mL) followed by SOCl₂(7.4g,62mmol) was added dropwise to the mixture and heated under reflux for 2.5 hours. The mixture was cooled to 0 deg.C, triethylamine (10mL,71mmol) was added dropwise to maintain the temperature below 5 deg.C for longer than 20 minutes, then morpholine (7.2mL,82mmol) was added dropwise for longer than 15 minutes, at which time a large amount of solid appeared, and the mixture was slowly allowed to stir at room temperature overnight. Ice water (250mL) was added to the mixture, cooled to 0 ℃ and filtered to give a yellow solid, which was washed with ice water (50mL) and dried to give the product (11.95g, 90%).

Step two 4- (3, 4-dinitrobenzyl) morpholine

NaBH in the protection of nitrogen₄(3.36g,89.78mmol) was dispersed in THF (360mL), after cooling to 0 deg.C, boron trifluoride diethyl etherate (11.3mL,89.78mmol) was added, with the evolution of hydrogen noted, followed by a single addition of (3, 4-dinitrophenyl) (morpholino) methanone (11.91g,42mmol), which was removed from the cold bath and allowed to stir at room temperature for 2 hours. Methanol (100mL) was added carefully and the mixture was heated to reflux for 1 hour. The liquid was concentrated, dissolved with EtOAc (100mL), and saturated NaHCO₃/H₂O (1/1,100mL) washed the organic phase, EtOAc (50mL) extracted the aqueous phase, combined organic phases, washed with saturated brine (50mL), dried, concentrated to a solid, and recrystallized from methanol (10mL) to give the product (10g, 89.3%).

Step III 4- (Morpholinomethyl) phenyl-1, 2-diamine

10% Pd/C (0.525g) and 4- (3, 4-dinitrobenzyl) morpholine (10.5g,39.29mmol) were dissolved in ethanol (200mL) under nitrogen, the mixture was cooled to 0 ℃ and the nitrogen was replaced with hydrogen, and the mixture was stirred overnight at room temperature. The mixture was filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give the product (6.34g, 61%).

¹H NMR(400MHz,DMSO-d₆):δ6.47(d,J＝2.0Hz,1H),6.40-6.42(d,J＝7.6Hz,1H),6.27-6.29(m,1H),4.32-4.38(d,J＝21.2Hz,4H),3.52-3.54(t,J＝4.8Hz,4H),3.18(d,J＝2.0Hz,2H),2,28(s,4H).

Step four 4- ((2- (4-nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) morpholine

4- (Morpholinomethyl) phenyl-1, 2-diamine (2.3g,1.11mmol), 4-nitro-1H-pyrazole-3-carboxylic acid (1.57g,1mmol), EDCl (2.13g,1.11mmol) and HOBt (1.5g,1.11mmol) were dissolved in anhydrous DMF (25mL) and stirred at room temperature overnight. The solvent was removed under reduced pressure, glacial acetic acid (40mL) was added, the mixture was heated to reflux for 3 hours, the solvent was removed under reduced pressure, and the product was purified on a column (dichloromethane/methanol (v/v) ═ 10/1) and then washed with methanol (10mL), and a yellow solid insoluble in methanol was obtained as a product (0.9g, 27%).

LC-MS：329[M+1]⁺,327[M-1]^-.

Step five 3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine

4- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d ] imidazol-5-yl) methyl) morpholine (0.9g,2.74mmol) was dissolved in DMF (30mL) under nitrogen protection, 10% Pd/C (0.088g) was added, hydrogen gas was substituted, the mixture was stirred at room temperature for 5 hours, the solid was removed by filtration, the solid was washed with methanol (10mL), and the filtrate was concentrated to give a brownish black solid, which was directly subjected to the next reaction. The product was obtained (0.84g, > 100%).

Step six 8- (Morpholinylmethyl) -2H-benzo [4,5] imidazo [1,2-c ] pyrazoline [3,4-e ] pyrimidin-5 (4H) -one

3- (5- (Morpholinylmethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.6g,2.0mmol) and CDI (0.64g,3.96mmol) were dissolved in THF (10mL) and heated at reflux for 16H. The mixture was cooled to room temperature, filtered, and the filter cake was collected, washed with THF (5mL), dried, and directly subjected to the next reaction. An off-white solid was obtained (0.56g, 86.59%).

Step hepta 1-ethyl-1-methyl-3- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (Morpholinylmethyl) -2H-benzo [4,5] imidazo [1,2-c ] pyrazoline [3,4-e ] pyrimidin-5 (4H) -one (0.145g,0.45mmol) and methylethylamine (0.38mL,3.67mmol) were dissolved in DMF (6mL) and heated to 100 ℃ for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a pale yellow solid (0.163g, 76%).

LC-MS：384.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.02(s,1H),12.91(s,1H),9.93(d,J＝7.2Hz,1H),8.01(s,1H),7.54(t,J＝8.0Hz,1H),7.42(d,J＝8.4Hz,1H),7.14-7.20(m,1H),3.56(d,J＝7.6Hz,5H),3.41-3.47(m,2H),3.03(d,J＝6.8Hz,4H),2.36(s,4H),1.19(t,J＝7.2Hz,3H).

Example 17

N- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) cyclopentanecarboxamide

3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.83g,2.78mmol), cyclopentanecarboxylic acid (0.317g,2.78mmol) and HATU (1.16g,3.06mmol) were dissolved in DMF (8mL), stirred at room temperature over-solution, the mixture was concentrated, and column-purified (dichloromethane/methanol (v/v) ═ 10/1) to give a pale yellow solid (0.12g, 12%).

LC-MS：395.1[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.16(s,1H),12.96(s,1H),10.44(s,1H),8.24(s,1H),7.59(s,1H),7.43(s,1H),7.18(d,J＝8Hz,1H),3.57(t,J＝5.4Hz,6H),2.86-2.93(m,1H),2.37(s,4H),1.96-2.01(m,2H),1.79-1.82(m,2H),1.71-1.76(m,2H),1.62-1.65(m,2H).

Example 18

N- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) piperidine-1-carboxamide

8- (Morpholinylmethyl) -2H-benzo [4,5] imidazo [1,2-c ] pyrazoline [3,4-e ] pyrimidin-5 (4H) -one (0.25g,0.76mmol) and piperidine (0.73mL,6.11mmol) were dissolved in DMF (5mL) and heated to 100 ℃ for 16H. The mixture was cooled to room temperature, concentrated, and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a pale yellow solid (0.32g, 84%).

LC-MS：410.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.04(s,1H),12.93(s,1H),10.03(d,J＝13.2Hz,1H),8.02(s,1H),7.55(t,J＝8.4Hz,1H),7.42(d,J＝8.0Hz,1H),7.17(dd,J＝8.3Hz,15.8Hz,1H),3.56(d,J＝6.8Hz,6H),3.51(s,4H),2.37(s,4H),1.58(s,6H).

Example 19

N- (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) cyclohexanecarboxamide

3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (0.6g,2.0mmol), cyclohexanoic acid (0.31g,2.41mmol) and HATU (0.91g,2.41mmol) were dissolved in DMF (7mL), stirred at room temperature over liquid, the mixture was concentrated, and column-purified (dichloromethane/methanol (v/v) ═ 10/1) to give a pale yellow solid (0.17g, 21%).

LC-MS：409.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.18(s,1H),12.95(s,1H),10.47(s,1H),8.26(s,1H),7.60(d,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.14-7.20(m,1H),3.55(d,J＝4.8Hz,6H),2.36(s,4H),1.97(d,J＝12.0Hz,2H),1.77(d,J＝12.4Hz,2H),1.65(d,J＝12.0Hz,1H),1.45-1.53(m,2H),1.19-1.33(m,4H).

Example 20

Isopropyl (3- (5- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) carbamate

Step one tert-butyl-3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4-nitro-1H-pyrazole-1-carbonate

4- ((2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzo [ d)]Imidazol-5-yl) methyl) morpholine (1.2g,3.68mmol), (Boc)₂O (0.92g,4.23mmol) and 4-DMAP (0.047g,0.39mmol) were dissolved in dichloromethane (100mL) and stirred at room temperature for 1 hour until the solution was clear. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to give a product (870mg, 55%).

LC-MS：429.1[M+1]⁺.

Step di-tert-butyl-3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4-amino-1H-pyrazole-1-carbonate

Tert-butyl-3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4-nitro-1H-pyrazole-1-carbonate (0.87g,2.03mmol) was dissolved in methanol (10mL), and 10% Pd/C (0.1g) was added and stirred under hydrogen at room temperature overnight. Pd/C was removed by filtration, and the solvent was removed under reduced pressure, followed by column purification (dichloromethane/methanol (v/v) ═ 10/1) to give a product (0.69mg, 85%).

LC-MS：399.3[M+1]⁺.

Step tri-tert-butyl-4- ((isopropoxycarbonyl) amino) -3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazole-1-carbonate

Tert-butyl-3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -4-amino-1H-pyrazole-1-carbonate (0.68g,1.71mmol), isopropyl chloroformate (0.63g,5.13mmol), 4-DMAP (0.021g,0.17mmol) and pyridine (0.405g,5.13mmol) were dissolved in dichloromethane (15mL) and stirred at room temperature overnight. The mixture was washed with 0.5mol/L hydrochloric acid (30mL) to remove pyridine, and concentrated under reduced pressure and then directly subjected to the next step.

LC-MS：483.3[M-1]^-.

Step Tetraisopropyl (3- (6- (morpholinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) carbamate

Tert-butyl-4- ((isopropoxycarbonyl) amino) -3- (6- (morpholinomethyl) -1H-benzo [ d)]Imidazol-2-yl) -1H-pyrazole-1-carbonate (0.82g,1.71mmol) was dissolved in DCM (5mL), and a saturated solution of hydrogen chloride in ethyl acetate (10mL) was added, followed by stirring at room temperature for 10 hours. Filtration and the resulting solid dissolved in saturated NaHCO₃The solution (10mL) was extracted with dichloromethane (50mL), dried over anhydrous sodium sulfate (10g), and purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a pure product (30mg, 4.6%).

LC-MS：383.1[M-1]^-；

¹H NMR(400MHz,DMSO-d₆):δ13.19(s,1H),12.92(d,J＝7.6Hz,1H),9.42(d,J＝24.8Hz,1H),8.02(s,1H),7.62(t,J＝8.4Hz,1H),7.42(d,J＝7.6Hz,1H),7.14-7.20(m,1H),4.91-4.97(m,1H),3.56(d,J＝6.0Hz,6H),2.37(s,4H),1.30(d,J＝6.4Hz,6H).

Example 21

1, 1-diethyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrrole [3,4-e]Pyrimidin-5 (4H) -one (0.3g,0.82mmol) was dissolved in DMAC (6mL) and diethylamine (2mL,19.45mmol) was added and heated to 80 ℃ for 24 hours. The reaction solution was evaporated to dryness, the residue was dissolved in methylene chloride/methanol (10/1,55mL), washed once with saturated sodium bicarbonate solution (50mL) and saturated brine (50mL), and dried over anhydrous sodium sulfate (50 g). Evaporating the solvent and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give pure product (29mg, 8.1%).

LC-MS：440[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.01(s,1H),12.90(s,1H),9.96(d,1H),8.00(s,1H),7.48-7.52(m,1H),7.40-7.42(m,1H),7.13-7.19(m,1H),3.90(s,1H),3.78-3.87(s,3H),3.72-3.77(m,2H),3.51-3.55(m,6H),2.86-2.89(m,2H),2.56-2.61(m,2H),1.23-1.25(m,6H).

Example 22

1-Ethyl-1-methyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]DioxygenThe 2,3-c]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrrole [3,4-e]Pyrimidin-5 (4H) -one (0.25g,0.68mmol) was dissolved in DMAC (10mL) and N-methylethylamine (6mL,6.83mmol) was added and heated to 100 deg.C for 24 hours. The reaction solution was evaporated to dryness, the residue was dissolved in methylene chloride/methanol (20/1,105mL), and the mixture was washed once with saturated sodium bicarbonate solution (50mL) and once with saturated brine (50mL), and dried over anhydrous sodium sulfate (50 g). Evaporating the solvent and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give a pure product (88mg, 30.34%).

LC-MS：426[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.91-13.01(s,2H),9.95(d,1H),8.01(s,1H),7.53(d,J＝6.8Hz,1H),7.41(d,J＝15.4Hz,1H),7.12-7.18(m,1H),3.89(s,1H),3.81-3.86(m,3H),3.71-3.76(m,2H),3.61-3.64(m,3H),3.03(d,J＝11.0Hz,3H),2.60-2.87(m,2H),2.56-2.58(m,2H),1.18-1.21(m,4H).

Example 23

N- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) pyrrolidine-1-carboxamide

Step I8- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [1,2-c ] pyrazolo [3,4-e ] pyrimidin-5 (4H) -one

3- (6- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-amine (1.6g,4.81mmol) and CDI (1.53g,2.17mmol) were dissolved in THF (25mL) and heated to 75 deg.C with stirring overnight, TLC showed the starting material to react completely, and filtered to give an off-white solid (0.82g, 46%).

LC-MS：367.2[M+1]⁺.

Step two N- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) pyrrolidine-1-carboxamide

8- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5] imidazo [1,2-c ] pyrazolo [3,4-e ] pyrimidin-5 (4H) -one (0.2g,0.54mmol) was dissolved in DMF (5mL), pyrrolidine (0.5mL) was added and the reaction was heated to 100 ℃ overnight. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol (v/v) ═ 10/1) to obtain a pure product (110mg, 57%).

LC-MS：438.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.02(s,1H),12.89(s,1H),9.64(d,J＝8.8Hz,1H),8.06(s,1H),7.55(d,J＝9.6Hz,1H),7.40(d,J＝8.0Hz,1H),7.15(q,J＝8.0Hz,1H),3.89(d,J＝13.2Hz,2H),3.76-3.82(m,4H),3.62-3.64(m,6H),2.89(t,J＝7.2Hz,2H),2.59(t,J＝8.8Hz,2H),1.94(s,2H),1.22(s,2H).

Example 24

N- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) cyclopentanecarboxamide

3- (6- (((4aR,7aR) -tetrahydro-2H- [1, 4)]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d]Imidazol-2-yl) -1H-pyrazol-4-amine (0.3g,0.88mmol) was dissolved in DMF (6mL), and cyclohexanecarboxylic acid (0.12g,1.06mmol) and HATU (0.4g,1.06mmol) were added in this order, and the reaction was stirred at room temperature for 24 hours. The reaction solution was evaporated to dryness, the residue solution was taken up in dichloromethane/methanol (10/1,55mL), saturated sodium bicarbonate solution (50mL) and saturatedBrine (50mL) was washed once each and dried over anhydrous sodium sulfate (50 g). Evaporating the solvent and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give pure product (35mg, 9.11%).

LC-MS：437[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.18(brs,1H),10.44(s,1H),9.64(d,J＝8.0Hz,1H),8.24(s,1H),7.54-7.58(m,1H),7.49-7.51(m,1H),7.15-7.17(m,1H),4.01-4.03(m,1H),3.87(s,1H),3.81(s,1H),3.74-3.78(m,2H),3.62-3.64(m,2H),3.54-3.57(m,2H),1.96-1.98(m,4H),1.65-1.80(m,2H),1.55-1.60(m,4H),1.15-1.25(m,2H).

Example 25

1- (cyclopropylmethyl) -3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrrole [3,4-e]Pyrimidin-5 (4H) -one (0.48g,1.31mmol) was dissolved in DMAC (12mL) and then cyclopropylmethylamine (1.1mL,13.20mmol) was added and heated to 100 ℃ for 24 hours. The reaction solution was evaporated to dryness, the residue was dissolved in methylene chloride/methanol (20/1,105mL), and the mixture was washed once with saturated sodium bicarbonate solution (50mL) and once with saturated brine (50mL), and dried over anhydrous sodium sulfate (50 g). Evaporating the solvent and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give a pure product (53mg, 9.27%).

LC-MS：438[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.96(s,1H),12.73(s,1H),9.02(d,J＝5.1Hz,2H),8.04(s,1H),7.59(d,J＝14.5Hz,1H),7.39(d,J＝4.5Hz,2H),7.14(t,J＝9.2Hz,1H),4.01-4.03(m,1H),3.90(s,1H),3.82-3.87(m,3H),3.72-3.78(m,2H),3.01(d,J＝19.2Hz,2H),2.99(s,2H),2.59-2.60(d,J＝6.7Hz,2H),0.98(s,1H),0.443-0.45(d,J＝5.3Hz,2H),0.20-0.21(m,2H).

Example 26

1- (Pentane-3-yl) -3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl)) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrazole [3,4-e ]]Pyrimidin-5 (4H) -one (0.2g,0.54mmol) was dissolved in DMF (5mL), 3-aminopentane (0.5mL) was added, and the reaction was heated to 100 ℃ overnight. After removal of the solvent under reduced pressure, purification by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), yielding a pure product (196mg, 80%).

LC-MS：454.2[M+1]⁺；

¹HNMR(400MHz,DMSO-d₆):δ12.95(s,1H),12.72(s,1H),8.92(d,J＝44.0Hz,1H),8.06(s,1H),7.64(d,J＝17.6Hz,1H),7.39(s,1H),7.14(t,J＝7.2Hz,1H),3.79-3.91(m,2H),3.62-3.77(m,4H),3.56(s,2H),3.47-3.50(m,2H),2.89(t,J＝7.2Hz,2H),2.60(t,J＝8.0Hz,2H),1.47-1.52(m,2H),1.37-1.43(m,2H),0.88(t,J＝7.2Hz,6H).

Example 27

1-isopropyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl)) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrazole [3,4-e ]]Pyrimidin-5 (4H) -one (0.2g,0.55mmol) was dissolved in DMF (5mL), isopropylamine (0.37mL) was added and the reaction was heated to 100 ℃ overnight. After removal of the solvent under reduced pressure, purification by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), yielding a pure product (230mg, 98%).

LC-MS：427.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.96(s,1H),12.73(s,1H),8.90(d,J＝44.8Hz,1H),8.06(s,1H),7.64(d,J＝17.6Hz,1H),7.39(s,1H),7.14(t,J＝7.2Hz,1H),3.89(d,J＝13.2Hz,1H),3.79-3.87(m,3H),3.62-3.77(m,4H),3.56(s,2H),3.47-3.50(m,2H),2.89(t,J＝7.2Hz,2H),2.57-2.63(m,2H),1.13(d,J＝6.4Hz,4H).

Example 28

1- (cyclopentyl-3-yl) -3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl)) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrazole [3,4-e ]]Pyrimidin-5 (4H) -one (0.2g,0.54mmol) was dissolved in DMF (5mL), cyclopentylamine (0.5mL) was added, and the reaction was heated to 100 ℃ overnight. After removal of the solvent under reduced pressure, purification by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), yielding a pure product (120mg, 62%).

LC-MS：454.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.96(s,1H),12.73(s,1H),8.95(brs,J＝34.8Hz,1H),8.06(s,1H),7.59(s,1H),7.39(s,1H),7.28(s,1H),7.13(d,J＝8.0Hz,1H),3.95-4.00(m,1H),3.80-3.90(m,2H),3.61-3.77(m,4H),3.53-3.56(m,2H),2.88(t,J＝7.6Hz,2H),2.59(t,J＝8.8Hz,2H),1.85-1.97(m,2H),1.65-1.67(m,2H),1.42-1.55(m,4H).

Example 29

N- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) piperidine-1-carboxamide

Step I N- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) piperidine-1-carboxamide

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrazole [3,4-e ]]Pyrimidin-5 (4H) -one (0.2g,0.54mmol) was dissolved in DMF (5mL), 3-aminopentane (0.5mL) was added, and the reaction was heated to 100 ℃ overnight. After removal of the solvent under reduced pressure, purification by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), yielding a pure product (80mg, 36%).

LC-MS：451.2[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ13.03(s,1H),12.91(s,1H),10.03(d,J＝12.0Hz,1H),8.01(s,1H),7.53(t,J＝6.4Hz,1H),7.41(d,J＝10.0Hz,1H),7.13-7.19(m,1H),3.81-3.90(m,2H),3.62-3.78(m,4H),3.51-3.58(m,6H),2.88(t,J＝7.2Hz,2H),2.58(t,J＝7.6Hz,2H),1.58(s,6H).

Example 30

1, 1-diisopropyl-3- (3- (5- (((4aR,7aR) -tetrahydro-2H- [1,4] dioxin [2,3-c ] pyrrol-6 (3H) -yl) methyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (((4aR,7aR) -tetrahydro-2H- [1,4]Dioxin [2,3-c ]]Pyrrol-6 (3H) -yl) methyl) -2H-benzo [4,5]Imidazole [1,2-c ]]Pyrrole [3,4-e]Pyrimidin-5 (4H) -one (0.2g,0.55mmol) was dissolved in DMAC (8mL) and diisopropylamine (2.77mL,19.78mmol) was added and heated to 100 deg.C for 48 hours. The reaction solution was evaporated to dryness, the residue was dissolved in methylene chloride/methanol (50/1,51mL), and washed once with saturated sodium bicarbonate solution (50mL) and saturated brine (50mL), and dried over anhydrous sodium sulfate (10 g). Evaporating the solvent and purifying by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), to give a crude product which was then purified by preparative chromatography to give a pure product (60mg, 23.43%).

LC-MS：468[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.99(s,1H),12.88(s,1H),9.71(d,J＝15.2Hz,1H),8.03(s,1H),7.49(t,J＝12.8Hz,1H),7.41(d,J＝10.0Hz,1H),7.13-7.19(m,1H),4.06-4.12(m,2H),3.82-3.90(m,2H),3.63-3.78(m,4H),3.56(t,J＝5.6Hz,2H),2.86-2.90(m,2H),2.58-2.61(m,2H),1.36(d,J＝6.8Hz,12H).

Example 31

1, 1-diisopropyl-3- (3- (5- (maleinomethyl) -1H-benzo [ d ] imidazol-2-yl) -1H-pyrazol-4-yl) urea

8- (Morpholinomethyl) -2H-benzo [4,5]]Imidazole [1,2-c ]]Pyrazoline [3,4-e]Pyrimidin-5 (4H) -one (0.2g,0.54mmol) and diisopropylamine (0.61mL,4.35mmol) were dissolved in DMF (8mL) and heated to 120 ℃ for 24 hours. The mixture is cooled to room temperature, concentrated and purified by column Chromatography (CH)₂Cl₂/CH₃OH (V/V) ═ 10/1), yielding a white solid (11mg, 4.8%).

LC-MS：423.3[M+1]⁺；

¹H NMR(400MHz,DMSO-d₆):δ12.98(s,1H),12.87(s,1H),9.71(d,J＝14.0Hz,1H),8.03(s,1H),7.50(t,J＝8.0Hz,1H),7.41(s,1H),7.12-7.23(m,1H),4.06-4.12(m,2H),3.56-3.62(m,4H),3.51(s,2H),3.34(s,2H),2.37(s,2H),1.36(d,J＝6.4Hz,12H).

Biological activity

In vitro Aurora-A and Aurora-B kinase inhibition assay

Compounds were diluted 50-fold of the highest final concentration with 100% DMSO. 100 μ L of the compound solution at this concentration was transferred to one well of a 96-well plate. For example, if 10. mu.M is used at the highest inhibitory concentration, a 500. mu.M solution in DMSO is prepared. Then, 10 equal concentration solutions were prepared by diluting the mixture with 100% DMSO in a 4-fold concentration gradient. Each concentration was then diluted 10-fold with water. Subsequently, 5 μ L of compound was added to each well of the assay plate. The "complete" and "blank" control wells were replaced with 10 μ L of 10% DMSO. Wherein the "complete" control well is the no compound group and the "blank" control well is the no kinase group. Then, 10. mu.L of a 2.5 Xkinase solution (kinase was added to 1.25 Xkinase base buffer (62.5mM HEPES pH7.5, 0.001875% Brij-35, 12.5mM MgCl)₂2.5mM DTT)) was added to each well of the assay plate. Incubate for 10 minutes at room temperature. mu.L of 2.5 Xpeptide solution (prepared by adding FAM-labeled peptide and ATP to 1.25 Xkinase base buffer) was added to each well of the detection plate. Incubate at 28 ℃ for 1 hour. mu.L of stop solution (100mM HEPES, pH7.5, 0.015% Brij-35, 0.2% Coating Reagent #3,50mM EDTA) to stop the reaction. Then reading the plate by a Caliper for detection, and finally, calculating the IC according to the Conversion value and the inhibition concentration mapping₅₀The value is obtained.

The test results are shown in table 2:

the data in Table 2 illustrate that in this assay, the compounds of the invention have the ability to inhibit Aurora-A kinase, Aurora-B kinase activity, and are derivatives of Aurora kinase inhibitors with superior inhibitory activity.

Claims

1. A substituted pyrazole derivative is shown as a formula (I) or a formula (Ia), or pharmaceutically acceptable salt of the structure shown as the formula (I) or the formula (Ia),

wherein:

q is-NH-, or-O-;

R¹is morpholinyl, C_5-12Bridged bicyclic radical, C_5-12Bridged bicyclic radical, C_5-12Condensed bicyclic group, or C_5-12A fused heterobicyclic group;

R²is R⁴R^4aN-C (═ O) -NH-or R⁵R^5aCH-C(＝O)-NH-；

R³Is H, or C_1-6An alkyl group;

wherein R is⁴Is H, C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or, R⁴And R^4aTogether with the N atom to which they are attached form C_2-9A heterocyclic group;

each R⁵And R^5aIndependently is H, or C_3-6A cycloalkyl group;

wherein, when Q is NH, and R¹Is morpholinyl, R³Is H, or C_1-6When the alkyl group is used, the alkyl group,

R²is R⁴R^4aN-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

wherein, R is¹，R²，R³，R⁴，R^4a，R⁵And R^5aThe bridged heterobicyclic group, bridged bicyclic group, fused heterobicyclic group, alkyl group, cycloalkyl group, cycloalkylalkyl group and heterocyclic group as described in (1) may be independently substituted with F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethylA radical or nitro, monosubstituted or polysubstituted in an identical or different manner.

2. The compound of claim 1, wherein,

q is-NH-;

R¹is morpholinyl, or the subformula:

wherein each Q¹And X³Independently is N, or CH;

each X¹，X²，X⁵，X⁶And X⁷Independently is-CH₂-，-O-，-NR^9a-, or-S-;

each q, m, p, r and s is independently 1 or 2;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C (═ O) -NH-or R⁵R^5aCH-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

R^4ais C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or, R⁴And R^4aTogether with the N atom to which they are attached form a 5-6 membered heterocyclyl;

each R⁵And R^5aIndependently is H or C_3-6A cycloalkyl group;

wherein, R is²，R³，R⁴，R^4a，R⁵And R^5aZhongshiSaid alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently;

wherein, when Q is NH, and R¹Is morpholinyl, R³Is H, or C_1-4When the alkyl group is used, the alkyl group,

R²is R⁴R^4aN-C(＝O)-NH-；

Wherein R is⁴Is C_2-6An alkyl group;

3. the compound of claim 2, wherein,

R¹is morpholinyl or the following subformula:

R²is R⁴R^4aN-C (═ O) -NH-or R⁵R^5aCH-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

wherein R is⁴Is H, methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethylene;

R^4ais methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl or cyclopropylmethylene; or, R⁴And R^4aTogether with the N atom to which they are attached form the following subformula:

each R⁵And R^5aIndependently is H, cyclopropyl, cyclopentyl, or cyclohexyl;

wherein, R is²，R³，R⁴，R^4a，R⁵And R^5aSaid methyl, ethyl, propyl, isopropyl, 1-ethyl-propyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethylene, heterocyclyl and said R¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently;

wherein, when Q is NH, and R¹Is morpholinyl, R³When H, methyl, ethyl, or propyl,

R²is R⁴R^4aN-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

4. the compound of claim 1, which is a substituted pyrazole derivative represented by formula (II) or formula (IIa),

wherein:

R¹is of the sub-structure:

wherein each Q¹And X³Independently is N, or CH;

each of q, m, p, r and s is independently 0,1 or 2;

each R^9aIndependently is H, acetyl, methyl or ethyl;

R²is R⁴R^4aN-C (═ O) -NH-or R⁵R^5aCH-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

each R⁵And R^5aIndependently is H or C_3-6A cycloalkyl group;

wherein, R is²，R³，R⁴，R^4a，R⁵And R^5aThe alkyl group, the cycloalkyl group, the heterocyclic group, the cycloalkylalkyl group and the R in (1)¹The sub-structural formula can be independently represented by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy radicals, cyanogenRadical, hydroxy radical, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

5. The compound of claim 4, wherein,

R¹is of the sub-structure:

R²is R⁴R^4aN-C (═ O) -NH-or R⁵R^5aCH-C(＝O)-NH-；

R³Is H, methyl, ethyl, or propyl;

each R⁵And R^5aIndependently H, cyclopropyl, cyclopentyl or cyclohexyl.

6. The substituted pyrazole derivatives according to claim 1, which are substituted pyrazole derivatives represented by formula (IIb) or formula (IIab), or pharmaceutically acceptable salts thereof,

wherein:

R²is R⁴R^4aN-C(＝O)-NH-；

R³Is H, or C_1-4An alkyl group;

wherein R is⁴Is C_2-6An alkyl group;

wherein, R is²，R³，R⁴And R^4aThe alkyl group and the heterocyclic group in (1) may be independently replaced by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

7. The compound of claim 6, wherein,

R²is R⁴R^4aN-C(＝O)-NH-；

Wherein R is⁴Is ethyl, propyl, isopropyl, butyl or 1-ethyl-propyl;

R³is H, methyl, ethyl, or propyl;

wherein, theR is as described²，R³，R⁴And R^4aThe methyl, ethyl, propyl, isopropyl, butyl, 1-ethyl-propyl and pentyl groups in (1) may be independently substituted by F, Cl, Br, C_1-4Alkyl, amino, C_1-4Alkoxy, cyano, hydroxy, C_1-4Alkylamino, oxo (═ O), acetyl, trifluoromethyl or nitro, monosubstituted or polysubstituted, identically or differently.

8. The compound of claim 1, comprising the structure of one of:

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1.

10. The pharmaceutical composition of claim 9, further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

11. The pharmaceutical composition of claim 9, further comprising an additional therapeutic agent that is at least one of a chemotherapeutic agent, an antiproliferative agent, an immunosuppressive agent, an immunostimulatory agent, an agent useful for treating atherosclerosis, and an agent useful for treating pulmonary fibrosis.

12. The pharmaceutical composition of claim 11, wherein the additional therapeutic agent is chlorambucil (chlomambucil), melphalan (melphalan), cyclophosphamide (cyclophosphamide), ifosfamide (ifosfamide), busulfan (busufan), carmustine (carmustine), lomustine (lomustine), streptozotocin (streptozotocin), cisplatin (cissplatin), carboplatin (carboplatin), oxaliplatin (oxaliplatin), oxaliplatin (oxliplatin), dacarbazine (dacarbazine), temozolomide (temozolomide), procarbazine (procarbazine), methotrexate (methtrotrexate), fluorouracil (fluorouracil), gemcitabine (gent), paclitaxel (rituximab), paclitaxel (muramyl), paclitaxel (muramylabrin), paclitaxel (muramylabratinb), paclitaxel (muramyl), (muramyl, rituximab (muramyl), (rituximab), paclitaxel), (rituximab (fossilib), fossilibinin), paclitaxel (gent (morphine (gent), paclitaxel (muramylonitine (muramylabrin), doxin), fossildenafibratin (doxylamine (morphine), or (morphine), paclitaxel), or (doxorubicin (murafenib), or (doxorubicin (murafenib), or (doxorubicin (murafeni (doxorubicin (murafenib), or (doxorubicin), or (murafeni (murafenib), or (luteinib), or (.

13. Use of a compound according to claim 1 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prevention, treatment or alleviation of a condition mediated by eulerian kinase in a patient.

14. Use according to claim 13, wherein the orula kinase is orula-a kinase or orula-B kinase.

15. Use of a compound of claim 1 or a pharmaceutical composition of claim 9 for the manufacture of a medicament for the prevention, treatment, or amelioration of a proliferative disease in a patient.

16. The use according to claim 15, wherein the proliferative disease is colorectal cancer, gastric cancer, breast cancer, lung cancer, liver cancer, prostate cancer, pancreatic cancer, thyroid cancer, bladder cancer, kidney cancer, brain tumors, neck cancer, central nervous system cancer, glioblastoma, myeloproliferative disorders, atherosclerosis, pulmonary fibrosis, leukemia, lymphatic cancer, rheumatic diseases, chronic inflammation, cryoglobulinemia, non-lymphoid reticulum tumors, papular mucinous deposition, familial splenic anemia, multiple myeloma, amyloidosis, solitary plasmacytoma, heavy chain disease, light chain disease, malignant lymphoma, chronic lymphocytic leukemia, primary macroglobulinemia, hemimolecular disease, monocytic leukemia, primary macroglobulinemic purpura, secondary benign monoclonal gammopathy, osteolytic lesions, myeloma, acute lymphocytic leukemia, lymphoblastoma, partial non-hodgkin lymphoma, Sezary syndrome, infectious mononucleosis, acute histiocytosis, hodgkin lymphoma, hairy cell leukemia, colon cancer, rectal cancer, intestinal polyps, diverticulitis, colitis, pancreatitis, hepatitis, small cell lung cancer, neuroblastoma, neuroendocrine cell tumor, islet cell tumor, medullary thyroid cancer, melanoma, retinoblastoma, uterine cancer, chronic hepatitis, cirrhosis, ovarian cancer, cholecystitis, head and neck squamous cancer, digestive tract malignancy, non-small cell lung cancer, cervical cancer, testicular tumor, bladder cancer, or myeloma.