CN101006063A - Five-membered heterocycles useful as serine protease inhibitors. - Google Patents
Five-membered heterocycles useful as serine protease inhibitors. Download PDFInfo
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- CN101006063A CN101006063A CN200580027843.XA CN200580027843A CN101006063A CN 101006063 A CN101006063 A CN 101006063A CN 200580027843 A CN200580027843 A CN 200580027843A CN 101006063 A CN101006063 A CN 101006063A
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- phenyl
- replace
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- alkyl
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Abstract
The present invention provides a method for treating a thrombotic or an inflammatory disorder administering to a patient in need thereof a therapeutically effective amount of at least one compound of Formula (I) or Formula (V): (I) or a stereoisomer or pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, L, Z, R3, R4, R6, R11, X1, X2, and X3 are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also provides compounds within the scope of Formula I and relates to pharmaceutical compositions comprising these compounds.
Description
Technical field
The invention provides a kind of method for the treatment of thrombotic or inflammatory diseases, this method comprises at least a formula (I) or the formula V compound to patient's drug treatment significant quantity of needs treatment:
Perhaps its steric isomer or pharmacy acceptable salt or solvate forms, wherein variables A, L, Z, R
3, R
4, R
6, R
11, X
1, X
2And X
3As defined herein.Formula (I) compound can be used as in coagulation cascade and/or the contact activation system for example selective depressant of zymoplasm, factor Xa, factor XI, plasma thromboplastin antecedent a, factors IX a, factor VIIa and/or plasma kallikrein of serine protease.The present invention be more particularly directed to compound as factor XI, plasma thromboplastin antecedent a selective depressant or fXIa and plasma kallikrein double inhibitor.The invention still further relates to pharmaceutical composition that comprises these compounds and the method for using them.
Background technology
Factor XI, plasma thromboplastin antecedent a is a kind of blood plasma serine protease that participates in blood coagulation.Because blood coagulation is an essential and part and parcel of regulating the organism homeostasis, therefore unusual blood coagulation also can produce deleterious effects.For example, thrombosis is in the blood vessel or the reason that blood clot forms or occurs in the chambers of the heart.This blood clot can be deposited on the circulation of blood vessel internal congestion, and cardiac trigger onste or apoplexy.Thrombotic disease is the fatal and main reason that disables in the industrialization world.
Blood coagulation combines generation factor VIIa (FVIIa) by tissue factor (TF) in vivo and causes with factor VII (FVII).The TF:FVIIa mixture that is produced makes factors IX (FIX) and factor X (FX) activation, thereby causes producing factor Xa (FXa).The FXa that is produced this path be organized factor pathway inhibitor (TFPI) close before the catalysis thrombogen be converted into a spot of zymoplasm.Then, coagulation process by the zymoplasm of catalytic amount by feedback activation factor V, VIII and XI further advance (Walsh, P.N.Thromb.Haemostasis.1999,82,234-242).Factor XI, plasma thromboplastin antecedent a plays a part crucial in this expansion loop advances, and therefore becomes noticeable target in the antithrombotic treatment.
The another kind of approach that causes blood coagulation can be when blood contacts artificial surface (for example hemodialysis, ' extracorporeal circulation ' operation on vessels of heart, vascular graft, bacterium septicemia during) be activated.This process also is called contact activation.Surface adsorption factor XI, plasma thromboplastin antecedent I causes factor XI, plasma thromboplastin antecedent I molecule occurred conformation to change, thereby promotes the activation of proteolytic activity factor XI, plasma thromboplastin antecedent I molecule (factor XI, plasma thromboplastin antecedent Ia and factor XI, plasma thromboplastin antecedent If).Factor XI, plasma thromboplastin antecedent Ia (or XIIf) has a lot of target proteins, comprises the former and factor XI, plasma thromboplastin antecedent of plasma kallikrein.The further activation factor XII of active plasma kallikrein causes enlarging contact activation.Contact activation is the process of a kind of surface mediation, participate in the adjusting of part thrombosis and inflammation, and to small part by molten fibre-, compensatory-, prokinin/kassinin kinin-and the mediation of other body fluid and cellularity path (referring to summary, Coleman, R.ContactActivation Pathway, p103-122 among the Hemostasis and Thrombosis, Lippincott Williams ﹠amp; Wilkins 2001; Schmaier A.H.ContactActivation, the p105-128 among the Thrombosis and Hemorrhage, 1998).
Factor XI, plasma thromboplastin antecedent is a kind of proenzyme of serine protease of trypsin-like, and it is present in the blood plasma with relatively low concentration.The proteoclastic activation in inherent R369-I370 key place produces a long-chain (369 amino acid) and a short chain (238 amino acid).The latter comprises the catalysis triplet state (H413, D464 and S557) of a typical trypsin-like.Believe that factor XI, plasma thromboplastin antecedent is taken place on electronegative surface by the activation meeting of zymoplasm, is most likely on the activatory platelet surface and takes place.Thrombocyte contains high affinity (0.8nM) specific site (130-500/ thrombocyte) of activated factor XI.After the activation, factor XI, plasma thromboplastin antecedent a keeps and surface bonding, and with factors IX be identified as its normal macromolecule substrate (Galiani, D.Trends Cardiovasc.Med.2000,10,198-204).
Except that above-mentioned feedback activate mechanism, the fibrinolytic inhibitor (TAFI) of activated by thrombin thrombin activation, a kind of blood plasma carboxypeptidase, its cracking carbon teminal Methionin also stays on the scleroproein arginine residues, reduces fibrinous promotion tissue type plasminogen activator (tPA) dependent form Profibrinolysin activatory ability.In the presence of FXIa antibody, the dissolving of blood clot can not rely on blood plasma TAFI concentration and carry out sooner (Bouma, B.N. etc., Thromb.Res.2001,101,329-354).Therefore, expection factor XI, plasma thromboplastin antecedent a inhibitor has the effect of anti-freezing and molten fibre.
The heredity evidence shows that normal homeostasis does not need factor XI, plasma thromboplastin antecedent, and hint factor XI, plasma thromboplastin antecedent mechanism forms mechanism than competitive antithrombotic and has more superior security feature.Compare with hemophilia A (Factor IX defective) or hemophilia B (factors IX defective), the factor XI, plasma thromboplastin antecedent transgenation causes factor XI, plasma thromboplastin antecedent defective (hemophilia C), the result only causes the slight physique of bleeding to moderate, and principal character is hemorrhage after postoperative or the wound, hematostaxis seldom occurs.Postoperative hemorrhage occurs in the tissue (for example, oral cavity and urogenital system) with high density endogenous cellulolytic activity mostly.Under without any the situation of the history of bleeding before, unexpectedly identified owing to the prolongation of APTT (built-in system) before the art.
The following fact has further been supported the security that XIa has suppressed as the raising of anticoagulant therapy: do not pound out that the mouse experience is normal grows but do not have the proteic factor XI, plasma thromboplastin antecedent of detection limit factor XI, plasma thromboplastin antecedent, and have a normal life span.Do not find spontaneous hemorrhage evidence.APTT (built-in system) prolongs in the mode that gene dosage relies on.What is interesting is that even blood coagulation system is being carried out severe irritation (afterbody is cross-section) afterwards, the bleeding time hybridizes to compare with wild type and heterozygous does not have significant the prolongation yet.(Gailiani, D.Frontiers in Bioscience 2001,6,201-207; Gailiani, D. etc., Blood Coagulation and Fibrinolysis 1997,8,134-144).These observed results are connected, show that high-level supressor XIa will be tolerated well.This and other coagulation factor gene target test has formed contrast.
The activation of body intrinsic factor XI can be by measuring with the mixture of Cl inhibitor or alpha1 Anti-trypsin formation.In the research to 50 Acute Myocardial Infarctions (AMI) patient, about 25% patient has the mixture ELISA value that is higher than normal range.These researchs can be looked at as at least the evidence that in AMI patient's the subgroup activation of factor XI, plasma thromboplastin antecedent helps the formation of zymoplasm (Minnema, M.C. etc., Arterioscler.Thromb.Vasc.Biol.2000,20,2489-2493).Another research the degree of coronary sclerosis and and alpha1 Anti-trypsin compound factor XI, plasma thromboplastin antecedent a between established positive correlation (Murakami, T. etc., ArteriosclerThromb Vasc Biol 1995,15,1107-1113).In another research, the factor XI, plasma thromboplastin antecedent level is higher than 90% patient, the risk of venous thrombosis will raise 2.2 times (Meijers, J.C.M. etc., N.Engl.J.Med.2000,342,696-701).
Plasma kallikrein is a kind of proenzyme of serine protease of trypsin-like, and it exists with the concentration of 35 to 50 μ g/mL in blood plasma.Its gene structure is similar to factor XI, plasma thromboplastin antecedent, and generally, the aminoacid sequence of plasma kallikrein and factor XI, plasma thromboplastin antecedent have 58% homology.The proteoclastic activation in the inherent I389-R390 key place that factor XI, plasma thromboplastin antecedent Ia causes produces a long-chain (371 amino acid) and a short chain (248 amino acid).The avtive spot of kallikrein is contained on the short chain.The short chain of plasma kallikrein and proteinase inhibitor reaction comprise alpha2 Macroglobulin and Cl inhibitor.What is interesting is that in the presence of high molecular weight kininogen (HMWK), heparin has quickened the inhibition of Antithrombin III to plasma kallikrein significantly.In blood, most of plasma kallikreins are with the form circulation of HMWK mixture.Kallikrein cracking HMWK is to discharge bradykinin.The release of bradykinin causes vascular permeability to improve and the vasorelaxation enhancing (referring to summary, Coleman, R.Contact ActivationPathway, the p103-122 among the Hemostasis and Thrombosis, LippincottWilliams ﹠amp; Wilkins 2001; Schmaier A.H.Contact Activation, the p105-128 among the Thrombosis and Hemorrhage, 1998).
Protein or the polypeptide of the supressor XIa that is reported are disclosed among the WO01/27079.Yet, in pharmacy, adopt the small molecules organic compound to have more advantage, for example micromolecular compound has the consistency of better oral administration biaavailability and preparation preparation usually, compares the release that more helps medicine with high molecular weight protein or polypeptide.The micromolecular inhibitor of factor XI, plasma thromboplastin antecedent a is disclosed among U.S. patent application gazette US20040235847A1 and the US patent application gazette US20040220206A1.
And, still need to find to compare the new compound of pharmacological characteristics with improvement with known serpin.For example, preferred discovery has the inhibition activity of improved factor XI, plasma thromboplastin antecedent a and with respect to other serine proteases XIa is had optionally new compound.And preferred discovery has improved plasma kallikrein and suppresses activity and with respect to other serine proteases plasma kallikrein is had optionally new compound.Also need and preferred the discovery: (a) medicinal property following but be not limited to the following compound that has the characteristic of advantage and improvement aspect one or more; (b) dosage requirement; (c) reduce haemoconcentration peak-to the factor of-paddy feature; (d) factor of increase receptor site active medicine concentration; (e) reduce the tendentious factor of clinical medicine-drug interaction; (f) factor of minimizing harmful side effect possibility; (g) improve the factor of production cost or feasibility.
Summary of the invention
Summary of the invention
The invention provides new five-membered ring derivative and analogue thereof, it can be used as the serine protease particularly selective depressant of factor XI, plasma thromboplastin antecedent a and/or plasma kallikrein, perhaps its steric isomer or pharmacy acceptable salt, solvate or prodrug.
The present invention also provides method and the intermediate for preparing The compounds of this invention or its steric isomer or pharmacy acceptable salt, solvate or prodrug form.
The present invention also provides pharmaceutical composition, and it comprises at least a The compounds of this invention or its pharmacy acceptable salt, solvate or the prodrug form of a kind of pharmaceutically acceptable carrier and treatment significant quantity.
The present invention also provides a kind of method of regulating coagulation cascade and/or contact activation system, comprises at least a The compounds of this invention or its pharmacy acceptable salt, solvate or prodrug form to host's drug treatment significant quantity of this treatment of needs.
The present invention also provides a kind of method for the treatment of thrombotic disease, comprises at least a The compounds of this invention or its pharmacy acceptable salt, solvate or prodrug form to host's drug treatment significant quantity of this treatment of needs.
The present invention also provides a kind of method for the treatment of the inflammatory diseases disorder, comprises at least a The compounds of this invention or its pharmacy acceptable salt, solvate or prodrug form to host's drug treatment significant quantity of this treatment of needs.
The present invention also provides new five-membered ring derivative and analogue thereof, is used for the treatment of.
The present invention also provides the purposes of five-membered ring derivative and analogue thereof, is used to prepare the medicine for the treatment of thrombotic disease.
The present invention also provides the purposes of five-membered ring derivative and analogue thereof, is used to prepare the medicine for the treatment of inflammatory diseases.
Is this discovery of inhibitor of inhibitor and/or the plasma kallikrein of effective factor XI, plasma thromboplastin antecedent a based on the inventor at present claimed new compound of the present invention or its pharmacy acceptable salt or prodrug form; finished these and other embodiment, it will become clearly in following detailed description.
Detailed Description Of The Invention
In aspect first, the present invention especially comprises formula (I) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-10Carbocyclic ring perhaps comprises carbon atom and 1-4 and is selected from N, O and S (O)
pHeteroatomic 5-to 12-unit heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, then A is not connected on the L by any nitrogen-atoms on the A ring;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-C
3Alkyl) ,-N (C
1-C
3Alkyl)
2,-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7CO
2R
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-C
3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
1And R
2When group was substituted on the adjacent annular atoms, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b,-(CH
2)
rSR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c,-C (O)-C
1-C
4Alkyl ,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3c,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
26Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group was positioned on the adjacent atom, they can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
6Be H;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-to 10-unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl or-(CH
2)
n-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When group was connected on the identical nitrogen-atoms, it was combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-4Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-to 10-unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(Cl-4 alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl, heteroaryl are chosen wantonly by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the identical nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
d(the CH that replaces
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bGet-(CR
14R
15)
r-C
3-10Carbocyclic ring or-(CR
14R
15)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
Perhaps, R
14With R
15In conjunction with formation=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heterocyclic group are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5 to 10 yuan of heteroaryls)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; And
S is selected from 1,2,3 and 4 at every turn when occurring;
Prerequisite is:
(a) when L be-during C (O) NH-, R
3Be not 2,4 dichloro benzene base, 4-nitrophenyl or pentafluorophenyl group;
(b) when L be-during C (O) NH-, R
11Be not-CH
2-(3-indyl) ,-(CH
2)
4NHCO
2(t-Bu) or-(CH
2)
4NH
2
In aspect second, the present invention includes formula (I) compound, in the scope aspect first, wherein:
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2CONR
10-or-NR
10COCH
2-;
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
r-CONR
8R
9, by 0-2 R
11aThe C that replaces
1-6Alkyl, by 0-2 R
11aThe C that replaces
2-6Thiazolinyl, by 0-2 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
In the third aspect, the present invention includes formula (I) compound, in the scope aspect first, wherein:
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-C (Me)
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aWith 0-1 R
3dThe naphthyl that replaces, by 0-2 R
3aWith 0-1 R
3dThe indanyl that replaces or-(CH
2)
r-5 to 10 yuan comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, CF
3, OMe, NH
2, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph; And
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace.
In aspect the 4th, the present invention includes formula (II) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl (phthalazinyl);
L is-C (O) NH-or-NHC (O)-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aThe phenyl that replaces, by 0-2 R
3aThe naphthyl that replaces, by 0-2 R
3aIndanyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aReplace;
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
4bReplace;
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or by 0-2 R
11bReplace-(CH
2)
r-5-to 10-unit heteroaryl, and be selected from thiazolyl, azoles base, triazolyl, tetrazyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indoline base (indolinyl), isoindoline base, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, tetrahydric quinoline group and tetrahydro isoquinolyl; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph or Bn;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
In aspect the 5th, the present invention includes formula (II) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-CO
2Me-cyclohexyl, 4-CONH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl, phenyl, 4-Me-phenyl, 3-OMe-phenyl, 4-CH
2NH
2-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-amidino groups-phenyl, 4-amidino groups-phenyl, 2-F-4-Me-phenyl, 2-Bn-4-CH
2NH
2-phenyl, 4-SO
2NH
2-phenyl, 2-F-5-OMe-phenyl, 2-F-4-Cl-phenyl, 2-F-4-CH
2NH
2-phenyl, 2-F-4-CONH
2-phenyl, 2-Cl-4-CONH
2-phenyl, 2-Et-4-CH
2NH
2-phenyl, 2-NHEt-4-CH
2NH
2-phenyl, 2-OMe-4-CONH
2-phenyl, 3-OMe-4-CONH
2-phenyl, 1,2,3,4-naphthane-2-base, 3-Cl-thiophene-2-base, indoles-5-base, indoles-6-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-indazole-5-base, 1-Me-3-NH
2-indazole-6-base, 3-NH
2-benzisoxa azoles-6-base, 1,2,3,4-tetrahydroisoquinoline-6-base, 1,2,3,4-tetrahydroisoquinoline-3-base, 2-COPh-1,2,3,4-tetrahydroisoquinoline-3-base, 2-CO
2Bn-1,2,3,4-tetrahydroisoquinoline-3-base, 1,2,3,4-tetrahydroisoquinoline-1-ketone-6-base, 2H-isoquinoline 99.9-1-ketone-6-base, isoquinoline 99.9-6-base, 1-NH
2-isoquinoline 99.9-6-base, 1-NH
2-3-Me-isoquinoline 99.9-6-base, 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base, 4-NH2-quinazoline-7-base, 3H-quinazoline-4-one-7-base,
R
3Be CO
2H, CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, phenyl, styroyl ,-(CH=CH)-and phenyl, 3-xenyl, 4-xenyl, 3,4-methylenedioxyphenyl, 1-naphthyl, 2-naphthyl, 3-NH
2-phenyl, 3-NMe
2-phenyl, 4-OPh-phenyl, 4-OBn-phenyl, 4-(t-fourth oxygen methyl)-phenyl, 4-SO
2Me-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 3-Br-phenyl, 4-Br-phenyl, 3-OH-phenyl, 4-OH-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 3-CF
3-phenyl, 4-CF
3-phenyl, 3-CO
2H-phenyl, 4-CO
2H-phenyl, 3-CO
2Me-phenyl, 4-CO
2Me-phenyl, 3-CH
2CO
2H-phenyl, 4-CH
2CO
2H-phenyl, 4-CH
2CO
2Me-phenyl, 3-CH
2CO
2Et-phenyl, 4-CH
2CO
2Et-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-CH
2CONH
2-phenyl, 4-CH
2CONH
2-phenyl, 4-CONHMe-phenyl, 4-CONMe
2-phenyl, 4-amidino groups-phenyl, 3-NHCOMe-phenyl, 4-NHCOMe-phenyl, 4-NHCO
2Me-phenyl, 4-SO
2NH
2-phenyl, 3-NHSO
2Me-phenyl, 4-NHSO
2Me-phenyl, 2,4-two fluoro-phenyl, 3-F-4-CN-phenyl, 3-CN-5-F-phenyl, 3-F-4-CONH
2-phenyl, 3-CO
2H-4-CN-phenyl, 3-NMe
2-4-CN-phenyl, 3-Ph-4-CONH
2-phenyl, 4-(2-oxo-1-piperidino-(1-position only))-phenyl, thiazol-2-yl, 4-CO
2Me-thiazol-2-yl, 4-CONH
2-thiazol-2-yl, 1-Bn-pyrazoles-4-base, 5-Ph- azoles-2-base, 5-CONH
2-thiophene-2-base, 5-CO
2H-thiophene-2-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, 6-NH
2-pyridin-3-yl, benzimidazolyl-2 radicals-Ji, 1-Me-benzimidazolyl-2 radicals-Ji, benzoxazol-2-base, benzothiazole-2-base, 3-NH
2-benzisoxa azoles-6-base, 3-NH
2-benzisoxa azoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base, 4-imino--3,4-dihydro-2H-phthalazines-1-ketone-7-base, 3-(5-tetrazyl)-phenyl, 2,3-dihydro-isoindole-1-ketone-6-base, quinoline-5-base, quinoline-6-base, quinoline-8-base, isoquinoline 99.9-5-base, 2H-isoquinoline 99.9-1-ketone-6-base, 2,4-diamino quinazoline-7-base or 4-NH
2-quinazoline-7-base;
R
4Be H, Me, Br, Cl, CF
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For Me, neo-pentyl, cyclohexyl methyl ,-CH
2CH
2CONHBn ,-CH
2CH
2CONH (CH
2CH
2Ph) ,-CH
2CH
2CON (Me) Bn, benzyl, styroyl, 2-Me-benzyl, 3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl, 4-Br-benzyl, 3-CF
3-benzyl, 4-CF
3-benzyl, 2-NH
2-benzyl, 3-NH
2-benzyl, 2-NO
2-benzyl, 3-NO
2-benzyl, 4-NO
2-benzyl, 3-OMe-benzyl, 4-OMe-benzyl, 3-OCF
2H-benzyl, 2-OCF
3-benzyl, 3-OCF
3-benzyl, 2-OPh-benzyl, 3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl, 3-CO
2H-benzyl, 3-CO
2Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl, 2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N (Me) COPh-benzyl, 3-(NHCOCH
2CH
2Ph)-benzyl, 2-NHSO
2Ph-benzyl, 3-NHSO
2Ph-benzyl, 3-[SO
2N (Me) Ph]-benzyl, 3-[N (Me) SO
2Ph]-benzyl, 3-[CONH (i-Bu)]-benzyl, 3-[CONH (t-Bu)]-benzyl, 3-[CONH (isopentyl)]-benzyl, 3-[CONH (2-Me-Ph)]-benzyl, 3-[CONH (3-Me-Ph)]-benzyl, 3-[CONH (4-Me-Ph)]-benzyl, 3-[CONH (4-F-Ph)]-benzyl, 3-[CONH (1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl, 3-[CONH (4-Cl-Bn)]-benzyl, 3-[CONH (4-OMe-Bn)]-benzyl, 3-[CONHCH
2CH
2Ph]-benzyl, 3-[CONHCH
2CH
2(4-OMe-Ph)]-benzyl, 3-[CONHCH
2CH
2(2-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(3-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(4-Cl-Ph)]-benzyl, 3-[CONH (CH
2)
3Ph]-benzyl, 3-[CONMe
2]-benzyl, 3-[CON (Me) are (Et)]-benzyl, 3-[CON (Me) (i-Pr)]-benzyl, 3-[CON (Me) (i-Bu)]-benzyl, 3-[CON (Me) Ph]-benzyl, 3-[CON (Me) (3-Me-Ph)]-benzyl, 3-[CON (Me) (4-Me-Ph)]-benzyl, 3-[CON (Me) Bn]-benzyl, 3-[CON (Me) (3-Cl-Bn)]-benzyl, 3-[CON (Me) (4-Cl-Bn)]-benzyl, 3-[CON (Me) (CH
2CH
2Ph)]-benzyl, 3-[CON (Et) Ph]-benzyl, 3-[CO (1-piperidino-(1-position only))]-benzyl, 3-[CO (4-Ph-1-piperidino-(1-position only))]-benzyl, 3-[CO (1,2,3,4-tetrahydroisoquinoline subbase (isoquinolino))]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl, 4-Ph-benzyl, 3-styroyl-benzyl ,-CH
2OBn ,-CH
2SBn, 1-menaphthyl, 2-menaphthyl, thiazole-4-ylmethyl, pyridine-2-ylmethyl, pyridin-3-yl methyl, pyridin-4-yl methyl, 1-Bn-imidazol-4 yl methyl, benzothiazole-2-ylmethyl,
In aspect the 6th, the present invention includes formula (II) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
R
3Be 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-benzisoxa azoles-6-base, 3-NH
2-benzisoxa azoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base, isoquinoline 99.9-5-base, quinoline-5-base, quinoline-8-base, 2H-isoquinoline 99.9-1-ketone-6-base, 2,4-diamino quinazoline-7-base or 4-NH
2-quinazoline-7-base.
In aspect the 7th, the present invention includes formula (IIa) compound, in the scope aspect the 6th, wherein:
L is-C (O) NR
10-or-NR
10C (O)-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-C (Me)
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph;
R
11Be C
1-C
6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-N
8CO
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph or Bn.
In aspect the 8th, the present invention includes formula (II) compound, in the scope aspect the 7th, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl; And
R
10Be H.
In aspect the 9th, the present invention includes formula (II) compound, in the scope aspect the 8th, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-CO
2Me-cyclohexyl, 4-CONH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl, phenyl, 4-Me-phenyl, 3-OMe-phenyl, 4-CH
2NH
2-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-amidino groups-phenyl, 4-amidino groups-phenyl, 2-F-4-Me-phenyl, 2-Bn-4-CH
2NH
2-phenyl, 4-SO
2NH
2-phenyl, 2-F-5-OMe-phenyl, 2-F-4-Cl-phenyl, 2-F-4-CH
2NH
2-phenyl, 2-F-4-CONH
2-phenyl, 2-Cl-4-CONH
2-phenyl, 2-Et-4-CH
2NH
2-phenyl, 2-NHEt-4-CH
2NH
2-phenyl, 2-OMe-4-CONH
2-phenyl, 3-OMe-4-CONH
2-phenyl, 1,2,3,4-naphthane-2-base, 3-Cl-thiophene-2-base, indoles-5-base, indoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-indazole-5-base, 1-Me-3-NH
2-indazole-6-base, 3-NH
2-benzisoxa azoles-6-base, 1,2,3,4-tetrahydroisoquinoline-6-base, 1,2,3,4-tetrahydroisoquinoline-3-base, 2-COPh-1,2,3,4-tetrahydroisoquinoline-3-base, 2-CO
2Bn-1,2,3,4-tetrahydroisoquinoline-3-base, 1,2,3,4-tetrahydroisoquinoline-1-ketone-6-base, 2H-isoquinoline 99.9-1-ketone-6-base, isoquinoline 99.9-6-base, 1-NH
2-isoquinoline 99.9-6-base, 1-NH
2-3-Me-isoquinoline 99.9-6-base, 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base, 4-NH
2-quinazoline-7-base, 3H-quinazoline-4-one-7-base,
R
4Be H, Me, Br, Cl, CF
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For Me, neo-pentyl, cyclohexyl methyl ,-CH
2CH
2CONHBn ,-CH
2CH
2CONH (CH
2CH
2Ph) ,-CH
2CH
2CON (Me) Bn, benzyl, styroyl, 2-Me-benzyl, 3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl, 4-Br-benzyl, 3-CF
3-benzyl, 4-CF
3-benzyl, 2-NH
2-benzyl, 3-NH
2-benzyl, 2-NO
2-benzyl, 3-NO
2-benzyl, 4-NO
2-benzyl, 3-OMe-benzyl, 4-OMe-benzyl, 3-OCF
2H-benzyl, 2-OCF
3-benzyl, 3-OCF
3-benzyl, 2-OPh-benzyl, 3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl, 3-CO
2H-benzyl, 3-CO
2Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl, 2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N (Me) COPh-benzyl, 3-(NHCOCH
2CH
2Ph)-benzyl, 2-NHSO
2Ph-benzyl, 3-NHSO
2Ph-benzyl, 3-[SO
2N (Me) Ph]-benzyl, 3-[N (Me) SO
2Ph]-benzyl, 3-[CONH (i-Bu)]-benzyl, 3-[CONH (t-Bu)]-benzyl, 3-[CONH (isopentyl)]-benzyl, 3-[CONH (2-Me-Ph)]-benzyl, 3-[CONH (3-Me-Ph)]-benzyl, 3-[CONH (4-Me-Ph)]-benzyl, 3-[CONH (4-F-Ph)]-benzyl, 3-[CONH (1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl, 3-[CONH (4-Cl-Bn)]-benzyl, 3-[CONH (4-OMe-Bn)]-benzyl, 3-[CONHCH
2CH
2Ph]-benzyl, 3-[CONHCH
2CH
2(4-OMe-Ph)]-benzyl, 3-[CONHCH
2CH
2(2-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(3-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(4-Cl-Ph)]-benzyl, 3-[CONH (CH
2)
3Ph]-benzyl, 3-[CONMe
2]-benzyl, 3-[CON (Me) are (Et)]-benzyl, 3-[CON (Me) (i-Pr)]-benzyl, 3-[CON (Me) (i-Bu)]-benzyl, 3-[CON (Me) Ph]-benzyl, 3-[CON (Me) (3-Me-Ph)]-benzyl, 3-[CON (Me) (4-Me-Ph)]-benzyl, 3-[CON (Me) Bn]-benzyl, 3-[CON (Me) (3-Cl-Bn)]-benzyl, 3-[CON (Me) (4-Cl-Bn)]-benzyl, 3-[CON (Me) (CH
2CH
2Ph)]-benzyl, 3-[CON (Et) Ph]-benzyl, 3-[CO (1-piperidino-(1-position only))]-benzyl, 3-[CO (4-Ph-1-piperidino-(1-position only))]-benzyl, 3-[CO (1,2,3,4-tetrahydroisoquinoline subbase)]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl, 4-Ph-benzyl, 3-styroyl-benzyl ,-CH
2OBn ,-CH
2SBn, 1-menaphthyl, 2-menaphthyl, thiazole-4-ylmethyl, pyridine-2-ylmethyl, pyridin-3-yl methyl, pyridin-4-yl methyl, 1-Bn-imidazol-4 yl methyl, benzothiazole-2-ylmethyl,
In aspect the tenth, the present invention includes formula (II) compound, in the scope aspect the 8th, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl or 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base;
L is-C (O) NH-or NHC (O)-;
R
3Be indazole-5-base, indazole-6-base, 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base or 4-NH
2-quinazoline-7-base;
R
4Be H, Me, F, Br, Cl or CF
3And
R
11For by 0-2 R
11bThe benzyl that replaces.
In aspect the 11, the present invention includes formula (II) compound, in the scope aspect the tenth, wherein:
A is 4-CH
2NH
2-cyclohexyl;
L is-C (O) NH-; And
R
3Be 3-NH
2-indazole-6-base or 4-NH
2-quinazoline-7-base.
In aspect the 12, the present invention includes formula (II) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
A is by 0-2 R
1With 0-1 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NR
10-or-NR
10C (O)-;
R
3For-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace.
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace; And
R
11For by 0-2 R
11bThe benzyl that replaces.
In another aspect, the present invention includes formula (II) compound, in the scope aspect the 12, wherein:
R
3For-(CH
2)
r-9 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic bicyclic heterocycles, wherein said heterocycle is by 0-3 R
3aReplace.
In aspect the 13, the present invention includes formula (II) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NR
10-or-NR
10C (O)-;
R
3For by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl or by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl;
R
4Be H, Me, Br, Cl, CF when occurring independently at every turn
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For by 0-2 R
11bThe benzyl that replaces.
In one aspect of the method, the present invention includes formula (II) compound, its
In aspect the 13, wherein
R
3By 0-3 R
3aReplace-(CH
2)
r-phenyl.
In aspect the 14, the present invention includes formula (III) compound,
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, Me, CN, OH, NH
2, OMe, O (t-Bu), OBn, CF
3, CO
2H, CO
2Me ,-CH
2CO
2H ,-CH
2CO
2Me ,-CH
2CO
2Et ,-NHCOMe ,-CONH
2,-CH
2CONH
2,-CONHMe ,-CONMe
2,-C (=NH) NH
2,-NR
7R
8,-SO
2Me ,-SO
2NH
2, Ph or 2-oxo-piperidines-1-base;
R
3dBe H or C
1-4Alkyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
r-CONR
8R
9, by 0-2 R
11aThe C that replaces
1-6Alkyl, by 0-2 R
11aThe C that replaces
2-6Thiazolinyl, by 0-2 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
In aspect the 15, the present invention includes formula (III) compound, in the scope aspect the 14, wherein:
R
1When occurring be independently-NH at every turn
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH (Me) NH
2,-C (Me)
2NH
2, or-CH
2CH
2NH
2
R
10Be H, Me, benzyl or styroyl; And
R
11For Me, by 0-1 R
11bReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heteroaryl, wherein said heterocycle is by 0-1 R
11bReplace.
In aspect the 16, the present invention includes formula (IV) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect first, wherein:
A is by 1 R
1The cyclohexyl that replaces, by 1 R
1The phenyl that replaces, by 1 R
1The pyridyl that replaces, by 1 R
1The naphthyl that replaces, by 1 R
1The benzisoxa azoles base that replaces or by 0-1 R
1The isoquinolyl that replaces;
L is-C (O) NH-,-C (O) NMe-,-C (O) N (benzyl)-,-C (O) N (styroyl)-,-NHC (O)-,-CH
2C (O) NH-,-NHC (O) CH
2-,-C (O) NHCH
2-or-NHC (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-C (=NH) NH
2,-C (O) NH
2, or-CH
2NH
2
R
3aBe F, Cl, Br, Me, CN, OMe, CF
3, CO
2H, CO
2Me, CO
2Et ,-CH
2CO
2H ,-CH
2CO
2Me ,-CH
2CO
2Et, CONH
2,-CONHMe ,-CON (Me)
2,-CH
2CONH
2, or-C (=NH) NH
2
R
6Be H;
R
10Be H, Me, benzyl or styroyl; And
R
11For Me, by 0-1 R
11bReplace-(CH
2)
r-phenyl or by 0-1 R
11bReplace-(CH
2)
r-5-10 unit heteroaryl, and be selected from thiazolyl, imidazolyl, pyridyl and benzothiazolyl.
In aspect the 17, the present invention includes formula (IV) compound, in the scope aspect the 16, wherein:
A is 4-CH
2NH
2-cyclohexyl or 4-amidino groups-phenyl; And
R
3aBe CO when occurring independently at every turn
2H, CO
2Me ,-CH
2CO
2H ,-CH
2CO
2Et ,-CONH
2, or-CH
2CONH
2
In aspect the 18, the present invention is particularly including the formula V compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-10Carbocyclic ring or 5-to 12-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring.
X
1, X
2, and X
3Be CR independently
3, CR
4, CR
4R
5, O, S (O)
p, N, NR
3, NR
6, or C (O); Prerequisite is not have S-S, S-O or O-O key on the ring;
Prerequisite is
Be not
Z is-C (R
11) (R
12)-,-C (R
11) (R
12)-(CH
2)-,-NR
13-or-NR
13CH
2-; L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-3Alkyl) ,-N (C
1-3Alkyl)
2,-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7C (O) OR
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8a), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy;
In addition, work as R
1And R
2When group was substituted on the adjacent ring atom, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2)
sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b,-(CH
2)
rSR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c,-C (O)-C
1-4Alkyl ,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3b,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
2-6Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group was positioned on the adjacent atom, it can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
5Be H, F, OCF when occurring independently at every turn
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
5aThe C that replaces
1-6Alkyl, by 0-2 R
5aThe C that replaces
2-6Thiazolinyl, by 0-2 R
5aThe C that replaces
2-6Alkynyl, by 0-3 R
5bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
5bReplace;
R
5aWhen occurring at every turn independently for H ,=O, OR
a, SR
a, F, Cl, Br, I, CF
3, OCF
3, CN, NO
2,-NR
7R
8,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
5bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
R
6Be H, C when occurring independently at every turn
1-6Alkyl, C
1-4Haloalkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c,-S (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl or-(CH
2)
n-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle; Wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When being connected on the same nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-6Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl and heteroaryl are optional by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the same nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CR
14R
15)
r-C
3-10Carbocyclic ring or-(CR
14R
15)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2, NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
12Be H, F or C when occurring independently at every turn
1-4Alkyl;
R
13Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O) OR
c,-CONR
8R
c,-OCONR
8R
c,-S (O)
2R
c,-C (O) O-(C
1-4Alkyl)-OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl)-OC (O)-(C
6-10Aryl); Wherein said alkyl, phenyl, heteroaryl, aryl are chosen wantonly by 0-2 R
fReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
R in addition
14Can with R
15Be combined together to form=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10 yuan comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heteroaryl groups are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5-to 10-unit heteroaryl)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; With
S is selected from 1,2,3 and 4 at every turn when occurring;
Prerequisite is:
(a) work as group
Be
I. and when L be-NHC (O)-time, R
14Not with R
15Be combined together to form=O;
Ii. and when L is phenyl for-C (O) NH-and A, R
1Be not-NHC (O) H;
(b) work as group
Be
I. and as L be-NHC (O)-and R
3With R
4During in conjunction with formation and thiazole condensed phenyl ring, phenyl ring is by at least one R
3aReplace;
Ii. and as L be-C (O) NH-, and A is when being phenyl R
1Be not-NHC (O) H; And
(c) A is not for replacing or unsubstituted azoles quinoline ketone, thiophene, diazole or furans.
In aspect nineteen, the present invention includes the formula V compound, in the scope aspect the 18, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-8Cycloalkyl, by 0-1 R
1With 0-3 R
2The C that replaces
4-8Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring;
Z is-C (R
11) (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-8Cycloalkyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
In aspect the 20, the present invention includes the formula V compound, in the scope aspect the 18, wherein:
A is by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkyl, by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace; With
R
6Be H or C when occurring independently at every turn
1-6Alkyl.
In aspect the 21, the present invention includes the formula V compound, in the scope aspect the 18, wherein:
Group
Be selected from:
In aspect the 22, the present invention includes the formula V compound, in the scope aspect the 18, wherein:
Group
Be selected from:
In aspect the 23, the present invention includes the formula V compound, in the scope aspect the 18, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
Group
Be selected from:
Z is-CH (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
3aWith 0-1 R
3dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
4bReplace;
R
6Be H, C
1-6Alkyl or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
12Be H, F or Me when occurring independently at every turn.
In another aspect, the present invention includes the formula V compound, in the scope aspect the 22, wherein:
Group
For
In aspect the 24, the present invention includes formula (VI) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect the 18, wherein:
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
sC (O) NR
8(CH
2)
rCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aReplace-(CH
2)
r-naphthyl, by 0-2 R
3aReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
In aspect the 25, the present invention includes formula (VI) compound, in the scope aspect the 24, wherein:
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aWith 0-1 R
3dThe naphthyl that replaces, by 0-2 R
3aWith 0-1 R
3dThe indanyl that replaces or-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aWith 0-1 R
3dReplace;
R
6Be H;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph; And
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace;
In aspect the 26, the present invention includes formula (VII) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect the 18, wherein:
A is by 0-2 R
1With 0-1 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NH-or-NHC (O)-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aThe phenyl that replaces, by 0-2 R
3aThe naphthyl that replaces, by 0-2 R
3aIndanyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aReplace;
R
4Be H, F, Cl, Br, CF
3, CO
2H, CO
2Me, CO
2Et, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
4bReplace;
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or by 0-2 R
11bReplace-(CH
2)
r-5-to 10-unit heteroaryl, and be selected from thiazolyl, azoles base, triazolyl, tetrazyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indoline base, isoindoline base, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, tetrahydric quinoline group and tetrahydro isoquinolyl; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph or Bn;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace.
In aspect the 27, the present invention includes the formula V compound, in the scope aspect the 26, wherein:
A is 4-CH
2NH
2-cyclohexyl or 4-amidino groups-phenyl; And
R
3Be phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-Br-phenyl, 4-Br-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 3-CF
3-phenyl, 4-CF
3-phenyl, 3-CO
2H-phenyl, 4-CO
2H-phenyl, 4-CO
2Me-phenyl, 4-CH
2CO
2H-phenyl, 4-CH
2CO
2Me-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 4-CONHMe-phenyl, 4-CON (Me)
2-phenyl, 4-CH
2CONH
2-phenyl, 4-amidino groups-phenyl or 2,4-two fluoro-phenyl.
In aspect the 28, the present invention especially comprises a kind of method for the treatment of thromboembolic states or inflammatory diseases, and this method comprises: at least a formula (I) compound of patient's drug treatment significant quantity of needs treatments:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, wherein:
A is by 0-3 R
1With 0-1 R
2The C that replaces
3-C
10Carbocyclic ring perhaps comprises carbon atom and 1-4 and is selected from N, O and S (O)
pHeteroatomic 5-to 12-unit heterocycle, wherein said heterocycle is by 0-3 R
1With 0-1 R
2Replace;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-C
3Alkyl) ,-N (C
1-C
3Alkyl),
2-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7CO
2R
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-C
3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8a), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, CF
3, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
1And R
2When group was substituted on the adjacent annular atoms, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3For F, Cl, Br ,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b, SR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c, C
1-C
4Alkyl-C (O)-,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3c,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
2-6Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4For H ,=O, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group was positioned on the adjacent atom, they can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl, C
1-4Haloalkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c,-S (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-to 10-unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl or-(CH
2)
n-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When group was connected on the identical nitrogen-atoms, it was combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-4Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-to 10-unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl and heteroaryl are optional by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the identical nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
d(the CH that replaces
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CR
14R
15)
r-C
3-10Carbocyclic ring or-(CR
14R
15)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
14Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
Perhaps, R
14With R
15In conjunction with formation=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heterocyclic group are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5 to 10 yuan of heteroaryls)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; And
S is selected from 1,2,3 and 4 at every turn when occurring.
In aspect second nineteen, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, this method comprises: at least a formula (I) compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 28, wherein:
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2CONR
10-or-NR
10COCH
2-;
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3aReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
1-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
6Be H, C
1-6Alkyl ,-CH
2OR
aPerhaps by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
r-CONR
8R
9, by 0-2 R
11aThe C that replaces
1-6Alkyl, by 0-2 R
11aThe C that replaces
2-6Thiazolinyl, by 0-2 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace.
In aspect the 30, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula (I) compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 28, wherein:
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-C (Me)
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2OR
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aWith 0-1 R
3dThe naphthyl that replaces, by 0-2 R
3aWith 0-1 R
3dThe indanyl that replaces or-(CH
2)
r-5 to 10 yuan comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
6Be H, Me, benzyl or styroyl;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph; And
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace.
In aspect hentriaconta-, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula (II) compound of patient's drug treatment significant quantity of needs treatment:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, in the scope aspect the 28, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NH-,-C (O) NMe-,-C (O) N (benzyl)-,-C (O) N (styroyl)-,-NHC (O)-,-S (O)
2NH-,-CH
2C (O) NH-,-C (O) NHCH
2-,-CH
2NHC (O)-or-NHC (O) CH
2-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aThe phenyl that replaces, by 0-2 R
3aThe naphthyl that replaces, by 0-2 R
3aIndanyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aReplace;
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
4bReplace;
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or by 0-2 R
11bReplace-(CH
2)
r-5-to 10-unit heteroaryl, and be selected from thiazolyl, azoles base, triazolyl, tetrazyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indoline base, isoindoline base, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, tetrahydric quinoline group and tetrahydro isoquinolyl; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1--C
4-alkyl, Ph or Bn;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
In aspect the 32, the present invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases especially, comprises: at least a formula V compound of patient's drug treatment significant quantity of needs treatments:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug, wherein:
A is by 0-3 R
1With 0-1 R
2The C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
1With 0-1 R
2Replace;
X
1, X
2, and X
3Be CR independently
3, CR
4, CR
4R
5, O, S (O)
p, N, NR
3, NR
6, or C (O); Prerequisite is not have S-S, S-O or O-O key on the ring;
Prerequisite is
Be not
Z is-C (R
11) (R
12)-,-C (R
11) (R
12)-(CH
2)-,-NR
13-or-NR
13CH
2-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-3Alkyl) ,-N (C
1-3Alkyl)
2,-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7C (O) OR
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8a), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, CF
3, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy;
In addition, work as R
1And R
2When group was substituted on the adjacent ring atom, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3When occurring at every turn independently for F, Cl, Br ,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2)
sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b, SR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c, C
1-4Alkyl-C (O)-,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3c,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
2-6Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group is positioned on the adjacent atom, can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
5Be H, F, OCF when occurring independently at every turn
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
5aThe C that replaces
1-6Alkyl, by 0-2 R
5aThe C that replaces
2-6Thiazolinyl, by 0-2 R
5aThe C that replaces
2-6Alkynyl, by 0-3 R
5bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
5bReplace;
R
5aWhen occurring at every turn independently for H ,=O, OR
a, SR
a, F, Cl, Br, I, CF
3, OCF
3, CN, NO
2,-NR
7R
8,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
5bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
R
6Be H, C when occurring independently at every turn
1-6Alkyl, C
1-4Haloalkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c,-S (O)
2R
c, or by 0-3 R
3dReplace-(CH
2)
r-phenyl;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl or-(CH
2)
n-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle; Wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When being connected on the same nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-6Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl and heteroaryl are optional by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the same nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CR
14R
15)
r-C
3-10Carbocyclic ring or-(CR
14R
15)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O) pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
12Be H, F or C when occurring independently at every turn
1-4Alkyl;
R
13Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O) OR
c,-CONR
8R
c,-OCONR
8R
c,-S (O)
2R
c,-C (O) O-(C
1-4Alkyl)-OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl)-OC (O)-(C
6-10Aryl); Wherein said alkyl, phenyl, heteroaryl, aryl are chosen wantonly by 0-2 R
fReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
R in addition
14Can with R
15Be combined together to form=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10 yuan comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heteroaryl groups are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5-to 10-unit heteroaryl)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; And
S is selected from 1,2,3 and 4 at every turn when occurring;
In aspect the 33, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula V compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 32, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-8Cycloalkyl, by 0-1 R
1With 0-3 R
2The C that replaces
4-8Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace;
Z is-C (R
11) (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring at every turn independently for F, Cl, Br ,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-8Cycloalkyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
In aspect the 34, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula V compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 32, wherein:
A is by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkyl, by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace;
R
3When occurring at every turn independently for F, Cl, Br ,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
6Be H or C when occurring independently at every turn
1-6Alkyl.
In aspect the 35, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula V compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 32, wherein:
Group
Be selected from:
In aspect the 36, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula V compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 32, wherein:
Group
Be selected from:
With
In aspect the 37, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula (III) compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 32, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
Group
Be selected from:
Z is-CH (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring at every turn independently for F, Cl, Br ,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
3aWith 0-1 R
3dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
4bReplace;
R
6Be H, C
1-6Alkyl or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
12Be H, F or Me when occurring independently at every turn;
In another aspect, the invention provides a kind of method for the treatment of thromboembolic states or inflammatory diseases, comprise: at least a formula (III) compound of patient's drug treatment significant quantity of needs treatments, in the scope aspect the 28, wherein:
Group
Be
In another aspect, L is-C (O) NR
10-or-NR
10C (O)-;
In another aspect, L is-C (O) NR
10-;
In another aspect, L is-NR
10C (O)-;
In another aspect, L be-C (O) NH-or-NHC (O)-;
In another aspect, L is-C (O) NH-;
In another aspect, L be-NHC (O)-.
In another aspect, the invention provides compound or its steric isomer, tautomer, pharmacy acceptable salt, solvate or the prodrug that is selected from illustrated embodiment.
In another embodiment, the invention provides a kind of new pharmaceutical composition, it comprises: The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or the prodrug form of pharmaceutically acceptable carrier and treatment significant quantity.
In another embodiment, the invention provides a kind of novel method for preparing The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form.
In another embodiment, the invention provides a kind of new intermediate that is used to prepare The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form.
In another embodiment, the invention provides a kind of pharmaceutical composition, it further comprises other treatment agent (), is selected from potassium channel openers, calcium channel blocker, nhe inhibitor, anti-arrhythmic, antiatherosclerotic, antithrombotics, anti-thrombosis drug, prothrombolytic agents, fibrinogen antagonist agent, diuretic(s), antihypertensive drug, atpase inhibitor, mineralocorticoid receptor antagonists, phosphodiesterase inhibitor, antidiabetic drug, antiphlogiston, antioxidant, angiogenesis modulators, anti-osteoporotic, the hormone replacement therapy agent, the hormone receptor conditioning agent, oral contraceptive, antiadipositas drug, thymoleptic, anxiolytic, antipsychotic drug, antiproliferative pharmaceutical, antitumour drug, antiulcer agent and gastroesophageal reflux disease medicament, growth hormone drug and/or tethelin urge to secrete agent, Tiroidina is intended like thing, anti-infective, antiviral drug, antiseptic-germicide, anti-mycotic agent, decreasing cholesterol/fat-reducing medicament and fat type curative, and the medicine of imitation local asphyxia pre-treatment and/or cardiac muscle stupor, perhaps their combination.
In another embodiment, the invention provides a kind of pharmaceutical composition, it further comprises other treatment agent (), be selected from anti-arrhythmic, antihypertensive drug, antithrombotics, antiplatelet drug, thrombin inhibitors, thrombolytic agent, fibrinolytic agent, calcium channel blocker, decreasing cholesterol/fat-reducing medicament, or their combination.
In another embodiment, the invention provides a kind of pharmaceutical composition, it further comprises other treatment agent (), is selected from: warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentose class, r-hirudin, argatroban, Asprin, Ibuprofen BP/EP, Naproxen Base, sulindac, INDOMETHACIN, vialidon salt, Dipyridamole, bend former times health, diclofenac, sulfinpyrazone, piroxicam, Ticlopidine, clopidogrel, Tirofiban, Eptifibatide, ReoPro, Melagatran, Xi Meijia group, two sulfuric acid r-hirudins (disulfatohirudin), the tissue plasmin activator, modification tissue plasmin activator, Eminase, urokinase and streptokinase, perhaps their combination.
One preferred embodiment in, the invention provides a kind of pharmaceutical composition, wherein the other treatment agent is for being selected from the antihypertensive drug of ACE inhibitor, AT-1 receptor antagonist, ET receptor antagonist, ET/AII dual receptor antagonist and vasopeptidase (vasopepsidase) inhibitor; Be selected from the anti-arrhythmic of IKur inhibitor; Be selected from the anti-thrombosis drug of antithrombotics, wherein antithrombotics is selected from inhibitor, other kallikrein inhibitors, factor VIIa inhibitors and the factor Xa inhibitor of thrombin inhibitors, other factor XI, plasma thromboplastin antecedents a; Be selected from GPIIb/IIIa blocker, P2Y
1And P2Y
12The antiplatelet drug of antagonist, thromboxane receptor antagonist and Asprin; Perhaps their combination.
One preferred embodiment in, the invention provides a kind of pharmaceutical composition, wherein other treatment agent () is a kind of antiplatelet drug or their combination.
One preferred embodiment in, the invention provides a kind of pharmaceutical composition, wherein the other treatment agent is this antiplatelet drug clopidogrel.
In another embodiment, the invention provides a kind of method of regulating coagulation cascade and/or contact activation system, comprise at least a The compounds of this invention or its stereoisomerism, tautomer, pharmacy acceptable salt, solvate or prodrug form to patient's drug treatment significant quantity of this treatment of needs.
In another embodiment, the invention provides a kind of novel method for the treatment of thrombotic disease, comprise at least a The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form to patient's drug treatment significant quantity of this treatment of needs.
In another embodiment, the invention provides a kind of novel method, wherein thrombotic disease is selected from artery cardiovascular thromboembolic disease, vein cardiovascular thromboembolic disease, artery cerebrovascular thrombotic disease and vein cerebrovascular thrombotic disease.
In another embodiment, the invention provides a kind of novel method, wherein thrombotic disease is selected from unstable angina, acute coronary syndrome, auricular fibrillation, first myocardial infarction, the recidivity myocardial infarction, the ischemic sudden death, one property crossed local asphyxia outbreak, apoplexy, atherosclerosis, periphery occlusive artery disease, venous thrombosis, venous thrombosis, thrombophlebitis, arterial thrombosis disease, Coronary thrombosis, cerebral artery thrombosis forms, cerebral embolism disease, renal infarction disease, the thrombosis that pulmonary infarction disease and underlying cause cause: (a) artificial valve or other implants, (b) inlying catheter, (c) Si Tante support, (d) cardiopulmonary bypass, (e) hemodialysis, (f) other make blood impel thrombotic operation in artificial surface.
In another embodiment, the invention provides a kind of method for the treatment of inflammatory diseases, comprise: at least a The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or the prodrug form of patient's drug treatment significant quantity of this treatment of needs.
In another embodiment, the invention provides a kind of method, wherein inflammatory diseases is selected from pyemia, adult respiratory distress syndrome and systemic inflammatory response syndrome.
In another embodiment, the invention provides a kind of novel method that the patient who needs the thrombotic disease treatment is treated, comprise: give The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form with treatment thrombotic disease significant quantity.
In another embodiment, the invention provides a kind of method that the patient who needs the treatment of inflammatory diseases is treated, comprise: give The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form with treatment inflammatory diseases significant quantity.
In another embodiment, the invention provides a kind of coming of new goods, comprise:
(a) first container;
(b) place the pharmaceutical composition of first container, wherein composition comprises: first therapeutical agent comprises: The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form; And
(c) one illustrates that this pharmaceutical composition can be used for treating the package insert (insert) of thromboembolic states and/or inflammatory diseases.
Another preferred embodiment in, the invention provides a kind of new manufacturing goods, further comprise:
(d) second container,
Wherein member (a) and (b) place second container, member (c) to be positioned within second container or outside.
In another embodiment, the invention provides a kind of new manufacturing goods, comprise:
(a) first container;
(b) place the pharmaceutical composition of first container, wherein composition comprises: first therapeutical agent comprises: The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form; And
(c) this pharmaceutical composition of explanation can be used in combination the package insert (insert) for the treatment of thromboembolic states and/or inflammatory diseases with second therapeutical agent.
Another preferred embodiment in, the invention provides a kind of new manufacturing goods, it further comprises:
(d) second container,
Wherein member (a) and (b) place second container, member (c) to be positioned within second container or outside.
In another embodiment, the invention provides a kind of novel method, comprise: give The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form with treatment thromboembolic states and/or inflammatory diseases significant quantity.
In another embodiment, the invention provides a kind of The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form, it is used for the treatment of.
In another embodiment, the present invention also provides the application of The compounds of this invention or its steric isomer, tautomer, pharmacy acceptable salt, solvate or prodrug form, is used to prepare the medicine of treatment thromboembolic states and/or inflammatory diseases.
The present invention can be summarized as other specific forms under the prerequisite that does not deviate from its spirit and essential attribute.The present invention includes the combination of all preferred versions of the present invention of explanation herein.Be to be understood that any He all embodiments of the present invention can illustrate other preferred embodiments in conjunction with any other embodiment or embodiments.Each the single key element that it should also be understood that preferred implementation is itself independently preferred implementation.And the key element of any embodiment will combine with any and every other key element from any embodiment another embodiment is described.
Definition
The compounds of this invention can have one or more asymmetric centers.Except as otherwise noted, all chiralitys of The compounds of this invention (enantiomorph and diastereomer) and racemic form include within the scope of the present invention.The geometrical isomer of many alkene, the two keys of C=N etc. also may be present in the The compounds of this invention, and all this stable isomer are all in limit of consideration of the present invention.Therefore, The compounds of this invention can be separated optical activity form or racemic form.The well known optical activity form that how to prepare is for example by resolution of racemic form or synthetic by the optical activity raw material.All chiralitys of structure (enantiomorph with diastereomer) and racemic form and all geometrical isomer forms all are considered, unless specific stereochemistry or isomeric forms are had special instruction in addition.It is a part of the present invention that all tautomers of the compound that lists or describe also are considered.
The molecular weight of preferred The compounds of this invention is lower than every mole of about 500,550,600,650,700,750 or 800 gram.Preferred molecular weight is lower than every mole of about 800g.More preferably molecular weight is lower than every mole of about 750g.Further more preferably molecular weight is lower than every mole of about 700g.
Term used herein " alkyl " or " alkylidene group " are meant and comprise side chain and the straight chain radical of saturated aliphatic hydrocarbyl group with given number carbon atom.For example, " C
1-C
10Alkyl " or " C
1-10Alkyl " (perhaps alkylidene group) be meant and comprise C
1, C
2, C
3, C
4, C
5, C
6, C
7, C
8, C
9And C
10Alkyl.In addition, " C for example
1-6Alkyl " refer to have the alkyl of 1-6 carbon atom.Alkyl group can be unsubstituted or replace, thereby its one or more hydrogen atoms are replaced by another chemical group.The example of alkyl group is including, but not limited to methyl (Me), ethyl (Et), propyl group (for example n-propyl and sec.-propyl), butyl (for example normal-butyl, isobutyl-, the tertiary butyl), amyl group (for example n-pentyl, isopentyl, neo-pentyl) etc.
" thiazolinyl " or " alkenylene " is meant the hydrocarbon chain that comprises the straight or branched configuration, and it can one or more carbon-carbon double bonds occur in any stable position of chain." C for example
2-6Thiazolinyl " (or alkenylene) be meant and comprise C
2, C
3, C
4, C
5And C
6Alkenyl group.The example of thiazolinyl is including, but not limited to vinyl, 1-propenyl, 2-propenyl, crotyl, 3-butenyl, pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl etc.
" alkynyl " or " alkynylene " is meant the hydrocarbon chain that comprises the straight or branched configuration, and it can have one or more carbon-carbon triple bonds at any settling position of chain.For example, " C
2-6Alkynyl " (perhaps alkynylene) be meant and comprise C
2, C
3, C
4, C
5And C
6Alkynyl group; As ethynyl, proyl, butynyl, pentynyl, hexin base etc.
" halo " or " halogen " comprises fluorine, chlorine, bromine and iodine." haloalkyl " refers to the substituting group with one or more halogens of side chain and straight chain.The example of haloalkyl is including, but not limited to CF
3, C
2F
5, CHF
2, CCl
3, CHCl
2, C
2C
5Deng.
Term " alkoxyl group " or " alkyl oxy ", be meant-the O-alkyl group." C
1-6Alkoxyl group " (or alkyl oxy) be meant and comprise C
1, C
2, C
3, C
4, C
5And C
6Alkoxyl group.The example of alkoxyl group is including, but not limited to methoxyl group, oxyethyl group, propoxy-(as positive propoxy and isopropoxy) and butoxy etc.Similarly, the alkyl of carbonatoms shown in " alkylthio " or " sulfenyl thio alkoxy (thioalkoxy) " expression has as defined above, it connects by sulphur bridge; For example methyl-S-, ethyl-S-etc.
The haloalkyl of carbonatoms shown in " halogenated alkoxy " or " haloalkyl oxygen base " expression has as defined above, it connects by oxo bridge; For example, " C
1-6Halogenated alkoxy " be meant and comprise C
1, C
2, C
3, C
4, C
5And C
6Halo alkoxy group.The example of halogenated alkoxy is including, but not limited to trifluoromethoxy, 2,2,2-trifluoro ethoxy, five fluorine oxyethyl groups etc.Similarly, the haloalkyl of carbonatoms shown in " halogenated alkylthio " or " sulfo-halogenated alkoxy (thiohaloalkoxy) " expression has as defined above, it connects by sulphur bridge; For example trifluoromethyl-S-, pentafluoroethyl group-S-etc.
Term " cycloalkyl " is meant into the alkyl group of ring, comprises list, two or encircle ring system more.C
3-7Cycloalkyl is meant and comprises C
3, C
4, C
5, C
6And C
7Group of naphthene base.The example of cycloalkyl is including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norborneol alkyl etc.
" carbocyclic ring " used herein or " carbocyclic residue " are meant any stable 3-, 4-, 5-, 6-or 7-unit's monocycle or dicyclo or 7-, 8-, 9-, 10-, 11-, 12-or 13-unit's dicyclo or three rings, its any one all can be saturated, part is undersaturated, undersaturated or fragrant.This isocyclic example is including, but not limited to cyclopropyl, cyclobutyl, cyclobutene base, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, suberyl, cycloheptenyl, adamantyl, ring octyl group, cyclooctene base, cyclooctadiene base, [3.3.0] bicyclooctane, [4.3.0] bicyclononane, [4.4.0] two cyclodecane, [2.2.2] bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthryl and tetralyl (tetralin).As implied above, bridged ring is also included within the isocyclic range of definition (for example [2.2.2] bicyclooctane).Except as otherwise noted, preferred carbocyclic ring is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and indanyl.When using term " carbocyclic ring ", its implication comprises " aryl ".When one or more carbon atoms connect two non-conterminous carbon atoms, promptly produce bridged ring.Preferred bridge is one or two carbon atom.It is to be noted that bridge always is transformed into monocycle three rings.When a ring during by bridging, the substituting group of being quoted on the ring also can appear on the bridge.
" aryl " group is meant monocycle or polynuclear aromatics class, comprises for example phenyl, naphthyl, phenanthryl etc.Aryl moiety is known, and is described in for example Hawley ' s CondensedChemical Dictionary (13 ed.), R.J.Lewis, ed.J.Wiley ﹠amp; Sons, Inc. is among the New York (1997).Aromatic yl group can be that replace or unsubstituted.
Term used herein " heterocycle " or " heterocyclic group " are meant stable 5,6 or 7 yuan of monocycles or dicyclo or 7,8,9,10,11,12,13 or 14 yuan of bicyclic heterocycles, its be saturated, part is undersaturated or undersaturated fully, and constitute by carbon atom and 1,2,3 or 4 heteroatoms that is independently selected from N, O and S; And comprise wherein any heterocycle as defined above and any bicyclic radicals of phenyl ring condensed.It is oxidized that nitrogen and sulfur heteroatom can be chosen wantonly (is N → O and S (O)
p).Nitrogen-atoms can be that replace or unsubstituted (be N or NR, wherein R is H, if perhaps defined, is another substituting group).Heterocycle can link to each other with its side group at any heteroatoms that can form rock steady structure or carbon atom place.If the compound that forms is stable, heterocycle described herein can be substituted on carbon atom or nitrogen-atoms.Nitrogen on the heterocycle can be chosen wantonly by quaternized.Preferably when the S in the heterocycle and O total atom number surpassed 1, then these heteroatomss were non-conterminous each other.S and O total atom number in the preferred heterocycle are no more than 1.When using term " heterocycle ", its implication comprises heteroaryl.
The heterocyclic example is including, but not limited to acridyl (acridinyl), azocine base (azocinyl), benzimidazolyl-, benzofuryl, benzothienyl, the benzoxazol base, benzoxazol quinoline base, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, benzisoxa azoles base, the benzisothiazole base, the benzimidazoline base, carbazyl, the 4aH-carbazyl, carbolinyl, chromanyl, chromenyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5, the 2-dithiazine, dihydrofuran also [2,3-b] tetrahydrofuran (THF), furyl, the furazan base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, pseudoindolyl (indolenyl), indoline base (indolinyl), indolizinyl (indolizinyl), indyl, the 3H-indyl, isatin base (isatinoyl), isobenzofuran-base, the isochroman base, iso indazolyl, the isoindoline base, pseudoindoyl, isoquinolyl, isothiazolyl, isothiazole and pyridyl, different azoles base, different azoles and pyridyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, the octahydro isoquinolyl, the di azoly, 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly, 1,3,4- di azoly, the oxazolidinyl, azoles base, the oxindole base, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, phenoxathinyl, fen piperazine base, phthalazinyl, piperazinyl, piperidyl, piperidone base, the 4-piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, give a tongue-lashing azoles quinoline base, pyrazolyls, pyridazinyl, pyrido azoles, give a tongue-lashing pyridine and imidazoles, the pyrido thiazole, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, the 2-Pyrrolidone base, the 2H-pyrryl, pyrryl, quinazolyl, quinolyl, the 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, the thieno-thiazolyl, thieno- azoles base, the Thienoimidazole base, thiophenyl, triazinyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3,4-triazolyl and xanthenyl.Also comprise and contain for example above-mentioned heterocyclic condensed ring and spirocyclic compound.
The first heterocycle of preferred 5-to 10-is including, but not limited to pyridyl, furyl, thienyl, pyrryl, pyrazolyl, pyrazinyl, piperazinyl, piperidyl, imidazolyl, imidazolidyl, indyl, tetrazyl, different azoles base, morpholinyl, azoles base, the oxazolidinyl, tetrahydrofuran base, the thiadiazine base, thiadiazolyl group, thiazolyl, triazinyl, triazolyl, benzimidazolyl-, the 1H-indazolyl, benzofuryl, benzothienyl, the benzo tetrazyl, the benzotriazole base, benzisoxa azoles base, the benzoxazol base, the oxindole base, benzoxazol quinoline base, benzothiazolyl, the benzisothiazole base, the isatin base, isoquinolyl, the octahydro isoquinolyl, tetrahydro isoquinolyl, tetrahydric quinoline group, different azoles and pyridyl, quinazolyl, quinolyl, isothiazole and pyridyl, thiazole and pyridyl, azoles and pyridyl, imidazopyridyl and Pyrazolopyridine base.
The first heterocycle of preferred 5-to 6-is including, but not limited to pyridyl, furyl, thienyl, pyrryl, pyrazolyl, pyrazinyl, piperazinyl, piperidyl, imidazolyl, imidazolidyl, indyl, tetrazyl, different azoles base, morpholinyl, azoles base, oxazolidinyl, tetrahydrofuran base, thiadiazine base, thiadiazolyl group, thiazolyl, triazinyl and triazolyl.Also comprise and contain for example above-mentioned heterocyclic condensed ring and spirocyclic compound.
Term used herein " aromatic heterocycle group " or " heteroaryl " are meant stable monocycle and polynuclear aromatics, and it comprises at least one heteroatomic ring member such as sulphur, oxygen or nitrogen.Heteroaryl includes but not limited to pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indyl, pyrryl, azoles base, benzofuryl, benzothienyl, benzothiazolyl, different azoles base, pyrazolyl, triazolyl, tetrazyl, indazolyl, 1,2,4-thiadiazolyl group, isothiazolyl, purine radicals, carbazyl, benzimidazolyl-, indoline base, benzo dioxolanyl, benzo two alkane etc.Heteroaryl can be that replace or unsubstituted.Nitrogen-atoms can be that replace or unsubstituted (be N or NR, wherein R is H, if perhaps defined, is another substituting group).It is oxidized that nitrogen and sulfur heteroatom can be chosen wantonly (is N → O and S (O)
p).It is to be noted that S and O total atom number on the aromatic heterocycle are no more than 1.Bridged ring is also included within the heterocyclic range of definition.When one or more atoms (being C, O, N or S) connect two non-conterminous carbon or nitrogen-atoms, promptly produce bridged ring.Preferred bridge is including, but not limited to a carbon atom, two carbon atoms, nitrogen-atoms, two nitrogen-atoms and carbon nitrogen groups.It is to be noted that bridge always is transformed into monocycle three rings.When a ring during by bridging, the substituting group of being quoted on the ring also can appear on the bridge.
Term " counter ion " is used to represent little, electronegative ionic species for example muriate, bromide, oxyhydroxide, acetate and vitriol.
Terminology used here " replacement " is meant one or more hydrogen atoms by non-hydrogen group displacement, and prerequisite is to keep normal valency and replace producing stable compound.When substituting group is that ketone group (promptly=O) time, then replaced by 2 hydrogen on the atom.The ketone group substituting group does not appear on the aromatic residues.When pointing out ring system (for example carbocyclic ring or heterocycle), be meant carbonyl or two key a part (promptly in ring) for ring by carbonyl or the replacement of two key.
As any variable (R for example
2a, R
2bDeng) when in any composition of compound or structural formula, occurring more than one time, its definition when its definition when at every turn occurring is independent of every other the appearance.Like this, for example, when 1 group shows by 0-3 R
2bDuring replacement, then described group can be chosen wantonly by three R at the most
2bGroup replaces, and R when at every turn occurring
2bBe independently selected from R
2bDefinition.And the combination of substituting group and/or variable also allows, as long as this bonded result can form stable compound.
When the key on the substituting group shows when passing the key that connects two annular atomses, then this substituting group can be bonded on any atom on the ring.When substituting group was used for the mode of atom that key connects other parts of given structural formula compound and lists not indicate this substituting group, then this substituting group can connect by any atomic bond on this substituting group.The combination of substituting group and/or variable allows, as long as this bonded result can form stable compound.
When making the with dashed lines ring in 5-to 8-ring structure, this shows that this ring structure can be saturated, fractional saturation or undersaturated.
" blocking group " of employed here term amine is meant any known group that can be used for protecting amine groups in organic synthesis field, and it is to ester reductive agent, two replacement hydrazine, R
4-M and R
7-M, nucleophilic reagent, hydrazine reductant, activator, highly basic, bulky amine alkali and cyclizing agent are stable.This amine protecting group group that meets these standards is included in Greene and Wuts, " Protective Groups in Organic Synthesis " John Wiley ﹠amp; Sons, NewYork (1991) and " The Peptides:Analysis, Synthesis; Biology, Vol.3, Academic Press; listed those among the New York (1981), their disclosed contents are introduced among the present invention by reference.The example of amine protecting group group is including, but not limited to following group: (Fmoc); (1) for example formyl radical, trifluoroacetyl group, phthaloyl and p-toluenesulfonyl of acyl group type; (2) for example carbobenzoxy-(Cbz) (Cbz) and the carbobenzoxy-(Cbz), 1-(right-biphenyl)-1-methyl ethoxycarbonyl and the 9-fluorenylmethyloxycarbonyl (Fmoc) that replace of aromatic amino ester formate type; (3) for example tertbutyloxycarbonyl (Boc), ethoxycarbonyl, di-isopropyl methoxycarbonyl and allyloxycarbonyl of aliphatic urethane type; (4) for example cyclopentyloxy carbonyl and adamantyl oxygen base carbonyl of carboxylamine cycloalkyl ester type; (5) for example trityl and benzyl of alkyl type; (6) trialkyl silane trimethyl silane for example; (7) contain thioalcohol type for example thiophenyl carbonyl and dithia succinyl; (8) for example trityl, methyl and benzyl of alkyl type; With the alkyl type that replaces for example 2,2,2-three chloroethyls, 2-styroyl and the tertiary butyl; With trialkyl silane type such as trimethyl silane.
Phrase " pharmaceutically acceptable " is used in reference to here in the medical judgment scope of reasonable (sound), be suitable for organizing contacting and not producing over-drastic toxicity, stimulation, transformation reactions or other problem or complication, have compound, material, composition and/or the formulation of rational interests/risk ratio with the human and animal.
Term " pharmacy acceptable salt " is meant the acid or the alkali salt of compound described here.The example of pharmacy acceptable salt is including, but not limited to the inorganic or organic acid salt of alkaline residue such as amine; Acidic residues is the alkali salt or the organic salt of carboxylic acid for example; Deng.The pharmacy acceptable salt of The compounds of this invention can prepare with stoichiometric suitable alkali or sour the reaction in water or organic solvent or both mixtures by these compounds that make free acid or alkali form.Usually, preferred non-aqueous media such as ether, ethyl acetate, ethanol, Virahol or acetonitrile.The tabulation of acceptable acid addition salts is referring to Remington ' s Pharmaceutical Sciences, 17th ed., and Mack PublishingCompany, Easton, PA, 1985, p1418, its disclosed content is incorporated among the present invention by integral body by reference.The example of pharmacy acceptable salt is including, but not limited to the inorganic or organic salt of alkaline residue such as amine; The alkali of acidic residues such as carboxylic acid or organic salt; Or the like.Pharmacy acceptable salt comprises the conventional non-toxic salt or the quaternary ammonium salt of parent compound, and it is formed by nontoxic inorganic or organic acid.The nontoxic salt of this routine comprises that those derive from the salt of mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc.; By the salt of organic acid preparation, described organic acid such as acetic acid, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pounce on acid, toxilic acid, oxaloacetic acid, toluylic acid, L-glutamic acid, M-nitro benzoic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethionic acid, oxalic acid, isethionic acid etc.
In addition, formula I compound can have prodrug forms.Any compound that forms biologically active drug (being formula I compound) that transforms in vivo all is the scope of the invention and the interior prodrug of spirit.Various forms of prodrugs are being known in the art.The example of these prodrug derivants referring to:
a)Design of Prodrugs，edited by H.Bundgaard，(Elsevier，1985)，and Methods inEnzymology，Vol.42，at pp.309-396，edited by K.Widder，et.al.(AcademicPress，1985)；
b)A Textbook of Drug Design and Development，edited by Krosgaard-Larsenand H.Bundgaard，Chapter 5，“Design and Application of Prodrugs，”by H.Bundgaard，at pp.113-191(1991)；
c)H.Bundgaard，Advanced Drug Delivery Reviews，Vol.8，p.1-38(1992)；
d)H.Bundgaard，et al.，Journal of Pharmaceutical Sciences，Vol.77，p.285(1988)；and
e)N.Kakeya，et.al.，Chem Phar Bull.，Vol.32，p.692(1984).
The preparation of prodrug is well known in the art, and be described in for example MedicinalChemistry:Principles and Practice, F.D.King writes, The Royal Societyof Chemistry, Cambridge, UK, 1994, it is incorporated among the present invention by integral body by reference.
Radiolabeled The compounds of this invention also is provided here, and promptly wherein one or more described atoms are replaced (for example, C quilt by the radio isotope of this atom
13C or
14C replaces; The isotropic substance of hydrogen comprises tritium and deuterium).These compounds have a lot of potential to be used, and for example is used to measure the ability of potential drug in conjunction with target protein or acceptor as standard substance and reagent, perhaps makes in the body or the external The compounds of this invention imaging that is attached to biological acceptor.
The compounds of this invention is preferred separated after its preparation to be equal to or greater than 98%, preferred 99% composition (" pure basically ") with purifying to obtain the containing The compounds of this invention weight content, uses as described herein then or preparation.This " pure basically " compound also is considered as a part of the present invention at this.
" stable compound " and " rock steady structure " is meant in reach the purity separation process of useful degree from reaction mixture, and in the process of the effective therapeutical agent of preparation, can keeps sufficiently stable compound.Preferred The compounds of this invention does not contain N-halogen, S (O)
2H or S (O) H group.
The solvate (for example hydrate) that should further be understood that The compounds of this invention also falls within the scope of the invention.The solvation method is that this area is generally known.
Here employed " treatment " (" treating " or " treatment ") contains and covered the particularly treatment of people's morbid state of Mammals, and the appearance, particularly these Mammalss that comprise (a) prevention mammalian diseases state are in the easy infection morbid state but also are not diagnosed as situation about having infected; (b) suppress morbid state, promptly stop its development; And/or (c) alleviate morbid state, even morbid state disappears.
" treatment significant quantity " is meant the amount of the The compounds of this invention that comprises effective supressor XIa and/or plasma kallikrein when administration alone or in combination." treatment significant quantity " also refers to comprise the amount of the claimed combination of compounds of effective supressor XIa and/or plasma kallikrein.Combination of compounds is preferably synergistic combination.As for example Chouand Talalay, Adv.Enzyme Regul.1984, described in the 22:27-55, when the compound effect of combination medicine-feeding (here promptly to the restraining effect of factor XI, plasma thromboplastin antecedent a and/or plasma kallikrein) likens to when adding with better effects if for the individually dosed compound of single agent, promptly produced synergy.Usually, synergy can show under the inferior good concentration of compound the most significantly.Synergy can be based on the component of combination and compare the cytotoxicity of reduction, antithrombotic formation and/or antiphlogistic effects, perhaps other beneficial effects of increase with independent component.
The present invention further comprises the composition that comprises one or more The compounds of this invention and pharmaceutically acceptable carrier." pharmaceutically acceptable carrier " is meant and generally accepts to be used in this area to the animal medium of Mammals delivery of biologically active medicine particularly.Pharmaceutically acceptable carrier is prepared according to the many factors in those of ordinary skills' limit of power.These include but not limited to: the type of promoting agent to be prepared and character; The object that composition gave that comprises medicament; The predetermined route of administration of composition; The treatment indication of target.Pharmaceutically acceptable carrier comprises moisture or non-aqueous liquid media, and various solid and semisolid dosage form.This carrier can comprise a lot of different composition and additive and active medicines, and these added ingredientss are included in the preparation can be for various reasons, stabilizing active medicine for example, and tackiness agent etc., it is well known to those of ordinary skill in the art.Relevant suitable pharmaceutically acceptable carrier and select the description of related factor to be found in many existing literature references that are easy to obtain, Remington ' s Pharmaceutical Sciences for example, the 17th edition, MackPublishing Company, Easton, PA, 1985, it is incorporated among the present invention by integral body by reference.
Synthetic
Chemical combination of the present invention can be prepared by the known many methods of organic synthesis those skilled in the art.Compound of the present invention can adopt the known synthetic method of following method and synthetic organic chemistry field, and perhaps the differentiation method of the aforesaid method that those skilled in the art understood is synthesized.Preferable methods is including, but not limited to following method.Be reflected in the solvent of the conversion that is suitable for agents useful for same and raw material and is suitable for being realized and carry out.The technician in organic synthesis field knows that the functional group that exists in the molecule should be consistent with the conversion of being planned.These sometimes need to judge the order that changes synthesis step or select a specific method route to substitute the other method route to obtain required The compounds of this invention.And, in the explanation of following synthetic method, be to be understood that the reaction conditions of all suggestions, comprise choice of Solvent, reaction atmosphere, temperature of reaction, duration of experiment and post-treating method, all be carried out selection, to become the standard conditions of this reaction, this is that those skilled in the art are easy to expect.The technician in organic synthesis field knows that the existing functional group of molecule each several part must mate with reagent of being advised and reacting phase.The restriction that this substituting group and reaction conditions are complementary will become apparent to those skilled in the art that thereby must use the alternative method.
Another major consideration that also should expect designing in this area any synthetic route is that the blocking group () wisdom (PG) that is used to protect the active function groups that exists on the compound of the present invention is selected.The authority who sets forth many alternatives for the practitioner who trains records Greene and WutS (Protective Groups In Organic Synthesis, Wiley-Interscience, the 3rd edition, 1999).
So the reference of being quoted is incorporated among the present invention by integral body by reference here.
Be used for synthetic The compounds of this invention imidazolium compounds can by as 1 generalized general method of synthetic route synthesize (Con tour-Galcera etc., Bioorg.Med.Chem.Lett.2001,11 (5), 741-745).With appropriate protection or deutero-alpha amino acid [1; Y=R
10(PG) N-or Y=AC (O) N (R
10)-] or malonate derivative [1; Y=alkyl-OC (O)-] be dissolved in suitable solvent for example in the ethanol/water (1: 1), with alkali for example cesium carbonate handle to generate cesium salt.Salt separated and be suspended in once more in the suitable solvent such as dimethyl formamide, and with α-bromoketone 2 chemical combination, generate ketone ester 3.In addition, can also be by in identical solvent (for example dimethyl formamide), generating 1 the cesium salt be used for alkylation step, and the generation of ketone ester 3 (X=aryl or heteroaryl) can be carried out in single reactor.
Imidazoles with structure 4 can be by in suitable solvent such as xylene, and heating ketone ester 3 and dewaters and generates with dean stark trap to backflow in the presence of the excessive acetic acid ammonium.The generation of imidazoles can also by adopt microwave heating make ketone ester 3 and ammonium acetate suitable solvent such as dimethylbenzene or ethanol or solvent combine as dimethyl formamide and ethanol (1: 1) in chemical combination generate.Work as Y=R
10(PG) during N-, the protecting group on the amine is removed to prepare to carry out the acidylate of amine, and it is listed in the synthetic route 18.For example, when protecting group is the BOC part, adopt strong acid such as trifluoroacetic acid in suitable solvent such as methylene dichloride, the amine deprotection to be obtained compound 5, wherein Y '=R
10HN-.When Y=alkyl-OCO-, can be by ester being dissolved in the suitable solvent such as methyl alcohol, and handle ester and its hydrolysis is obtained 5 with alkali such as aqueous sodium hydroxide solution, Y=-CO wherein
2H.
Further the official can be united to be incorporated on the imidazole ring and can realize, thereby obtain compound 6 and 9 by the C-5 carbon that in suitable solvent such as methylene dichloride or chloroform, uses bromine for example or N-bromosuccinimide bromination imidazole ring.In addition, C-5 carbon for example can also use N-chlorosuccinimide to carry out chlorination to obtain compound 7 and 10 in suitable solvent such as methylene dichloride, acetonitrile or chloroform.
The imidazoles 6 and 9 of bromination provides suitable functional group to be used for the further processing that the various palladium catalysis of ability employing known to the skilled cross coupling method is carried out, for example the described method of Tsuji (Palladium Reagents and Catalysts:New Perspectives for the21
StCentury, John Wiley ﹠amp; Sons, Ltd., 2004).For instance, adopt people (Org.Lett.2004 such as Zhong, 6,929-931) and people such as Bellina (Synthesis 2004,15, change method 2419-2440) is used Suzuki coupling scheme, wherein at alkali, is generally ternary potassiumphosphate or yellow soda ash, and palladium catalyst, be generally two-(three-tertiary butyl phosphine) palladium (0), under the existence of three-(dibenzylidene-acetone) palladiums (0) or four-(triphenylphosphine) palladiums (0), in suitable solvent such as toluene or 1, in the 4-dioxane, adopt routine or microwave heating method to be heated to 80-110 ℃, bromizate thing 6 or 9 and boric acid chemical combination, obtain structure 8 and 11, wherein X=aryl or heteroaryl.
Synthetic route 1
The method of another kind of synthetic imidazole nucleus is shown in synthetic route 2.The trimeric dihydrate 13 of beta-amino aldehyde 12, the oxalic dialdehyde of appropriate protection and ammonia stirred under room temperature in suitable solvent such as methyl alcohol together carry out chemical combination.Gained imidazoles 14 is dissolved in the suitable solvent such as chloroform, with for example N-bromosuccinimide bromination.Other bromide reagent such as bromine can also be used, and other solvent that is suitable for the bromination condition such as methylene dichloride or tetracol phenixin can be used.Employing is by for example 1, the biphasic solvent system that 4-dioxane and water are formed, and in the presence of phase-transfer catalyst such as tetrabutylammonium hydrosulfate, with 4,5-dibromo imidazoles 15 usefulness reductive agents such as sodium bisulfite are handled.So list-the bromide 16 of preparation can be at suitable solvent as 1, in 4-dioxane or the toluene with suitable functionalized aryl boric acid or heteroaryl boric acid chemical combination, and the method for the improvement of the Zhong that quotes according to preamble etc. and Bellini etc., at high temperature use the agent combination of forming by for example palladium (I) three-tertiary butyl phosphine bromide dimer and ternary potassiumphosphate to handle.Other agent combination that can be used for the Suzuki couling process have palladium three-(dibenzylidene-acetone) palladium (0), three-(tertiary butyl)- four-fluoroborate and ternary potassiumphosphate.Remove protecting group on the amine and prepare to be used to prepare the acidylate of amine, it is listed in the synthetic route 17.For example, when protecting group is the BOC part, adopt strong acid such as trifluoroacetic acid in suitable solvent such as methylene dichloride, the amine deprotection to be obtained the amine 18 of two-tfa salt form.
Synthetic route 2
The another kind of alternative approach of synthetic imidazole ring is shown in synthetic route 3.With 3,3-two bromo-1,1,1-trifluoropropyl-2-ketone (19) is heated to 90 ℃ with ammonium acetate in suitable solvent such as water, and the aldehyde 12 that adds due care then carries out chemical combination.The trifluoromethyl imidazoles that so makes is provided for the intermediate of the C-5 trifluoromethyl analogue shown in the synthetic compound 24, wherein X=CF
3These compounds can obtain by the method shown in the said synthesis route 1 and 2.In addition, trifluoromethyl part can be hydrolyzed to obtain the ortho position ester using under the strong alkaline condition of sodium methylate for example, and it is hydrolyzed into methyl esters 21, wherein X=-CO
2CH
3This intermediate can be used to obtain compound as 24 by the method that illustrates in synthetic route 1 and 2, wherein X=-CO
2CH
3
Synthetic route 3
Adopt method known to those skilled in the art easily to make and have substituent phenylalanine analogues on the phenyl ring that can not obtain on the market.About the summary of the method that begins synthetic this analogue authority from glycine referring to Maruoka and Ooi (Chem.Rev.2003,103,3013-3028).
The 2-bromoacetophenone analogue that can not obtain on some market can begin to synthesize by obtainable from the market starting raw material.For example, 2-(4-(2-acetyl bromide) phenyl) ethyl acetate (27:R
3a=R
3b=H) can be shown in synthetic route 4 and prepare.With 2,4 '-dibromobenzene ethyl ketone (25:R
3a=R
3b=H) and bromoethyl acetate (26) be dissolved in suitable solvent such as the tetrahydrofuran (THF), (Chem.Commun.2001 669-670) at high temperature uses agent combination such as palladium (II) acetate, three-(1-naphthyl) phosphine and ternary potassiumphosphate to handle according to the method for Gossen etc.Intermediate 2-(4-acetyl phenyl) ethyl acetate (27) is dissolved in suitable solvent such as the chloroform and carries out bromination with bromide reagent such as bromine processing obtain 2-(4-(2-acetyl bromide) phenyl) ethyl acetate (28).This reaction sequence also can be used to prepare other compound 28 regional isomers and analogues that contain the functional group that is adapted to described reaction sequence.
Synthetic route 4
Be present in some functional group on the final structure, because incompatible with the formation of the imidazoles shown in the synthetic route 1-3, thereby must after imidazole ring forms, be incorporated on the structure.The example of this functional group is including, but not limited to formamyl, Aminoindazole base, amino benzisoxa azoles base and aminoquinazoline (quinazolinoyl) (referring to synthetic route 5 and 6).
Formamyl; as shown in the structure in the synthetic route 5 29, can (Synthesis 1989,12 according to Katritzky etc.; method 949-50) is by using salt of wormwood for example, hydrogen peroxide and being incorporated on the final structure as the DMSO hydrolysis nitrile of solvent.When nitrile is positioned at the contraposition of imidazole ring, must add magnesium oxide in the reaction mixture.The amidino groups group as shown in structure 31, can be incorporated on the final structure by Pinner reaction and ammonolysis reaction (ammonolysis) subsequently.In addition; nitrile 28 can alkali for example triethylamine in the presence of make amidoxim 32 with oxammonium hydrochloride chemical combination; it is after carrying out acetylize with diacetyl oxide; reduction can in all sorts of ways; palladium carbon and hydrogen carry out catalytic hydrogenation (Judkins etc., Syn.Comm.1996,26 to described method including, but not limited to for example using; 4351-4367), perhaps use reactive metal such as zinc.Son says that the precursor cyano group shown in the structure 28 of synthetic route 5 can adopt 4-(2-bromo-ethanoyl)-benzonitrile, 3-(2-bromo-ethanoyl) benzonitrile or 2-(2-bromo-ethanoyl)-benzonitrile as the BrCH described in the synthetic route 1 in independent reaction for example
2C (O) X reagent and being incorporated on the intermediate structure ().
Synthetic route 5
Aminoindazole, amino benzisoxa azoles and amido quinazoline functional group can use the conventional intermediate that comprises the phenyl ring that has adjacent fluorine nitrile as shown in structure 33 (synthetic route 6) to be incorporated on the final structure.Amino-indazole functional group (34) by for example in suitable solvent such as propyl carbinol heating 33 make with the hydrazine monohydrate.Heating can be undertaken by conventional heating means or microwave radiation, makes adjacent fluorine nitrile change into the required temperature of Aminoindazole and depends on that the regional isomerism between adjacent fluorine nitrile and the imidazole ring concerns.Usually, when nitrile was positioned at the contraposition of imidazole ring, the formation of Aminoindazole needed 160 ℃ temperature.Amido quinazoline (35) is heated to about 140 ℃ of chemical combination by the form with adjacent fluorine nitrile (33) and formamidine acetate and other acceptable acid addition salts and makes in suitable solvent such as N,N-DIMETHYLACETAMIDE or dimethyl formamide.Adjacent fluorine nitrile to the conversion of amino benzisoxa azoles (36) can by fluorine nitrile 33 and acetoxyl group hydroxamic acid alkali for example salt of wormwood in the presence of chemical combination realize.
Synthetic route 6
The general synthetic method of α bromoketone class that contains adjacent fluorine nitrile is shown in synthetic route 7.The bromo fluorinated acid (37) of suitable replacement is heated to 90 ℃ with for example zinc cyanide and palladium (0) four-(triphenylphosphine) in suitable solvent such as dimethyl formamide, changes into corresponding nitrile 38.The nitrile 38 that so makes is handled with oxalyl chloride in as the methylene dichloride that contains several DMF at suitable solvent successively, then suitable solvent or solvent combination as acetonitrile and hexane in the processing of trimethyl silyl diazomethane.The separation of intermediates diazo-ketones, and obtain α bromoketone 39 with Hydrogen bromide and acetic acid treatment.
Synthetic route 7
In addition, bromoketone 39 can be by the adjacent fluorine nitrile (40 that contains bromide of suitable replacement, synthetic route 8) synthetic, using tributyl-(1-methoxy-ethylene base) stannane and palladium catalyst to be heated to reflux in suitable solvent such as toluene as two-(triphenylphosphine)-two chloro-palladiums (II) successively it handles, then handles with the concentration of 5% (w/v) usually with aqueous hydrochloric acid.In suitable solvent such as chloroform or methylene dichloride, close and make bromoketone 39 obtaining methyl ketone 41 with bromination.The other synthetic route of the preparation 39 beyond shown in the synthetic route 7 and 8 it may occur to persons skilled in the art that, it depends on the market contained R on the obtainable carbocyclic ring
3aAnd R
3bThe regional isomer that may make up.
Synthetic route 8
Shown in synthetic route 9, another different chemical conversion order can be used to prepare the regional isomer of the glyoxaline compound of The compounds of this invention for synthetic another.α-the bromoketone 42 that will contain suitable substituent is heated to reflux in suitable solvent such as ethanol with sodium formiate and carries out chemical combination.The ketone ester 43 that so makes is dissolved in solvent for example in the ethanol, and alkali for example sodium bicarbonate in the presence of with amidine 44 (X=aryl or the heteroaryl) chemical combination of suitable replacement.So the imidazoles 45 that forms is compared with the glyoxaline compound shown in the synthetic route 1-3 and is had opposite area configuration.For preparing amino acetylize, carry out the removal of amine protecting group PG as mentioned above, obtain aminooimidazole 46.
Synthetic route 9
The benzimidazole compound that is used to prepare The compounds of this invention can be synthetic according to the general method shown in the synthetic route 10.The amino acid of appropriate protection and the phenylenediamine 22 that suitably replaces are dissolved in solvent for example in the pyridine, and form reagent such as BOP-agent treated with amido linkage.Reaction mixture is heated to 80 ℃ carries out closed loop, form benzoglyoxaline 23.Remove the protecting group on the amine as mentioned above, be used for the acidylate of the amine shown in following synthetic route 17 with preparation.
Synthetic route 10
Can be used for the 2-of synthetic The compounds of this invention and general synthetic method that the 4-position has substituent azole compounds shown in synthetic route 6.The amino acid/11 and the β-ketoamine 50 (X=aryl or heteroaryl) of appropriate protection are dissolved in the suitable solvent such as pyridine, and at room temperature handle with acid amides coupling reagent such as bop reagent.The keto-amide 51 that so forms is dissolved in the suitable solvent such as DMF, and at high temperature handles this solution dewater (Sow etc., J.Org.Chem.1990,55,386) with oxychlorination Asia phosphorus (phosphorous oxychloride).With azoles 52 deprotections, be used for the acidylate of amine 53 with preparation, shown in synthetic route 17.
Synthetic route 11
The suitable functionalized triazole class compounds that is used for synthetic The compounds of this invention can be synthetic according to the method shown in the synthetic route 12.The amino acid/11 and the hydrazine of due care are dissolved in the suitable solvent such as pyridine, and handle with amido linkage formation reagent.The imido-ester 55 (X=aryl or heteroaryl) that gained hydrazoic acid 54 usefulness are suitably replaced carries out condensation.When imido-ester is the form of hydrochloride, need to add for example triethylamine of alkali.Can use solvent such as acetonitrile.Triazole 56 deprotections that so form are obtained amine 57, and it is used for following synthetic route 17.For example, when protecting group was the BOC part, amine obtained the amine 53 of two-tfa salt form with trifluoroacetic acid deprotection in methylene dichloride.
Synthetic route 12
The pyrazole compound that is used for the suitable replacement of synthetic The compounds of this invention can adopt the method shown in synthetic route 13 to synthesize (Shunsaku Ohta etc., Chem.Pharm.Bull.1981,29 (10), 2762).The 'beta '-ketoester 58 (X=aryl or heteroaryl) that suitably replaces is dissolved in the suitable solvent, ester is hydrolyzed with for example sodium hydroxide.Acid is dissolved among suitable solvent such as methyl alcohol and the THF, adds magnesium ethylate then, form the magnesium salts (60) of β ketone acid 59.In an independent reaction sequence, with the amino acid/11 (Y=R of due care
10N (PG)-) carboxylic acid activate with for example carbonyl dimidazoles and obtain activated amino acid 61 (LG=imidazoles-1-yl in this example).Compound 60 and 61 chemical combination in suitable solvent such as DMF is obtained beta diketone 62.62 usefulness hydrazines are at high temperature handled obtain pyrazoles 63.When the amino when 64 was partly protected by CBz, protecting group can be removed by for example using palladium carbon and element hydrogen catalytic hydrogenation, obtains amine 64.
Synthetic route 13
The general formation method of substituted triazole ketone compounds that is used for synthetic The compounds of this invention is shown in synthetic route 14.The sodium salt that protected beta-amino nitrile 65 usefulness of suitable replacement are pure for example sodium methylate is handled formation imidoether 66.With hydrazine 67 (X=aryl or heteroaryl) the reaction formation amino amidine 68 (Yanagisawa etc., J.Med.Chem.1984,27 (7), 849) of imido-ester 66 with suitable replacement.68 usefulness two-activation carbonyl such as carbonyl dimidazoles (LG=imidazoles-1-yl) processing are obtained triazolone 69.Amino to 69 carries out deprotection, prepares to be used for the acidylate of nitrogen, shown in synthetic route 17.For example, when amine was partly protected by CBz, protecting group can palladium carbon and hydrogen carry out catalytic hydrogenation by for example using, and perhaps also can remove by handling in HOAC or pure TFA with HBr, obtain amine 70.
Synthetic route 14
The 4-position is synthetic shown in synthetic route 15 by the glyoxaline compound of condensed ring heterocyclic substituted.Due care and functionalized 4-trifluoromethyl imidazoles 71 can obtain according to the chemical process shown in the synthetic route 3.Imidazoles 71 is dissolved in the suitable solvent such as methyl alcohol, and alkali for example sodium methylate in the presence of heat.The methyl esters 72 that so forms is dissolved in suitable solvent for example in the tetrahydrofuran (THF), and aniline 47 chemical combination that replaced by hydroxyl, amino, alkyl monosubstituted amino or sulfydryl with the ortho position.Used aniline can have the known substituent R that adapts with reaction conditions of other those skilled in the art
3aAnd R
3eWith two reactants with protonic acid for example right-toluenesulphonic acids handles addition and cyclization subsequently and the dehydration to carry out aniline, formation condensed heterocycle 74.Remove protecting group on the amine to prepare to be used for the acidylate of the amine shown in synthetic route 17.When protecting group is the BOC part, adopt strong acid such as trifluoroacetic acid or HCl in suitable solvent such as methylene dichloride or dioxane, to make the amine deprotection, obtain the amine 75 of two-tfa salt form.
Synthetic route 15
The thiazol-2-yl imdazole derivatives that is used for synthetic The compounds of this invention can prepare shown in synthetic route 16.The ester 76 of suitable replacement and β amineothiot such as acthiol-J 77 handled with protonic acid such as camphorsulfonic acid in suitable solvent such as tetrahydrofuran (THF) carry out chemical combination.Other β amineothiot with the functional group that adapts with these conditions can be used for this reaction.With gained thiazolidine 78 usefulness for example Manganse Dioxide be oxidized to thiazole 79.Other suitable oxygenant is as 2,3-two chloro-5, and 6-dicyano-1, the 4-benzoquinones also can be used for this step.79 amino deprotection is prepared to be used for acidylate.For example, when protecting group was the BOC part, employing strong acid such as trifluoroacetic acid with the amine deprotection, obtained the amine 80 of two-tfa salt form in suitable solvent such as methylene dichloride.
Synthetic route 16
Above-mentioned reaction scheme 1-3 of each bar and 9-16 all generate a kind of heterocycle, and it contains under standard amide key coupling condition and to be fit to and the carboxylic acid of the suitable replacement aminoalkyl group side chain (synthetic route 17A) of N-Boc-tranexamic acid or the reaction of 4-cyanobenzoic acid for example.Can use the agent combination that is generally used for this conversion, it is including, but not limited to BOP-reagent and pyridine; EDCI, HOAt, N-methylmorpholine; Or EDCI, HOBt, N-methylmorpholine.The solvent that is suitable for this conversion is including, but not limited to pyridine, THF and dimethyl formamide.Can also use solvent combination, for example be fit to reach the methylene dichloride and the DMF of the ratio of agents useful for same solubleness.On the other hand, the amine of synthetic route 1-3 and 9-16 gained can adopt the alkylating reagent or the sulfonic acid halide reaction of method known to those skilled in the art and suitable replacement.Should expect that the compound that obtains in the synthetic route 17 is carried out other deprotection steps to the employing methods known in the art and the processing of further functional group will obtain other The compounds of this invention.
In addition, when heterocycle contained the aliphatic carboxylic acid of being with side chain, the formation of amido linkage can realize (synthetic route 17B) by amine or aniline reaction with agent combination described herein and suitable replacement.
Synthetic route 17A and 17B
Carboxylic acid (the A-CO of suitable replacement
2H) be used in the acid amides coupling shown in synthetic route 17A.These carboxylic acids are many to be can obtain on the market.For the situation of the carboxylic acid that can not obtain on the market, it can adopt methods known in the art, by corresponding bromide 87, alcohol 85, aldehyde 88 or ester 89 preparations, shown in synthetic route 18.R
1And R
2Group can adopt methods known in the art further to handle so that other The compounds of this invention to be provided.For example, cyano group can be used as R
1, it can be reduced into CH with appropriate reductant
2NH
2, perhaps by with azanol reaction, adopt above-described method to carry out palladium catalyzed hydrogenation then and change into amidine.
Synthetic route 18
When A is the isoquinoline 99.9 part, can adopt the method among the US2004/0077865 after the improvement.Heating 2-methyl benzonitrile derivative 90 and 1-(tert.-butoxy)-N in suitable solvent such as DMF, N, N ', N '-tetramethyl-methanediamine obtains enamine 91.With enamine 91 and 2, the 4-dimethoxybenzylamine in DMPU under high temperature condensation obtain 1-imino--1,2-dihydro-isoquinoline skeleton obtains 92 with posthydrolysis.In TFA, under high temperature, 92 debenzylations are obtained 1-amino-isoquinoline 99.9 93 with methyl-phenoxide.When A is 5,6,7, during 8-tetrahydroisoquinoline part, adopt the method (J.Org.Chem.2002,67,7890) of McEachern after improving etc.Acid 92 is converted into ester 94.In TFA under high temperature with methyl-phenoxide with 94 debenzylations, and carry out acetylize with Acetyl Chloride 98Min. and triethylamine and obtain 95.In the presence of TFA, obtain 1-amino-5,6,7, the 8-tetrahydroisoquinoline by platinum oxide hydrogenation.With NaOH ester is carried out saponification, and under acidic conditions, make amide hydrolysis obtain 96.
Synthetic route 19
When A is 4-amido quinazoline part, according to the method for the Lam after improving, heating suitably replaces in DMA adjacent fluorine benzonitrile 97 and formamidine acetate or ethanamidine acetate (Lam, P.Y.S. etc., J.Med.Chem.2003,46,4405.), obtain 4-amido quinazoline 98 and 99.Under alkaline condition, make the ester saponification, obtain 100 and 101.
Synthetic route 20
Other features of the present invention will become clearly in to the declarative procedure of exemplary embodiment following, and it is for the present invention is illustrated that exemplary embodiment is provided, rather than be used for it is limited.
Specific embodiments
Embodiment
Except as otherwise noted, the performance of the ratio of solution is volume relationship.Nmr chemical displacement (δ) is reported with per 1,000,000 umber.Flash chromatography carries out (Still, W.C. etc., J.Org.Chem.1978,43,2923) according to the method for Still on silica gel.
In entire description, used following chemical reagent abbreviation implication is as follows:
HOAc or AcOH=acetate
The Bn=benzyl
The Bu=butyl
The t-Bu=tertiary butyl
The Boc=tertbutyloxycarbonyl
Bop reagent=benzotriazole-1-base oxygen base-three (dimethylamino) hexafluorophosphate
The Brine=saturated sodium-chloride water solution
The CSA=camphorsulfonic acid
The DMF dimethyl formamide
The DMSO=methyl-sulphoxide
EDCI=1-(3-(dimethylamino) propyl group)-3-ethyl-carbodiimide hydrochloride
The Et=ethyl
EtOH=ethanol
The EtOAc=ethyl acetate
The Me=methyl
MeOH=methyl alcohol
The NaOAc=sodium acetate
The OAc=acetoxyl
The Ph=phenyl
The Pr=propyl group
The i-Pr=sec.-propyl
The i-PrOH=Virahol
The TFA=trifluoroacetic acid
The THF=tetrahydrofuran (THF)
℃=degree centigrade
The atm=normal atmosphere
Conc.=is dense
The eq=equivalent
H or hr=hour
The g=gram
The mg=milligram
The L=liter
The mL=milliliter
μ L=microlitre
The mmol=mmole
The M=mole
The meq=milliequivalent
Min=minute
The MW=molecular weight
The mp=fusing point
Rt or RT=room temperature
Sat or sat ' d=are saturated
ESI=electrospray ionization mass spectrum
The HPLC=high performance liquid chromatography
The MS=mass spectrum
The coupling of LC/MS=liquid chromatography mass
The HRMS=high resolution mass spectrometry
The NMR=NMR (Nuclear Magnetic Resonance) spectrum
The TLC=thin-layer chromatography
" α ", " β ", " R ", " S ", " E " and " Z " are stereochemistry nouns well known to those skilled in the art.The a certain steric isomer of formula I compound may show the activity more superior than other steric isomers.Therefore, each steric isomer of formula I compound all is considered to a part of the present invention.When needs, can realize the separation of racemize material by the following method: the HPLC that adopts chiral column, perhaps adopt for example Wilen, the method for splitting of the bronsted lowry acids and bases bronsted lowry of resolving agent described in the S.H.Tables ofResolving Agents and Optical Resolutions 1972,308 or enantiomer-pure.The chipal compounds of formula I can also adopt for example Jacobsen, E.Acc.Chem.Res.2000,33, chiral catalyst described in the 421-431 or chiral ligand adopt perhaps that the mapping that the technician in other asymmetric synthesis fields knows-and non-mapping-selective reaction and reagent are directly synthetic.
Following embodiment has adopted method preparation disclosed herein, separated and has characterized.Following examples illustration the part of the scope of the invention, rather than be used for the scope of the invention is limited.
Embodiment 1
(S)-and 4-carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) benzamide, two (trifluoroacetic acid acid) salt
Steps A: 2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl carbamic acid (the S)-tert-butyl ester:
To L-N-(Boc)-phenylalanine (750mg, EtOH/H 3.77mmo1)
2O (1: 1,7.4ml) add Cs in the solution
2CO
3(650mg, 1.89mmol).Reactant was at room temperature stirred 1 hour.Solvent removed in vacuo, and the salt of gained is suspended among the DMF (4.7ml).(1.0g 3.77mmol), and at room temperature stirred reactant 1.5 hours disposable adding 2-bromoacetophenone.Filtering reaction is removed CsBr.Solid is washed with DMF.The washings and the filtrate that merge are concentrated under vacuum, obtain yellow solid (650mg).Thick intermediate is placed the flask that dean stark trap is housed, and be dissolved in the dimethylbenzene (10ml).In flask, add NH
4OAc (2.64g, 30mmol), and with reactant reflux 3 hours.Reactant is cooled to room temperature, solvent removed in vacuo.Residue is dissolved among the EtOAc again, and uses saturated NaHCO
3Na is used in the aqueous solution and salt water washing
2SO
4Drying filters and is distilled to dried, obtains the required product of 780mg (productive rate 57%).MS 364.2(M+H)
+。
In addition, with ketone ester intermediate and 10 equivalent NH
4OAc is dissolved in the ethanol, in sealed tube by carry out microwave radiation heating to 160 ℃ and kept 30 minutes.Reactant is cooled to room temperature, and ethanol is removed in vacuum distilling, and residue is dissolved among the EtOAc once more.Organic layer with 1/2 saturated salt water washing (2 times), is used MgSO
4Drying, and be evaporated to dried.So the crude product of producing is enough pure, can be used to carry out next step.
Step B:(S)-and 2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethamine two-trifluoroacetate: (100mg 0.28mmol) is dissolved in CH with the product in embodiment 1 steps A
2Cl
2(2.8ml), and with pure TFA (0.2ml 10%v/v) handles.Reactant was at room temperature stirred 16 hours.Solvent removed in vacuo and TFA.Residue is dissolved in the methyl alcohol again.Solvent removed in vacuo is dissolved in the gained residue among the MeOH once more, and vacuum distilling obtains two-tfa salt of the thick amine of 124mg (productive rate 92%) except that desolvating.MS 262.2(M-H)
-。
Step C:(S)-4-carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) benzamide, two-trifluoroacetate: with the product (124mg among the embodiment 1 step B, 0.25mmol) and 4-amidino groups benzoate hydrochlorate (94mg 0.47mmol) is dissolved in the anhydrous pyridine (2ml).(249mg 0.56mmol), at room temperature stirred reactant 16 hours to add bop reagent.Solvent removed in vacuo, and residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1).Solution is filtered, and HPLC separates title compound by preparation, obtains the required product of 9.2mg (productive rate 3%).
1H-NMR (500MHz, d
4-MeOH) δ 3.37 (dd, J=8.5 and 13Hz, 1H), 3.46 (dd, J=8.5 and 13Hz, 1H), 5,48 (app t, J=8.2Hz, 1H), 7.14-7.21 (m, 5H), 7.34-7.41 (m, 3H), 7.56 (m, 2H), 7.68 (s, 1H), 7.80 (d, J=8.2Hz), 7.96 (d, J=8.2Hz, 2H): C
25H
23N
5The HRMS of O (M+H)
+, the m/z calculated value: 410.1981, measured value:
410.1974.
Embodiment 2
(S)-and 4-(amino methyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetic acid hydrochlorate.
Steps A: (S)-(4-((2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) carbamyl) cyclohexyl) the methyl carbamic acid tert-butyl ester: with the product (75mg among the embodiment 1 step B; 0.15mmol) and N-(Boc)-(75mg 0.29mmol) is dissolved in the pyridine (1.7ml) to aminomethyl hexahydrobenzoic acid (tranexamic acid).(152mg 0.344mmol), at room temperature stirred reactant 12 hours to add bop reagent.With the reactant dilute with water, and extract with EtOAc.With the organic layer salt water washing that merges, and use Na
2SO
4Drying is filtered and vacuum distilling.Crude product is not further purified and is used for next step.MS 503.2(M+H)
+。
In addition, the product among the embodiment 1 step B is carried out coupling with 1.0 normal N-Boc-to aminomethyl hexahydrobenzoic acid, 1.2 normal HOAt, 5.0 normal N-methylmorpholines and 1.2 normal EDCI.Amine, N-Boc-are dissolved among the DMF aminomethyl hexahydrobenzoic acid and HOAt.Add N-methylmorpholine again, then add EDCI.Reactant was at room temperature stirred 2 and 16 hours.Reactant is diluted with EtOAc,, use MgSO with 1/2 saturated brine washing (4-6 time)
4Drying filters and is evaporated to dried, obtains crude product.
Step B:(S)-and 4-(amino methyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate.The product (100mg) of embodiment 2 steps A is dissolved in the CH of 30%TFA
2Cl
2In the solution (2.0ml).Reactant was at room temperature stirred 3 hours.Again with reactant with dilution with toluene and vacuum-drying.Residue is dissolved in the toluene once more, and solution evaporation is extremely done.Crude product is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), HPLC separates title compound (46mg two-tfa salt, productive rate 49%) by preparation.
1H-NMR (500MHz, d
4-MeOH) δ 1.02-1.11 (m, 2H), 1.32-1.45 (m, 2H), 1.54-1.61 (m, 1H), 1.80 (br d, J=12.1Hz, 1H), 1.86 (br d, J=11.5Hz, 3H), 2.28 (dt, J=12.1,3.30Hz, 1H), 2.77 (d, J=7.15Hz, 2H), 3.28-3.33 (dd, 1H use CH
3OH observes the peak), 3.38 (dd, J=13.5,8.0Hz), 5.31 (t, J=8.25Hz, 1H), 7.18 (d, J=7.15Hz, 2H), 7.22-7.30 (m, 3H), 7.43-7.50 (m, 3H), 7.62 (app d, J=6.6Hz, 2H), 7.75 (s, 1H): MS403.2 (M+H)
+.
Embodiment 25
(S)-and 2-(4-(2-(1-(4-(amino methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate, two-trifluoroacetate
Steps A: 4-ethanoyl-Phenylacetic acid ethylester: with ethyl bromoacetate (1.70g, 10.2mmol), three-(1-naphthylidene) phosphines (379mg, 0.93mmol) and Tripotassium phosphate (10.8g 51mmol) places flask.Flask is vacuumized and recharges argon gas.(2.0g, anhydrous THF (40ml) solution 12.2mmol) joins in the flask with 4-phenyl methyl ketone ylboronic acid.Reactant was at room temperature stirred 16 hours.Reactant is diluted water and salt water washing, MgSO with EtOAc
4Drying filters and is evaporated to dried.With the residue preadsorption at SiO
2On, with product SiO
2Chromatographic separation obtains 616mg (29%) 4-phenyl methyl ketone ethyl acetate.MS 207.1(M+H)
+。
Step B:2-(4-(2-acetyl bromide) phenyl) ethyl acetate: (489mg 2.4mmol) is dissolved in CH with the 4-ethanoyl-Phenylacetic acid ethylester in embodiment 25 steps A
2Cl
2In.Dripping bromine (379mg, 2.4mmol).Reactant was at room temperature stirred 16 hours.Reactant is extremely light yellow by the rust red decolouring.Vacuum evaporating solvent obtains the light yellow oil of 680mg (99%) 2-(4-(2-acetyl bromide) phenyl) ethyl acetate.Product is not further purified and is used for next step.MS is equicohesive 287.0 and 289.0 (M+H)
+
Step C:(S)-and 2-(4-(2-(1-(tertbutyloxycarbonyl)-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate: (633mg 2.38mmol) is dissolved among the DMF (2.0ml) with N-(Boc)-phenylalanine.With Cs
2CO
3(775mg, 1.19mmol) disposable joining in the flask are stirred reactant 1 hour.(680mg, DMF 2.38mmol) (2.0ml) solution joins in the reaction vessel, and reactant was at room temperature stirred 16 hours with the 2-among the embodiment 25 step B (4-(2-acetyl bromide) phenyl) ethyl acetate.Filter out solid, and wash with DMF.Merge organic layer and be evaporated to dried.Residue is dissolved among the EtOAc again, and washs, use MgSO with 1: 1 water and salt brine solution
4Drying is filtered and evaporation, obtains the filbert solid of 1.03g.Solid is dissolved in the dimethylbenzene (14ml) again.Add NH
4(3.42g 44mmol), and loads onto dean stark trap with flask to OAc.The reactant reflux was dewatered in 5 hours.Reactant is cooled to room temperature, solvent removed in vacuo.Residue is dissolved among the EtOAc again, and water and salt water washing, MgSO used
4Drying is filtered and distillation, obtains the filbert solid of 951mg (96%).MS：450.1(M+H)
+。
Step D:(S)-2-(4-(2-(1-amino-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate: with the product (951mg among the embodiment 25 step C, 2.12mmol) handle according to the described method of embodiment 1 step B, obtain the dun glassy mass of 1.14g (100%), it is not further purified and is used for next step.MS：333.1(M-NH
2)
+。
Step e: (S)-2-(4-(2-(1-(4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate: with the product (729mg among the embodiment 25 step D, 1.26mmol), N-(Boc)-to aminomethyl hexahydrobenzoic acid (325mg, 1.26mmol) and HOAt (206mg 1.51mmol) is dissolved among the DMF (6.3ml).Add N-methylmorpholine (637mg, 6.3mmol), then add EDCI (289mmol, 1.51mmol).Reactant was at room temperature stirred 16 hours, with the EtOAc dilution, with 1: 1 water and the washing of brinish mixture, MgSO
4Drying is filtered also distillation, obtains 732mg (99%) product, and it is not further purified and is used for next step.MS 589.1(M+H)
+。
Step F: (S)-2-(4-(2-(1-(4-(amino methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate, two-trifluoroacetate: (99mg 0.17mmol) handles with TFA according to the described method of embodiment 1 step B with the product in embodiment 25 step e.Product is separated with preparation HLPC, obtain 61mg (50%) title compound two-tfa salt.
1H-NMR (500MHz, d
4-MeOH) δ 1.02-1.11 (m, 2H), 1.24 (t, J=7.15Hz, 3H), 132-1.45 (m, 2H), 1.53-1.61 (m, 1H), 1.80 (dr d, J=12.6Hz, 1H), 1.86 (br d, J=11.0Hz, 3H), 2.28 (tt, J=12.4,3.0Hz, 1H), 2.775 (d, J=7.15Hz, 2H), 3.28-3.32 (dd is sheltered by the MeOH peak), 3.38 (dd, J=13.5,8.0Hz, 1H), 3.70 (s, 2H), 4.145 (q, J=7.15Hz, 2H), 5.31 (t, J=8.5Hz, 1H), 7.175 (d, J=7.15Hz, 2H), and 7.22-7.30 (m, 3H), 7.41 (d, J=8.25,2H), 7.59 (d, J=8.25Hz; 2H), 7.74 (s, 1H) .C
29H
36N
4O
3HRMS (M+H)
+, the m/z calculated value: 489.2866, measured value: 489.2861.
Embodiment 26
(S)-and 2-(4-(2-(1-(4-(amino methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) acetate, two-trifluoroacetate
With (the S)-2-among the embodiment 25 (4-(2-(1-(4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) ethyl acetate two-trifluoroacetate (30mg, 0.042mmol) be dissolved among the MeOH (2ml), and handle with the NaOH (0.2ml) of 1N.Reactant was at room temperature stirred 16 hours.Solvent removed in vacuo is dissolved in residue the MeOH/H that contains 0.1%TFA again
2Among the O (9: 1), and, obtain the 22mg title compound as its two-tfa salt (productive rate 76%) by preparation HPLC purifying.
1H-NMR (500MHz, d
4-MeOH) δ 1.02-1.11 (m, 1H), 1.31-1.45 (m, 2H), 1.53-1.61 (m, 1H), 1.79 (br d, J=12.1Hz, 1H), 1.865 (br d, J=12.1Hz, 3H), 2.28 (tt, J=3.2 and 12.1Hz, 1H), 2.77 (d, J=7.15Hz, 2H), 3.28-3.32 (dd, MeOH shelters at the peak), 3.375 (dd, J=8.0 and 13.4Hz, 1H), 3.67 (s, 2H), 5.31 (t, J=8.25Hz, 1H), 7.175 (d, J=6.6Hz, 2H), 7.22-7.30 (m, 3H), 7.42 (d, J=8.25Hz, 2H), 7.59 (d, J=8.25Hz, 2H), 7.74 (s, 1H) .C
27H
32N
4O
3HRMS (M+H)
+, the m/z calculated value: 461.2553, measured value: 461.2572.
Embodiment 27
(S)-4-(aminomethyl)-N-{1-[(4-carboxamide methyl-phenyl)-1H-imidazoles-2-yl]-the 2-phenylethyl }-cyclohexane carboxamide, two-trifluoroacetate
Steps A: (S)-2-(4-(2-(1-(4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) phenyl) acetate: with the product (200mg in embodiment 25 step e, 0.34mmol) be dissolved among the MeOH (3ml), and handle with the NaOH (0.34ml) of 1N.Reactant was at room temperature stirred 16 hours.Solvent removed in vacuo.Residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1).Product is separated (90mg, 47%) with preparation HPLC.MS 561.1(M+H)
+。
Step B:(S)-(4-((1-(4-(4-(2-amino-2-oxoethyl) phenyl)-1H-imidazoles-2 base)-2-styroyl) formamyl) cyclohexyl) methyl carbamic acid-tertiary butyl ester: with the product (33mg in embodiment 27 steps A; 0.060mmol) and HOAt (9.7mg 0.071mmol) is dissolved among the DMF (1ml).Add successively N-methylmorpholine (18.2mg, 0.18mmol) and EDCI (13.6mg, 0.071mmol).Reactant was at room temperature stirred 30 minutes.Add strong aqua (adding 5), and reactant was at room temperature stirred 16 hours by the Pasteur transfer pipet.Reactant is diluted with EtOAc, and, use MgSO with 1: 1 water and brinish mixture (5x), the 1N HCl aqueous solution and salt water washing
4Drying is filtered and vacuum-drying.Residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), product separates with preparation HPLC, obtains 9mg (22%).MS 560.1(M+H)
+。
Step C:(S)-N-(1-(4-(4-(2-amino-2-oxoethyl) phenyl)-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl)-cyclohexane carboxamide, two (trifluoroacetic acid) salt: with the product (9mg of embodiment 27 step B, 0.016mmol) handle with TFA according to the method described in the embodiment 1 step B, obtain title compound (11mg, 99%).
1H-NMR (500MHz, d
4-MeOH) δ 1.02-1.11 (m, 2H), 1.28-1.44 (m, 2H), 1.57 (m, 1H), 1.79 (br d, J=12.6Hz, 1H), 1.85 (br d, J=11Hz, 3H), 2.28 (tt, J=3.0,12.1Hz, 1H), 2.77 (d, J=7.15Hz, 2H), (3.28-3.32 dd is sheltered by MeOH), 3.375 (dd, J=8.0,13.0Hz, 1H), 3.57 (s, 2H), 5.31 (t, J=8.2Hz, 1H), 7.175 (d, J=7.2Hz, 2H), 7.22-7.30 (m, 3H), 7.43 (d, J=8.2Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.74 (s, 1H); C
27H
33N
5O
2HRMS (M+H)
+, the m/z calculated value: 460.2713, measured value: 460.2714.
Embodiment 28
4-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
Steps A: methyl carbamic acid tertiary butyl ester trans-4-(((S)-1-(4-(4-carbamyl phenyl)-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl): will according to the method for embodiment 1 steps A-B and embodiment 2 steps A by 2-bromo-4 '-(trans-4-(((S)-1-(4-(4-cyano-phenyl)-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) methyl carbamic acid tertiary butyl ester (117mg that cyano-acetophenone makes; 0.22mmol) be dissolved among the DMSO (2ml), and under argon gas, use K
2CO
3(90.0mg 0.65mmol) handles.H with 30%
2O
2The aqueous solution (0.8ml, 2.4mmol) and magnesium oxide (44mg 1.11mmol) joins in the reactant successively.Reactant was at room temperature stirred 4 hours.Reactant is diluted with EtOAc, with HCl and the salt water washing of 1N, MgSO
4Drying filters and is evaporated to dried.Isolate yellow solid product (109mg, productive rate 90%).MS 546.3(M+H)
+。
Step B:4-(2-((S)-1-(trans-4-(amino methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl) benzamide, the di-trifluoromethyl acetate: (109mg 0.20mmol) handles with TFA according to the described method of embodiment 2 step B with the product in embodiment 28 steps A.By preparation HLPC separated product, obtain 17.3mg title compound (20%).
1HNMR (500MHz, d
4-MeOH) δ 0.36 (m, 2H), 0.68 (m, 2H), 0.87 (m, 1H), 1.14 (m, 3H), 2.07 (d, J=7.15Hz, 2H), 2.63 (m, 2H), 4.61 (t, J=8.25Hz, 1H), 6.47 (d, J=7.15Hz, 2H), 6.53 (t, J=7.42Hz, 1H), 6.58 (t, J=7.15Hz, 2H), 7.04 (d, J=8.25Hz, 2H), 7.14 (s, 1H), 7.28 (d, J=8.25Hz, 2H); C
26H
31N
5O
2HRMS (M+H)
+, the m/z calculated value: 446.2556, measured value: 446.2570.
Embodiment 29
3-(2-((S)-1-(4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
Title compound is by using the method described in the embodiment 28 synthetic suitably.
1HNMR(500MHz，d
4-MeOH)δ1.06(m，2H)，1.39(m，2H)，1.57(m，1H)，1.80(d，J＝12.10Hz，1H)，1.86(d，J＝11.55Hz，3H)，2.28(tt，J＝12.10，3.30Hz，2H)，2.77(d，J＝7.15Hz，2H)，3.34(d，J＝8.25Hz，1H)，3.39(dd，J＝13.40，8.25Hz，1H)，3.98(s，1H)，5.34(t，J＝8.25Hz，1H)，7.19(d，J＝6.60Hz，2H)，7.24(t，J＝7.15Hz，1H)，7.29(t，J＝7.15Hz，2H)，7.60(t，J＝7.70Hz，1H)，7.82(m，J＝5.50Hz，2H)，7.93(d，J＝8.25Hz，1H)8.18(s，1H)；MS446.2(M+H)
+.
Embodiment 30
4-(2-((S)-1-(trans-4-(amino methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl)-N-methyl-benzamide, two-trifluoroacetate
Steps A: 4-(2-((S)-1-(trans)-4-((tertbutyloxycarbonyl) methyl) cyclohexyl formamido group)-2-styroyl)-1H-imidazol-4 yl) phenylformic acid: the method that will adopt embodiment 1 steps A-B and embodiment 2 steps A by 2-bromo-4 '-(162mg 0.28mmol) is dissolved among MeOH (5ml) and the EtOAc (1ml) methyl benzoate for the 4-(2-((S)-1-(trans-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) of carboxyl methyl acetophenone preparation.(112mg 2.8mmol), and at room temperature stirred mixture 5 hours to add 1N NaOH (2ml) and magnesium oxide successively.Solvent vacuum-evaporation is extremely done.Handle with the residue dilute with water and with 1N HCl.Gained solution is diluted with EtOAc, use the salt water washing, MgSO
4Drying is filtered and evaporation, gets 75mg (productive rate 60%) transparent glass shape thing.MS 548.0(M+H)
+。
Step B:(is trans)-4-(((S)-1-(4-(4-(methylamino formyl radical) phenyl)-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) the methyl carbamic acid tertiary butyl ester: according to the condition described in the embodiment 2 step B; replace HOAt with HOBt; with the product (45mg in embodiment 30 steps A; 0.08mmol) and methylamine (0.2ml 0.09mmol) handles.Gained yellow oil (44.0mg, productive rate 93%) is not further purified and is used for next step.MS560.1(M+H)
+。
Step C:4-(2-((S)-1-(trans)-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl)-N-methyl-benzamide, two-trifluoroacetate: (44.0mg 0.079mmol) handles with TFA according to the described method of embodiment 2 step B with the product among the embodiment 30 step B.The gained residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), and, obtain 1.0mg title compound (3%) with preparation HPLC separation.
1HNMR (500MHz, d
4-MeOH) δ 1.05 (m, 1H), 1.39 (ddd, J=30.24,12.92,3.02Hz, 1H), 1.55 (m, J=12.10Hz, 1H), 1.79 (m, 1H), 1.86 (d, J=11.00Hz, 1H), 2.26 (m, 1H), 2.77 (d, J=7.15Hz, 1H), 2.92 (s, 1H), 3.15 (m, 1H), 3.3 (m, 2H), 5.29 (t, J=8.25Hz, 1H), 7.16 (d, J=7.15Hz, 1H), 7.23 (t, J=7.15Hz, 1H), 7.28 (t, J=7.15Hz, 1H), 7.72 (d, J=8.25Hz, 1H), 7.86 (s, 1H), 7.92 (d, J=8.80Hz, 1H); C
27H
33N
5O
2HRMS (M+H)
+, the m/z calculated value: 460.2713, measured value: 460.2735.
Embodiment 31
(S)-and 4-(2-(1-trans-(4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl)-N, N-dimethyl benzamide, two-trifluoroacetate
Title compound synthesizes by using synthetic embodiment 30 described methods suitably.
1HNMR (500MHz, d
4-MeOH) δ 1.06 (m, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.81 (d, J=14.85Hz, 1H), 1.86 (d, J=10.45Hz, 3H), 2.28 (tt, J=12.30,3.30Hz, 1H), 2.77) (d, J=7.15Hz, 2H), 3.01 (s, 3H), 3.12 (s, 3H), 3.39 (dd, J=13.30,8.24Hz, 1H), 5.31 (t, J=8.25Hz, 1H), 7.18 (d, J=7.15Hz, 2H), 7.24 (t, J=7.15Hz, 1H), 7.29 (t, J=7.42Hz, 2H), 7.55 (d, J=8.25Hz, 2H), 7.72 (d, J=8.25Hz, 2H), 7.85 (s, 1H); C
28H
35N
5O
2HRMS (M+H)
+, the m/z calculated value: 474.2870, measured value: 474.2875.
Embodiment 32
Trans-N-((S)-1-(4-(1H-benzo [d] imidazoles-2-yl)-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl) cyclohexane carboxamide, three-trifluoroacetate
Steps A: (S)-2-phenyl-1-(4-(trifluoromethyl)-1H-imidazoles-2-yl) ethyl carbamic acid tertiary butyl ester: the sodium acetate in being dissolved in 3ml water (0.88g 6.44mmol) adds 1 in the solution, and 1-dibromo trifluoroacetone (0.87g, 3.22mmol).With mixture at N
2Down in 90 ℃ of heating 30 minutes.It is cooled to 0 ℃, and (1.73g, 2.93mmol) solution add dense ammonium hydroxide (4ml strong solution) again to add (S)-(-)-2-(uncle-butoxy carbonyl the amino)-3-phenylpropionaldehyde that is dissolved in 15ml methyl alcohol.With the gained mixture under nitrogen in stirring at room 12 hours.Remove and desolvate, and add entry.Filtering-depositing, and then be dissolved among the EtOAc.With the salt water washing of EtOAc solution, Na
2SO
4Drying is filtered then.Concentrated filtrate obtains the pale solid (productive rate 76.9%) of the required product of 0.80g.MS，356.30(M+H)
+。
Step B:(S)-2-phenyl-1-(4-(trimethoxy methyl)-1H-imidazoles-2-yl) ethyl carbamic acid tertiary butyl ester: with the product (0.1g in embodiment 32 steps A, 0.4mmol) be dissolved among the MeOH (2ml), and with NaOMe (methanol solution of 25%wt, 1.7ml 7.4mmol) handle.In sealed tube, adopt microwave radiation to heat 5 minutes down reaction mixture in 100 ℃.After being cooled to room temperature, solvent removed in vacuo is dissolved in residue among the EtOAc (15ml).With solution H
2Na is used in O, salt water washing
2SO
4Drying is filtered, and is evaporated to driedly, obtains brown jelly (0.15g).MS 392.1(M+H)
+。
Step C:(is trans-4-(((S)-1-(4-(1H-benzo [d] imidazoles-2-yl)-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) and the methyl carbamic acid tertiary butyl ester: the thick intermediate among the embodiment 32 step B is dissolved in THF (2ml).With 1, (41mg, 0.38mmol) (7.3mg 0.038mmol) joins reactant to the 2-phenylenediamine with the tosic acid monohydrate.Reactant was at room temperature stirred 6 hours, then solvent removed in vacuo.Residue is dissolved among the EtOAc, and with saturated NaHCO
3Na is used in the aqueous solution and salt water washing
2SO
4Drying filters and is evaporated to dried.Residue with purification by flash chromatography (silica gel, the hexane solution gradient of 0-100%EtOAc), is obtained 59mg (37%) yellow solid.C
23H
26N
5O
2[M+H]
+HRMS m/z calculated value: 404.2087.Measured value 404.2079.
Step D: trans-N-((S)-1-(4-(1H-benzo [d] imidazoles-2-yl)-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl) cyclohexane carboxamide, two-trifluoroacetate: (59mg 0.15mmol) is dissolved in CH with the product among the embodiment 32 step C
2Cl
2(0.7ml), and with pure TFA (0.3ml 30%v/v) handles.Reactant was at room temperature stirred 1 hour.Solvent removed in vacuo and TFA.Residue is dissolved among the DMF (1ml) again.Add Et
3N (0.073ml, 0.53mmol), N-Boc-to the aminomethyl hexahydrobenzoic acid (42mg, 0.16mmol), HOBt (0.03g, 0.23mmol) and EDCI (43mg 0.23mmol), and at room temperature stirred reactant 4 hours.Add EtOAc (15ml), then add H
2O (10ml).With isolating organic phase water, salt water washing, use Na
2SO
4Drying filters and is evaporated to dried.Residue is dissolved in CH
2Cl
2(0.7ml), and with pure TFA (0.3ml 30%v/v) handles.After at room temperature reacting 40 minutes, reactant is concentrated.By preparation HPLC purifying, obtain 66mg (56%) title compound.
1H-NMR (400MHz, CD
3OD) δ 0.99-1.09 (m, 2H), 1.27-1.49 (m, 2H), 1.54-1.60 (m, 1H), 1.69-1.72 (m, 1H), 1.82-1.85 (m, 3H), 2.16-2.23 (m, 1H), 2.76 (d, J=7.0Hz, 2H), 3.20 (dd, J=8.8,13.6Hz, 1H), 3.46 (dd, J=6.6,13.6Hz, 1H), 5.35 (dd, J=7.0,8.8Hz, 1H), 7.16-7.26 (m, 5H), 7.54-7.58 (m, 2H), 7.72-7.76 (m, 2H), 8.04 (s, 1H); C
26H
31N
6O[M+H]
+HRMS m/z calculated value: 443.2559.
Measured value 443.2545.
The embodiment 33-35 that lists in table 2 is synthetic similarly by being used for embodiment 32 described methods suitably.
Embodiment 36
2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) thiazole-4-methyl-formiate, two-trifluoroacetate
Steps A: 2-(2-((S)-1-(uncle-butoxy carbonyl)-2-styroyl)-1H-imidazol-4 yl)-4,5-thiazoline-4-methyl-formiate: (0.43g 1.21mmol) is dissolved in MeOH (5ml) with (S)-2-phenyl-1-prepared in embodiment 32 steps A (4-(trifluoromethyl)-1H-imidazoles-2-yl) ethyl carbamic acid tertiary butyl ester.Adding NaOMe (the MeOH solution of 25%wt, 5.5ml, 24.2mmol).Reaction mixture was heated 42 hours down at 60 ℃, be cooled to room temperature then.Solvent removed in vacuo is dissolved in residue among the EtOAc (50ml).With solution with water, salt water washing, use Na
2SO
4Drying filters and is evaporated to dried, obtains brown jelly (0.54g).The thick intermediate of a part (0.19g) is dissolved among the THF (5ml).In reactant, add L-acthiol-J hydrochloride (0.073g, 0.43mmol) and CSA (0.01g, 0.043mmol).Reactant was at room temperature stirred 22 hours, then solvent removed in vacuo.Residue by purification by flash chromatography, is obtained the required product of 0.022g (12%) yellow solid.MS 431.08(M+1)
+。
Step B:2-(2-((S)-1-(uncle-butoxy carbonyl)-2-styroyl)-1H-imidazol-4 yl) thiazole-4-methyl-formiate: (0.022g 0.051mmol) is dissolved in the toluene (1ml), and uses MnO with the product in embodiment 36 steps A
2(0.067g 0.77mmol) handles.Reactant was at room temperature stirred 5 hours.Reaction mixture is filtered, and filter cake washs with EtOAc.Be concentrated into the filtrate that merges dried.With the residue purification by flash chromatography, obtain 0.017g triazole (78%) white solid.C
21H
25N
4O
5S[M+H]
+HRMS m/z calculated value: 429.1597.Measured value 429.1586.
Step C:2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) thiazole-4-methyl-formiate; two-trifluoroacetate: with the product among the embodiment 36 step B by with the identical method TFA deprotection described in the embodiment 32 step D; and with N-(the Boc)-aminomethyl hexahydrobenzoic acid is carried out coupling; deprotection then; by obtaining title compound (0.014g, 50%) behind the preparation HPLC purifying.
1HNMR (400MHz, CD
3OD) δ 0.96-1.10 (m, 2H), 1.27-1.47 (m, 2H), 1.51-1.61 (m, 1H), and 1.72-1.89 (m, 4H), 2.18-2.28 (m, 1H), 2.76 (d, J=7.0Hz, 2H), 3.25-3.35 (m, 2H), 3.94 (s, 3H), 5.31 (t, J=7.9Hz, 1H), 7.17-7.28 (m, 5H), 7.98 (s, 1H), 8.43 (s, 1H); C
24H
30Cl
2N
5O
3S (M+H)
+HRMS m/z calculated value: 468.2069. measured value 468.2063.
Embodiment 37
2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-methyl-formiate, two-trifluoroacetate
Steps A: (S)-2-(1-amino-2-styroyl)-1H-imidazoles-4-methyl-formiate: (492mg 1.43mmol) handles according to being used for the described method of embodiment 1 step B, obtains 350mg product (99%) with the product that generates among the embodiment 32 step B.MS 244.22(M-1)
-。
Step B:2-((S)-1-is trans)-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-the 2-styroyl)-1H-imidazoles-4-methyl-formiate: with the product (350mg that generates in embodiment 37 steps A, 1.4mmol) according to being used for described method of embodiment 2 steps A and N-(Boc)-, obtain 290mg product (43%) to the coupling of aminomethyl hexahydrobenzoic acid.MS 485.22(M+H)
+。
Step C:2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-methyl-formiate, two-trifluoroacetate is with the product (290mg that generates among the embodiment 37 step B, 0.60mmol) handle according to being used for the described method of embodiment 2 step B, obtain title compound (138mg, 49%).
1HNMR(500MHz，d
4-MeOH)δ1.05(ddd，J＝12.51，8.66，4.12Hz，3H)1.36(ddd，J＝29.14，12.65，3.30Hz，3H)1.56(dd，J＝7.15，3.85Hz，1H)1.75(d，J＝12.10Hz，1H)1.84(dd，J＝10.17，2.47Hz，4H)2.21(m，1H)2.63(d，J＝9.35Hz，1H)2.76(d，J＝7.15Hz，3H)3.24(dd，J＝7.97，2.47Hz，3H)3.88(s，4H)5.24(t，J＝7.97Hz，1H)7.12(d，J＝7.15Hz，3H)7.20(t，J＝7.15Hz，1H)7.25(m，3H)7.86(s，1H)；MS 385.33(M+H)
+.
Embodiment 38
2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formic acid, two-trifluoroacetate
Steps A: 2-((S)-1-(trans)-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formic acid: with the product (290mg among the embodiment 37 step B, 0.62mmol) be dissolved in the solution of NaOH (4ml) of MeOH (2ml) and 1 N, and at room temperature stirred 72 hours.Evaporating solvent is to doing.With the residue dilute with water, and handle with 1N HCl.Gained solution is diluted with ethyl acetate, use the salt water washing, use MgSO again
4Drying is filtered and evaporation, obtains 138g acid (49%).MS 471.05(M+1)
+。
Step B:2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formic acid, two-trifluoroacetate: (50mg 0.11mmol) handles with TFA according to the described method of embodiment 2 step B with the product of embodiment 38 steps A.The gained residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), and, obtain 17.1mg title compound (44%) by preparation HPLC separation.
1HNMR (500MHz, d
4-MeOH) δ 0.93 (m, 3H), 1.24 (m, 3H), 2.12 (m, 1H), 2.64 (d, J=6.87Hz, 3H), 2.73 (s, 1H), 2.86 (s, 1H), 3.13 (dd, J=13.75,8.25Hz, 1H), 3.2 (m, 2H), 7.01 (d, J=6.87Hz, 3H), 7.11 (d, J=7.33Hz, 1H), 7.15 (t, J=7.33Hz, 3H), 7.81 (s, 1H); C
20H
26N
4O
3HRMS (M+H)
+, the m/z calculated value: 371.2083, measured value: 71.2072.
Embodiment 39
2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formamido group) ethyl acetate, two-trifluoroacetate
Steps A: 2-(2-((S)-1-(trans-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formamido group) ethyl acetate: with embodiment 38 steps A product (30.0mg, 0.06mmol) and 2-ethyl aminoacetate (10mg, 0.09mmol) according to the condition described in embodiment 2 steps A, (10mg 0.09mmol) replaces HOAt and handles with HOBt.Gained yellow oil (33.0mg, productive rate 97%) is not further purified and is used for next step.MS 556.45(M+H)
+。
Step B:2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazoles-4-formamido group) ethyl acetate, two-trifluoroacetate: (33.0mg 0.06mmol) handles with TFA according to the described method of embodiment 1 step B with the product of embodiment 39 steps A.The gained residue is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), and, obtain 2.0mg title compound (7%) by preparation HPLC separation.
1HNMR (500MHz, d
4-MeOH) δ 1.03 (m, 3H), 1.27 (t, J=7.15Hz, 4H), 1.37 (m, 3H), 1.56 (m, 2H), 1.72 (d, J=13.20Hz, 1H), 1.83 (dd, J=8.80,3.85Hz, 4H), 2.20 (m, 1H), 2.76 (d, J=7.15Hz, 3H), 3.19 (dd, J=13.75,8.25Hz, 1H), 3.25 (m, 2H), 4.10 (s, 3H), 4.20 (q, J=7.15Hz, 3H), 5.25 (t, J=7.70Hz, 1H), 7.16 (t, J=7.15Hz, 3H), 7.19 (d, J=7.15Hz, 1H), 7.24 (t, J=7.15Hz, 3H), 7.67 (s, 1H): C
24H
33N
5O
4HRMS (M+Na)
+, the m/z calculated value: 478.2403, measured value: 478.2453.
Embodiment 42
2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-methyl-formiate, two-trifluoroacetate
Steps A: (S)-2-(1-(tertbutyloxycarbonyl)-2-styroyl)-1H-benzo [d] imidazoles-5-methyl-formiate: to L-N-(Boc)-phenylalanine (265mg, 1.0mmole) and bop reagent (464mg, 1.0mmole) pyridine (10ml) solution in add 3, the 4-diamino-methyl benzoate (166mg, 1.0mmole).Reaction mixture was stirred 3 days down at 80 ℃.Solvent removed in vacuo.Residue is dissolved among the EtOAc again.With solution with water and salt water washing, use Na
2SO
4Drying filters and is evaporated to dried.Crude product by preparation HPLC purifying, is obtained 178mg acid amides (45%).MS 340.2(M+H)
+。
Step B:(S)-2-(1-amino-2-styroyl)-1H-benzo [d] imidazoles-5-methyl-formiate: with the product (178mg that generates in embodiment 42 steps A, 0.45mmol) handle with TFA according to the described method of embodiment 1 step B, obtain 180mg amine (76%).MS 296.2(M+H)
+。
Step C:2-((S)-1-(trans-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-methyl-formiate: with the product (178mg that generates among the embodiment 42 part B, 0.34mmol) according to the described method of embodiment 2 steps A and N-(Boc)-, obtain the required product of 75mg (41%) to the coupling of aminomethyl hexahydrobenzoic acid.MS535.5(M+H)
+。
Step D:2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-methyl-formiate, two-trifluoroacetate: with the product (15mg that generates among the embodiment 42 step C, 0.028mmol) handle with TFA according to the described method of embodiment 2 step B, obtain 12mg title compound (65%).
1H-NMR(500MHz，d
4-MeOH)δ1.04-1.10(m，2H)，1.29-1.42(m，2H).1.52-1.60(m，1H)，1.75(m，1H)，1.83-1.86(m，3H)，2.27-2.29(m，1H)，2.77，(d，J＝7.15Hz，2H)，3.45(m，2H)，3.96(s，3H)，5.48(t，J＝8.25Hz，1H)，7.22-7.26(m，5H)，7.80(d，J＝7.0Hz，1H)，8.19(dd，J＝7.0Hz，1.2Hz，1H)，8.36(s，1H)；MS 435.3(M+H)
+.
Embodiment 43
2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-formic acid, two-trifluoroacetate
Steps A: 2-((S)-1-(trans-4-((tertbutyloxycarbonyl) methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-formic acid: adopt the described condition of embodiment 38 steps A, but exception is to replace methyl alcohol with ethanol, with the compound (50mg among the embodiment 42 step C, 0.093mmol) be hydrolyzed, obtain 38mg acid (78%).MS 521.3(M+H)
+。
Step B:2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-formic acid, two-trifluoroacetate: with the compound (15mg in embodiment 43 steps A, 0.029mmol) adopt the described method of embodiment 2 step B to change into title product (12mg, 64%).
1H-NMR (400MHz, d
4-MeOH) δ 1.04-1.10 (m, 2H), 1.29-1.42 (m, 2H), 1.56 (m, 1H), 1.75 (m, 1H), 1.83-1.86 (m, 3H), 2.27-2.28 (m, 1H), 2.77 (d, J=7.03Hz, 2H), 3.43 (d, J=8.34Hz, 2H), 5.48 (t, J=8.12Hz, 1H), 7.22-7.26 (m, 5H), 7.80 (d, J=8.78Hz, 1H), 8.19 (dd, J=8.35Hz and 1.3Hz, 1H), 8.36 (s, 1H); MS 421.2 (M+H)
+.
Embodiment 44
2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-methane amide, two-trifluoroacetate
Steps A: (trans-4-(((S)-1-(5-formamyl-1H-benzo [d] imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) methyl carbamic acid tertiary butyl ester: with the compound (23mg of embodiment 43 steps A; 0.044mmol) place the described condition of embodiment 1 step C; what make an exception is to replace 4-amidino groups benzoate hydrochlorate with ammonium hydroxide, obtains the required product of 18mg (79%).MS 520.0(M+H)
+。
Step B:2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-methane amide, two-trifluoroacetate: with the compound (18mg of embodiment 44 steps A, 0.034mmol) handle with TFA according to the condition of embodiment 2 step B, obtain 8mg title compound (36%).
1H-NMR(500MHz，d
4-MeOH)δ1.04-1.10(m，2H)，1.29-1.42(m，2H)，1.56(m，1H)，1.75(m，1H)，1.83-1.86(m，3H)，2.27-2.28(m，1H)，2.77(d，J＝7.14Hz，2H)，3.43(d，J＝7.70Hz，2H)，5.48(t，J＝8.24Hz，1H)，7.22-7.27(m，5H)，7.80(d，J＝8.78Hz，1H)，8.05(dd，J＝8.79Hz，1.64Hz，1H)，8.25(s，1H)；MS420.2(M+H)
+.
Embodiment 45
2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-yl) ethyl acetate, two-trifluoroacetate
Steps A: 2-(4-amino-3-nitrophenyl) ethyl acetate: to 4-(aminophenyl) ethyl acetate (538mg, add in acetate 3.0mmole) (20ml) solution nitric acid (90%, 420mg, 6mmole).Reaction mixture was stirred 4 hours down at 100 ℃.Then reactant is cooled to room temperature.Vacuum is removed part acetate.Residue is diluted with EtOAc.The pH of solution is adjusted to 8-9 with 10% NaOH.With its water and salt water washing, use Na
2SO
4Drying is filtered and evaporation.Crude product is separated by silica gel chromatography, obtain 128mg (productive rate 20%) glassy yellow solid.It is not further purified and is used for next step.
Step B:2-(3, the 4-diamino-phenyl) ethyl acetate: the product (128mg) that adds embodiment 45 steps A in 10% palladium carbon (15mg) suspension that is suspended in 2ml MeOH is dissolved in the solution of MeOH (8ml).With reaction mixture under a normal atmosphere hydrogen in stirring at room 4 hours.Filtering catalyst.In filtrate, add 1N HCl (0.1ml), then solvent evaporation is extremely done, obtain 130mg crude product HCl salt (productive rate 86%).MS 195.2(M+H)
+。
Step C:(S)-2-(2-(1-(uncle-butoxy carbonyl)-2-styroyl)-1H-benzo [d] imidazoles-5-yl) ethyl acetate: with the product (130mg of embodiment 45 step B, 0.49mmol) and L-N-(Boc)-phenylalanine (130mg, 0.49mmol) handle according to the described condition of embodiment 42 steps A, obtain the required product of 210mg (productive rate 100%).MS 424.3(M+H)
+。
Step D:2-(2-((S)-1-(trans-4-((amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-yl) ethyl acetate, two-trifluoroacetate: the product of embodiment 45 step C is handled with TFA according to the described method of embodiment 2 steps A, then with N-(Boc)-to the coupling of aminomethyl hexahydrobenzoic acid, obtain required product, it is handled with TFA according to the described condition of embodiment 2 step B, obtain title compound.
MS 463.43(M+H)+.
1H-NMR(500MHz，d
4-MeOH)δ1.05(m，2H)，1.24(t，J＝3.30Hz，3H)，1.35(m，2H)，1.56(m，1H)，1.78(br d，J＝12.65Hz，1H)，1.86(m，3H)，2.28(m，1H)，2.77(d，J＝7.15Hz，2H)，3.31(s，2H)，3.42(d，J＝7.70Hz，2H)，3.84(s，2H)，4.16(q，J＝7.15Hz，2H)，5.46(t，J＝8.25Hz，1H)，7.23(m，5H)，7.51(d，J＝8.80Hz，1H)，7.68(d，J＝8.80Hz，2H)；MS 463.4(M+H)
+.
Embodiment 46
2-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-benzo [d] imidazoles-5-yl) acetate, two-trifluoroacetate
With the product LiOH hydrolysis of embodiment 45 step D, handle with TFA according to the described condition of embodiment 2 step B then, obtain title compound.
MS 435.4(M+H)
+.
1H-NMR(500MHz，d
4-MeOH)δ1.05(m，2H)，1.35(m，2H)，1.55(m，1H)，1.78(br d，J＝12.10Hz，1H)，1.86(m，3H)，2.28(m，1H)，2.77(d，J＝6.60Hz，2H)，3.31(s，2H)，3.42(d，J＝8.25Hz，2H)，3.82(s，2H)，5.46(t，J＝8.25Hz，1H)，7.23(m，5H)，7.52(d，J＝8.24Hz，1H)，7.67(d，J＝8.25Hz，2H)；MS 435.4(M+H)
+.
Embodiment 47
Trans-N-((S)-1-(5-(2-amino-2-oxoethyl)-1H-benzo [d] imidazoles-2-yl)-2-styroyl)-4-(amino methyl) cyclohexane carboxamide, two-trifluoroacetate
This compound adopts the product preparation of embodiment 44 identical method described in synthetic by embodiment 45 step D.
1H-NMR(500MHz，d
4-MeOH)δ1.06(m，2H)，1.35(m，2H)，1.55(m，1H)，1.78(br d，J＝11.86Hz，1H)，1.86(m，3H)，2.28(m，1H)，2.77(d，J＝7.03Hz，2H)，3.31(s，2H)，3.42(d，J＝8.35Hz，2H)，3.70(s，2H)，5.46(t，J＝8.35Hz，1H)，7.23(m，5H)，7.52(d，J＝8.35Hz，1H)，7.67(d，J＝8.325Hz，2H)；MS 434.3(M+H)
+.
Embodiment 48
Trans-4-(amino methyl)-N-((S)-2-phenyl-1-(5-phenyl azoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate
Steps A: (S)-2-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-and N-(2-oxo-2-phenylethyl)-3-Phenylpropionamide: (290mg, 1mmol) (171mg 1mmol) is dissolved in the 10ml pyridine with the 2-aminoacetophenone with N-phthalyl-L-phenylalanine.Adding Bop reagent (470mg, 1.1mmol).With mixture under nitrogen in stirring at room 12 hours.Remove and desolvate.Residue is dissolved among the EtOAc, and water and saturated NaHCO
3Washing.With organic layer Na
2SO
4Drying is filtered, and concentrates, and obtains 412mg product (productive rate 100%).MS413.2(M+H)
+。
Step B:(S)-2-(2-phenyl-1-(5-phenyl azoles-2-yl) ethyl) isoindoline-1,3-diketone: with the product (412mg of embodiment 48 steps A, 1mmol) be dissolved among the DMF, and according to (J.Org.Chem. such as Robert Dow, 1990,55,386) described method is used the inferior phosphorus (460mg of oxychlorination down at 90 ℃, 3mmol) handle, obtain 160mg (productive rate 41%) product.MS 395.2(M+H)
+。
Step C:(S)-2-phenyl-1-(5-phenyl azoles-2-yl) ethamine: with the product of embodiment 48 step B (160mg, EtOH 0.4mmol) (10ml) solution join hydrazine (39mg, 1.2mmol) in.With reaction mixture refluxed 2 hours.It is cooled to room temperature.Vacuum is removed EtOH.Residue is dissolved in the methylene dichloride again.Remove by filter undissolved solid.Concentrated filtrate obtains 95mg product yellow solid (productive rate 90%).MS 265.1(M+H)
+。
Step D: trans-4-(aminomethyl)-N-((S)-2-phenyl-1-(5-phenyl azoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate: (95mg 0.35mmol) changes into title compound (26%) with the product of embodiment 48 step C by using embodiment 2 steps A and the described method of step B successively.
1H-NMR(500MHz，d
4-MeOH)δ1.04-1.10(m，2H)，1.29-1.42(m，2H)，1.56(m，1H)，1.75(m，1H)，1.83-1.86(m，3H)，2.22(m，1H)，2.77(d，J＝7.14Hz，2H)，3.20(m，1H)，3.33(m，1H)，5.41(m，1H)，7.22-7.27(m，5H)，7.34(t，J＝7.15Hz，1H)，7.42(m，3H)，7.63-7.65(d，J＝8.25Hz，2H)；MS 404.3(M+H)
+.
Embodiment 49
Trans-4-(amino methyl)-N-((S)-2-phenyl-1-(5-phenyl-2H-1,2,4-triazole-3-yl) ethyl) hexanaphthene-methane amide, two-trifluoroacetate
Steps A: (S)-2-phenyl-1-(5-phenyl-2H-1,2,4-triazole-3-yl) ethyl carbamic acid tertiary butyl ester: adopt the described condition of embodiment 1 step C with L-N-(Boc)-phenylalanine (265mg, 1mmole) and hydrazine (64mg, 2mmol) chemical combination generates 279mg hydrazoic acid (productive rate 100%).MS 280.1(M+H)
+。To hydrazoic acid (279mg, 1.0mmole) and Et
3N (161mg, and adding benzene imido acid carbethoxy hydrochloride in acetonitrile 1.6mmole) (10ml) solution (278mg, 1.5mmole).With reactant reflux 24 hours.Reactant is cooled to room temperature, and dilutes with EtOAc.With mixture water and salt water washing, use Na
2SO
4Drying is filtered and vacuum-evaporation is extremely done.Crude product by preparation HPLC purifying, is obtained 154mg oil (productive rate 42%).MS 365.2(M+H)
+。
Step B: trans-4-(amino methyl)-N-((S)-2-phenyl-1-(5-phenyl-2H-1,2,4-triazole-3-yl) hexanaphthene-methane amide ethyl), two-trifluoroacetate: (154mg 0.42mmol) changes into title compound (28%) with the product of embodiment 49 steps A by using embodiment 1 step B, embodiment 2 steps A and the described method of part B successively.
1H-NMR(400MHz，d
4-MeOH)δ1.02-1.06(m，2H)，1.29-1.42(m，2H)，1.56(m，1H)，1.75(m，1H)，1.83-1.86(m，3H)，2.21(m，1H)，2.77(d，J＝7.03Hz，2H)，3.18-3.21(m，1H)，3.31(m，1H)，5.42(t，J＝8.12Hz，1H)，7.22-7.26(m，5H)，7.51-7.52(m，3H)，7.96-7.98(m，2H)；MS 404.2(M+H)
+.
Embodiment 50
Trans-4-(amino methyl)-N-((S)-2-phenyl-1-(3-phenyl-1H-pyrazoles-5-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate
Steps A: 3-oxo-3-phenylpropionic acid: (2.88g adds 1N NaOH (30ml) in EtOH 15mmol) (30ml) solution to ethyl benzoylacetate.Reaction mixture was at room temperature stirred 72 hours.It is cooled to 0 ℃, and with 1N HCl acidifying.EtOH is removed in decompression.With twice of dichloromethane extraction of water layer.With the dichloromethane solution salt water washing that merges, use Na
2SO
4Drying is filtered, and vacuum concentration, obtains light yellow solid (600mg, 24%).MS165.1(M+H)
+。
Step B:(S)-3,5-dioxo-1,5-phenylbenzene penta-2-aminocarbamic acid benzyl ester: to the product of embodiment 50 steps A (600mg, add in THF 3.65mmol) (20ml) and MeOH (20ml) solution magnesium ethylate (417mg, 3.65mmol).Mixture was at room temperature stirred 4 hours.Removal of solvent under reduced pressure.Crude product is dissolved among the DMF (2ml), and with its join N-CBZ-L-phenylalanine among the DMF (4ml) that at room temperature stirs 2 hours (800mg, 2.68mmol) and 1,1 '-(520mg is 3.21mmol) in the mixture for carbonyl dimidazoles.The gained mixture at room temperature stirred spend the night.It is diluted with EtOAc,, and use Na with rare HCl, water and salt water washing
2SO
4Drying is filtered and vacuum concentration.Crude product by preparation HPLC purifying, is obtained product (140mg, 13%).MS 402.1(M+H)
+。
Step C:((S)-2-phenyl-1-(3-phenyl-1H-pyrazoles-5-yl) ethyl carbamic acid benzyl ester: to the product of embodiment 50 step B (32mg, add in EtOH 0.08mmol) (3ml) solution hydrazine hydrate (3mg, 0.09mmol).Reaction mixture was heated 3 hours down at 60 ℃.Vacuum is removed EtOH, obtains required product (0.32mg, 100%).MS 398.1(M+H)
+。
Step D:(S)-and 2-phenyl-1-(3-phenyl-1H-pyrazoles-5-yl) ethamine: in the MeOH solution (3ml) of embodiment 50 step C products, add 10%Pd/C (5mg).With reaction mixture under hydrogen in stirring at room 4 hours.Remove by filter catalyzer.Crude mixture by preparation HPLC purifying, is obtained required product (12mg, 57%).MS 262.2(M-H)
-。
Step e: trans-4-(aminomethyl)-N-((S)-2-phenyl-1-(3-phenyl-1H-pyrazoles-5-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate: with the product (12mg of embodiment 50 step D, 0.046mmol) change into title compound (11mg, 46%) by adopting embodiment 2 steps A and the described method of step B successively.
1H-NMR(500MHz，d
4-MeOH)δ1.02-1.06(m，2H)，1.30-1.33(m，1H)，1.43-1.46(m，1H)，1.56(m，1H)，1.64(m，1H)，1.83(m，3H)，2.16-2.18(m，1H)，2.75(d，J＝7.03Hz，2H)，3.08-3.10(m，1H)，3.27(m，1H)，5.35(t，J＝8.12Hz，1H)，6.61(s，1H)，7.22(m，1H)，7.23(m，4H)，7.35-7.36(t，J＝7.15Hz，1H)，7.41-7.44(t，J＝7.70Hz，2H)，7.69-7.71(d，J＝7.15Hz，2H)；MS403.1(M+H)
+.
Embodiment 51
Trans-4-(amino methyl)-N-((S)-1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-yl)-2-styroyl)-cyclohexane carboxamide, two-trifluoroacetate
Steps A: (S)-1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-yl)-2-styroyl aminocarboxylic acid benzyl ester: with (S)-N-CBZ-phenylalanine nitrile (140mg, 0.5mmol) and sodium methylate (13mg, MeOH 0.24mmol) (4ml) solution stirred 3 hours down at 30 ℃.Add acetate (1mg, 0.2mmol), add then phenylhydrazine (108mg, 1mmol).Reaction mixture was at room temperature stirred 18 hours.Mixture is cooled to 0 ℃, then solids removed by filtration.MeOH solution by the silica gel chromatography purifying, is obtained yellow oil, it is dissolved among the THF (6ml), add 1,1 again '-carbonyl dimidazoles (68mg, 0.42mmole).Mixture heating up was refluxed 48 hours.Reactant is cooled to room temperature, uses CH
2Cl
2Dilution, water and salt water washing, Na
2SO
4Drying is filtered and vacuum concentration, obtains 38mg (66%) product, is red solid.MS 413.2(M-H)
-。
Step B: trans-4-(amino methyl)-N-((S)-1-(5-oxo-1-phenyl-4,5-dihydro-1H-1,2,4-triazole-3-yl)-the 2-styroyl)-cyclohexane carboxamide, two-trifluoroacetate: with the product (38mg of embodiment 51 steps A, 0.09mmol) change into title compound (8mg, 17%) by the method for Application Example 50 step D and embodiment 2 steps A and step B successively.
1H-NMR(500MHz，d
4-MeOH)δ1.02-1.06(m，2H)，1.30-1.33(m，1H)，1.43-1.46(m，1H)，1.56(m，1H)，1.67(m，1H)，1.81-1.86(m，3H)，2.16-2.18(m，1H)，2.75(d，J＝7.15Hz，2H)，3.08-3.10(m，1H)，3.31(m，1H)，5.15-5.17(m，1H)，7.19-7.21(m，2H)，7.27-7.28(m，4H)，7.40-7.43(t，J＝7.97Hz，2H)，7.85-7.87(d，J＝7.69Hz，2H)；MS 420.1(M+H)
+.
Embodiment 52
Trans-4-(amino methyl)-N-((S)-2-phenyl-1-(2-phenyl-1H-imidazol-4 yl) ethyl) hexanaphthene-methane amide, two-trifluoroacetate
Steps A: (S)-2-phenyl-1-(2-phenyl-1H-imidazol-4 yl) ethyl carbamic acid benzyl ester: with (S)-4-bromo-3-oxo-1-phenyl fourth-2-aminocarbamic acid benzyl ester (376mg, 1.0mmole) and sodium formiate (68mg, EtOH 1.0mmole) (15ml) vlil 14 hours.With benzamidine (240mg, 1.5mmole) and sodium bicarbonate (400mg 4.7mmole) joins in the reaction.The reaction mixture reheat was refluxed 24 hours.Reactant is cooled to room temperature, and vacuum-drying.Residue is dissolved among the EtOAc again, and Na is used in water and salt water washing
2SO
4Drying is filtered, and vacuum concentration.With the crude product silica gel purification, obtain 33mg (productive rate 8%).MS 398.1(M+H)
+。
Step B: trans-4-(amino methyl)-N-((S)-2-phenyl-1-(2-phenyl-1H-imidazol-4 yl) ethyl) hexanaphthene-methane amide, two-trifluoroacetate: with the product (33mg of embodiment 52 steps A, 0.083mmol) change into title compound (5mg, productive rate 12%) by the method for Application Example 50 step D and embodiment 2 steps A and step B successively.
1H-NMR(400MHz，d
4-MeOH)δ1.02-1.06(m，2H)，1.30-1.33(m，1H)，1.43-1.46(m，1H)，1.56(m，1H)，1.67(m，1H)，1.83(m，3H)，2.16-2.18(m，1H)，2.75(d，J＝7.03Hz，2H)，3.08-3.10(m，1H)，3.31(m，1H)，5.34-5.36(m，1H)，7.22-7.29(m，5H)，7.51(s，1H)，7.62-7.68(m，3H)，7.87-7.89(m，2H)；MS 403.3(M+H)
+.
Embodiment 53
N-(4-carbamimidoyl phenyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide, two-trifluoroacetate
Steps A: 2-benzyl-3-methoxyl group-3-oxo propionic acid: (19.4g 0.10mol) is dissolved among the 180ml MeOH with benzyl malonic acid.Mixture is cooled off in ice bath, and to wherein through 30 minutes thionyl chloride (7.3ml, 0.10mol).Mixture was stirred 30 minutes in ice bath under nitrogen, at room temperature stirred then 30 minutes.Remove and desolvate, residue is dissolved in NaHCO
3In the aqueous solution.Basic solution is extracted to remove two-ester and to discard with EtOAc.Use the HCl acidified aqueous solution to pH5 the aqueous solution then, and extract with EtOAc.With the salt water washing of EtOAc extract, use Na
2SO
4Drying concentrates then, obtains 7.2g 2-benzyl-3-methoxyl group-3-oxo propionic acid (35%).MS 209.24(M+H)
+。
Step B:3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) methyl propionate: (1.04g 5.0mmol) is dissolved among the EtOH (13ml), adds Cs with the product of embodiment 53 steps A
2CO
3(0.81g, H 2.5mmol)
2O (13ml) solution.With reaction mixture under nitrogen in stirring at room 1 hour.Solvent removed in vacuo is suspended in gained salt among the DMF (20ml).Disposable adding 2-bromoacetophenone (1.3g, 6.6mmol), again with reactant under nitrogen in stirring at room 2 hours.The filtering reaction thing is removed CsBr.Solid is washed with DMF.Washings and filtrate vacuum concentration with merging obtain yellow solid.Thick intermediate is placed the flask that dean stark trap is housed, and be dissolved in dimethylbenzene (40ml).With NH
4(7.78g 100mmol) joined in the flask OAc, with reactant reflux 3 hours.Reactant is cooled to room temperature, solvent removed in vacuo.Residue is dissolved among the EtOAc again, uses saturated NaHCO
3Na is used in the aqueous solution and salt water washing
2SO
4Drying is filtered, and concentrates, and by purification by flash chromatography (silica gel EtOAc/ hexane), obtains the required product of 600mg (39%).MS307.29(M+H)
+。
Step C:3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid: (350mg 1.14mmol) is dissolved among the 9ml EtOH, and adds 1NNaOH (3ml) with the product of embodiment 53 step B.With mixture under nitrogen in stirring at room 30 minutes.The HCl aqueous solution is joined in the reaction mixture, reach 5 up to pH.Filter formed solid, and dry, obtain the required product of 284mg (85%).MS 293.33(M+H)
+。
Step D:N-(4-carbamimidoyl phenyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide two tfa salts: with the product (40mg of embodiment 53 step C, 0.14mmo1) and 4-amidino groups benzamidine hydrochloride (48mg 0.16mmol) is dissolved in the anhydrous pyridine (2ml).Add bop reagent (90mg, 0.16mmol), with reactant under nitrogen in stirring at room 48 hours.Solvent removed in vacuo.Residue is dissolved in again the CH that contains 0.1%TFA
3OH/H
2Among the O (9: 1), and by reversed-phase HPLC purifying (C18,28 * 100mm, MeOH/H
2O/0.1%TFA, gradient), obtain 15mg title compound (productive rate 17%).
1H-NMR (400MHz, d
4-MeOH) δ 3.33 (dd, J=13.40,9.45Hz, 1H), 3.52 (dd, J=13.62,7.03Hz, 1H), 4.54 (dd, J=9.23,7.03Hz, 1H), 7.12 (m, 5H), 7.39 (m, 3H), 7.57 (d, J=6.59Hz, 2H), 7.70 (m, 3H), 7.76 (m, 2H) .C
25H
24N
5The HRMS of O (M+H)
+, the m/z calculated value: 410.1981, measured value: 410.2001.
Embodiment 54
N-(3-carbamimidoyl phenyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide, two-trifluoroacetate
Title compound adopts the 53 described identical method preparations with embodiment.
NMR(400MHz，d
4-MeOH)δ3.42(dd，J＝13.62，9.23Hz，1H)，3.61(dd，J＝13.62，7.03Hz，1H)，4.61(dd，J＝9.01，7.25Hz，1H)，7.24(m，5H)，7.51(m，5H)，7.66(d，J＝7.91Hz，2H)，7.77(m，2H)，8.19(s，1H)；MS 410.20，(M+H)
+.
Embodiment 55
Trans-N-(4-(amino methyl) cyclohexyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide, two-trifluoroacetate
Steps A: (trans-the 4-aminocyclohexyl) methyl carbamic acid benzyl ester: with trans-(344mg 1.5mmol) is dissolved in CH to 4-aminomethyl cyclohexyl t-butyl carbamate
2Cl
2(7ml), and in ice bath, cool off.Add triethylamine (0.21ml, 1.5mmol), drip then chloroformic acid benzyl ester (0.22ml, 1.5mmol).With reaction mixture under nitrogen in stirring at room 2 hours.With reaction mixture CH
2Cl
2Na is used in dilution, and water and salt water washing
2SO
4Drying is filtered, and concentrates, and obtains white solid.Solid is dissolved in the 10ml 4N HCl-dioxane, and at room temperature stirred 10 minutes.Remove and desolvate.Described residue is dried to the product (78%) of the described required white solid form that obtains 350mg in a vacuum.MS 263.36(M+H)
+。
Step B:(is trans-4-(3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionamido) cyclohexyl) and methyl carbamic acid benzyl ester: with the product (75mg of embodiment 55 steps A, 0.25mmol) and the product of embodiment 53 step C (60mg 0.21mmol) is dissolved in the anhydrous pyridine (5ml).Add bop reagent (115mg, 0.26mmol), with reactant under nitrogen in stirring at room 4 hours.Solvent removed in vacuo.Residue is dissolved among the EtOAc again, and water and salt water washing, Na used
2SO
4Drying concentrates and by purification by flash chromatography (EtOAc/ hexane), obtains the required product of 50mg (44%).MS 537.32(M+H)
+。
Step C:N-(trans-4-(aminomethyl) cyclohexyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide, two-trifluoroacetate: with the product (50mg of embodiment 55 step B, 0.093mmol) be dissolved among the MeOH (8ml), and add the 10%Pd/C of catalytic amount.Mixture was placed 1 normal atmosphere hydrogen following 4 hours.It is filtered by Celite, and wash with MeOH.Filtrate is concentrated, and, obtain 33mg title compound (56%) by the reversed-phase HPLC purifying.
1H-NMR(400MHz，d
4-MeOH)δ0.92-1.22(m，4H)，1.59(m，1H)，1.70-1.88(m，4H)，2.69(m，2H)，3.21(m，1H)，3.35(m，1H)，3.50(m，1H)，4.32(t，J＝8.35Hz，1H)，7.12-7.32(m，5H)，7.38-7.54(m，3H)，7.66(d，J＝7.03Hz，2H)，7.75(s，1H).MS 403.39(M+H)
+.
Embodiment 56
4-(2-(1-(4-carbamimidoyl phenylamino)-1-oxo-3-phenylpropyl alcohol-2-yl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
Steps A: 2-(4-(4-cyano-phenyl)-1H-imidazoles-2-yl)-3-phenylpropionic acid methyl esters: (5.0g 24.0mmol) is dissolved among the EtOH (40ml), and adds Cs with the 2-benzyl-3-methoxyl group-3-oxo propionic acid of embodiment 53 steps A
2CO
3(4.0g, H 12.0mmol)
2O (40ml) solution.With reaction mixture under nitrogen in stirring at room 1 hour.Solvent removed in vacuo is suspended in gained salt among the DMF (85ml).Disposable adding 4-(2-acetyl bromide) benzonitrile (5.4g, 24.0mmol), again with reactant under nitrogen in stirring at room 4 hours.The filtering reaction thing is removed CsBr.Solid is washed with DMF.Washings and filtrate vacuum concentration with merging obtain yellow solid.Thick intermediate is placed the flask that dean stark trap is housed, and be dissolved in the dimethylbenzene (200ml).With NH
4(38.9g 500mmol) joined in the flask OAc, with reactant reflux 3 hours.Reactant is cooled to room temperature, solvent removed in vacuo.Residue is dissolved among the EtOAc again, uses saturated NaHCO
3Na is used in the aqueous solution and salt water washing
2SO
4Drying is filtered, and concentrates, and by purification by flash chromatography (silica gel EtOAc/ hexane), obtains 2.4 required products (30%).MS 332.27(M+H)
+。
Step B:2-(4-(4-carbamyl phenyl)-1H-imidazoles-2-yl)-3-phenylpropionic acid: (0.99g 3.0mmol) is dissolved among the 10ml DMSO with the product of embodiment 56 steps A.Adding salt of wormwood (1.24g, 9.0mmol).Mixture is cooled to 0-5 ℃, adds 30%H
2O
2(aqueous solution of 3.18ml30%), add again magnesium oxide (0.24g, 15mmol).Shed the cryostat device, with mixture under nitrogen in stirring at room 4 hours.Filtering mixt is removed inorganics.In filtrate, add entry (30ml), the gained mixture was at room temperature stirred 40 minutes.Mixture is acidified to pH5 with 1NHCl.Filter the precipitation and the drying that form, obtain 0.67g acid (67%).MS336.30(M+H)
+。
Step C:4-(2-(1-(4-carbamimidoyl phenyl amino)-1-oxo-3-phenyl propyl-2-yl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate: with the acid (55mg of embodiment 56 step B, 0.16mmol) and 4-amidino groups benzamidine hydrochloride (58mg 0.34mmol) is dissolved in the anhydrous pyridine (3ml).Add bop reagent (108mg, 0.24mmol), with reactant under nitrogen in stirring at room 48 hours.Solvent removed in vacuo.Residue is dissolved in again the CH that contains 0.1%TFA
3OH/H
2Among the O (9: 1), and by reversed-phase HPLC purifying (MeOH/H
2O/0.1%TFA, gradient), obtain 11mg title compound (10%).
1H-NMR (400MHz, d
4-MeOH) δ 3.34 (m, 1H), 3.49 (m, 1H), 4.29 (t, J=7.91Hz, 1H), 7.17 (m, 1H), 7.22 (m, 4H), 7.56 (s, 1H), 7.78 (m, 6H), 7.89 (m, 2H) .C
26H
25N
6O
2HRMS (M+H)
+, the m/z calculated value: 453.2039, measured value: 453.2025.
Embodiment 57
4-(2-(1-(1-aminoisoquinoline-6-base is amino)-1-oxo-3-phenyl third-2-yl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
(36mg, 0.11mmol) (18mg 0.050mmol) is dissolved in the anhydrous pyridine (3ml) with 6-aminoisoquinoline-1-aminocarbamic acid tert-butyl ester with the 2-among the embodiment 56 step B (4-(4-formamyl phenyl)-1H-imidazoles-2-yl)-3-phenylpropionic acid.(50mg 0.11mmol), stirs reactant 3 hours in 60 ℃ under nitrogen, at room temperature stirs then 48 hours to add bop reagent.Solvent removed in vacuo.Residue is dissolved in EtOAc (1ml) and the 4N HCl-dioxane (1ml) again, and at room temperature stirred 1.5 hours.Mixture is concentrated, and then be dissolved in the CH that contains 0.1%TFA
3OH/H
2Among the O (9: 1), and by reversed-phase HPLC purifying (MeOH/H
2O/0.1%TFA, gradient), obtain 6.0mg title compound (17%).
1H-NMR(400MHz，MeOH-d
4)δ3.45(m，1H)，3.63(m，1H)，4.62(dd，J＝7.03Hz，1H)，7.14(d，J＝7.03Hz，1H)，7.26(m，5H)，7.53(d，J＝7.03Hz，1H)，7.79(d，J＝8.35Hz，2H)，7.85(dd，J＝9.23，2.20Hz，1H)，7.90(s，1H)，7.99(d，J＝8.35Hz，2H)，8.33(d，J＝1.76Hz，1H)，8.38(d，J＝8.79Hz，1H).MS 477.3(M+H)
+.
Embodiment 58
4-(2-(1-(isoquinoline 99.9-6-base is amino)-1-oxo-3-phenyl third-2-yl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
Title compound adopts the 57 described identical method preparations with embodiment.
1H-NMR(400MHz，MeOH-d
4)δ3.36(d，J＝7.47Hz，1H)，3.51(d，J＝8.35Hz，1H)，4.31(t，J＝7.91Hz，1H)，7.15(m，1H)，7.23(d，J＝6.59Hz，4H)，7.54(s，1H)，7.65(dd，J＝8.79，2.20Hz，2H)，7.74(d，J＝6.15Hz，1H)，7.80(d，J＝8.79Hz，2H)，7.89(m，2H)，8.03(d，J＝9.23Hz，1H)，8.35(m，1H)，9.10(s，1H).
Embodiment 59
4-(2-(4-(4-carbamimidoyl phenyl)-1H-imidazoles-2-yl)-3-phenyl propionamido) benzamide, two-trifluoroacetate
Steps A: 2-(4-(4-cyano-phenyl)-1H-imidazoles-2-yl)-3-phenylpropionic acid: (4-(4-cyano-phenyl)-1H-imidazoles-2-yl)-(60mg 0.20mmol) is dissolved among the 4ml EtOH 3-phenylpropionic acid methyl esters with the 2-in embodiment 56 steps A.Add NaOH (aqueous solution of 1.5ml 1N), and mixture was at room temperature stirred 1.5 hours.Mixture is acidified to pH5 with 1N HCl.Filter the precipitation and the drying that form, obtain 40mg acid (63%).MS 318.3(M+H)
+。
Step B:4-(2-(4-(4-cyano-phenyl)-1H-imidazoles-2-yl)-3-phenyl propionamido) benzamide: with the acid (100mg of embodiment 59 steps A, 0.32mmol), triethylamine (150 μ L, 1.2mmol) and bop reagent (210mg 0.48mmol) is dissolved among the THF (9ml).Mixture was at room temperature stirred 15 minutes, add then the 4-aminobenzamide (47mg, 0.35mmol).The gained mixture was heated 1 hour in 70 ℃ under nitrogen.Enriched mixture, and then be dissolved among the EtOAc.With its water and salt water washing, use Na
2SO
4Drying concentrates, and by purification by flash chromatography (silica gel, EtOAc/ hexane), obtains the required product of 45mg (32%).MS 436.3(M+H)
+。
Step C:4-(2-(4-(4-carbamimidoyl phenyl)-1H-imidazoles-2-yl)-3-phenyl propionamido) benzamide, two-trifluoroacetate: with oxammonium hydrochloride (72mg, 1.0mmol) be dissolved among the DMSO (1ml), add triethylamine (0.14ml, 10 equivalents) then.Mixture was stirred 5 minutes, leach precipitation then.With filtrate join embodiment 59 step B product (28mg, 0.064mmol) in, mixture was at room temperature stirred 15 minutes, add then the 4-aminobenzamide (47mg, 0.35mmol).The gained mixture was heated 1.5 hours in 65 ℃ under nitrogen.With its cooling, and add entry.Filter formed precipitation and dry.Then solid is dissolved in CH
2Cl
2(3ml), and add diacetyl oxide (13 μ L).With reaction mixture under nitrogen in stirring at room 1.5 hours.Remove CH
2Cl
2, residue is dissolved among the MeOH-HOAc (10: 1 solution of 3ml).Add Pd/C (10%, 18mg), and mixture placed the hydrogen balloon environment following 3 hours.It is filtered by Celite, concentrate, and then be dissolved in the CH that contains 0.1%TFA
3OH/H
2Among the O (9: 1), and by reversed-phase HPLC purifying (MeOH/H
2O/0.1%TFA, gradient), obtain 8.0mg title compound (18%).
1H-NMR(400MHz，MeOH-d
4)δ3.37(m，1H)，3.45(m，1H)，4.24(t，J＝7.91Hz，1H)，7.16(m，1H)，7.22(m，4H)，7.62(d，J＝8.79Hz，3H)，7.80(m，4H)，7.94(d，J＝8.79，2H).MS 453.4(M+H)
+.
Embodiment 60
4-(2-(1-(4-carbamimidoyl benzyl amino)-1-oxo-3-phenyl third-2-yl)-1H-imidazol-4 yl) benzamide, two-trifluoroacetate
With the method coupling of the acid of embodiment 56 step B and 4-cyano group benzylamine according to embodiment 59 step B.Then cyano group is adopted the method for embodiment 59 step C to change into corresponding benzamidine.
MS 467.22(M+H)
+.
1H-NMR(400MHz，MeOH-d
4)δ3.37(dd， J＝13.62，8.35Hz，1H)，3.53(m，1H)，4.37(d，J＝15.82Hz，1H)，4.55(m，2H)，7.22(m，2H)，7.29(m，5H)，7.71(d，J＝8.35Hz，2 H)，7.79(d，J＝8.79Hz，2H)，7.91(s，1H)，7.99(d，J＝8.35Hz，2H).
Embodiment 61
N-(4-carbamimidoyl phenyl)-4-phenyl-3-(4-phenyl-1H-imidazoles-2-yl) butyramide, two-trifluoroacetate
This compound is according to adopting 2-benzyl succsinic acid to prepare as starting raw material with embodiment 53 described identical methods.
MS 424.21(M+H)
+.
1H-NMR(400MHz，MeOH-d
4)δ3.107(d，J＝3.95Hz，1H)，3.15(m，1H)，3.25(dd，J＝13.40，6.37Hz，1H)，3.95(m，1H)，7.12(d，J＝6.95Hz，2H)，7.25(m，3H)，7.46(m，3H)，7.61(d，J＝7.03Hz，2H)，7.69(s，1H)，7.75(m，4H).
Embodiment 62
4-(amino methyl)-N-((S)-1-(4-(3-p-methoxy-phenyl)-1H-imidazoles-2-yl)-2-styroyl) hexanaphthene-methane amide, two-trifluoroacetate
Steps A: (S)-1-(1H-imidazoles-2-yl)-2-styroyl carbamyl tert-butyl ester: with (S)-1-oxo-3-phenyl third-2-aminocarbamic acid-tert-butyl ester (5.08g, 20.4mmol) and oxalic dialdehyde trimer dihydrate (2.2g 10.1mmol) is dissolved among the anhydrous MeOH (30ml).(2.0M, 45.6ml 92.4mmol), at room temperature stirred reactant 48 hours the methanol solution of adding ammonia.Solvent removed in vacuo.Gained oil is diluted with EtOAc, use the salt water washing, MgSO
4Drying is filtered and vacuum distilling, obtains 1.4g (47%) white solid.MS 288.15(M+H)
+。
Step B:(S)-and 1-(4,5-two bromo-1H-imidazoles-2-yls)-2-styroyl t-butyl carbamate: (510mg 1.8mmol) is dissolved in the chloroform (10ml), and (600mg 3.38mmol) handles at room temperature to use NBS with the product of embodiment 62 steps A.Reactant was stirred 1 hour.Solvent removed in vacuo adopts the silica gel chromatography purifying with crude product, obtains 510mg (64%) white solid.MS 445.91(M+H)
+。
Step C:(S)-and 1-(4-bromo-1H-imidazoles-2-yl)-2-styroyl t-butyl carbamate: (821mg 2.38mmol) is dissolved in the mixture of 1,4 dioxane (8ml) and water (2ml) with the product of embodiment 62 step B.Add S-WAT (3.00g, 23.8mmol) and the hydrogen sulfate tetrabutylammonium (2.01g, 5.95mmol).To be reflected at 100 ℃ stirred 48 hours down.Reactant is diluted with EtOAc, leach solid then.Filtrate is used the salt water washing, use MgSO
4Drying filters and is evaporated to dried.Crude product by the silica gel chromatography purifying, is obtained 200mg (24%) white solid.MS 366.3(M+H)
+。
Step D:(S)-and 1-(4-bromo-1H-imidazoles-2-yl)-2-phenyl-ethyl amine: (560mg 1.53mmol) handles with TFA according to the method for embodiment 1 step B, obtains containing the 490mg crude product yellow oil of excessive TFA with the product of embodiment 62 step C.Crude product is not further handled and is used for next step reaction.MS 268.3(M+H)
+。
Step e: ((1S; 4r)-and 4-(((S)-1-(4-bromo-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) the methyl carbamic acid tertiary butyl ester: with the product (494mg of embodiment 62 step D; 1.86mmol) and N-Boc-(480mg 1.8mmol) adopts the condition of embodiment 2 steps A to handle to the aminomethyl hexahydrobenzoic acid.Gained white solid (780mg, productive rate 83%) is not further purified and is used for next step.MS 503.28(M+H)
-。
Step F: ((1S; 4r)-and 4-(((S)-1-(4-(3-p-methoxy-phenyl)-1H-imidazoles-2-yl)-2-styroyl) formamyl) cyclohexyl) the methyl carbamic acid tert-butyl ester: with the product (30.0mg of embodiment 62 step e; 0.059mmol) weigh and place contain 3-anisole ylboronic acid (11mg, 0.07mmol) and K
3PO
4(38mg is in pipe-type bottles 0.177mmol).Solid is dissolved in 1,4 dioxane (0.5ml).Add palladium (I) tri-butyl phosphine bromide dimer (19mg, 0.024mmol), and with pipe-type bottles at the argon gas lower seal.Adopt microwave radiation to heat 1 hour down reactant at 110 ℃.Reactant is cooled to room temperature, and leaches solid.Collect filtrate and vacuum-drying.The crude product that contains starting raw material impurity is directly used in next step.MS 433.22(M+H)
+。
Step G:4-(amino methyl)-N-((S)-1-(4-(3-p-methoxy-phenyl)-1H-imidazoles-2-yl)-2-styroyl) hexanaphthene-methane amide, two-trifluoroacetate: (30mg 0.059mmol) handles with TFA according to the described method of embodiment 1 step B with the product in embodiment 62 step F.Product is separated with preparation HLPC, obtain 6.00mg (24%) title compound.
1HNMR(500MHz，d
4-MeOH)δ1.07(m，2H)1.16(dd，J＝12.37，3.57Hz，1H)1.27(d，J＝15.40Hz，1H)1.39(m，2H)1.57(m，2H)1.80(d，J＝12.10Hz，1H)1.86(d，J＝11.00Hz，3H)1.94(d，J＝11.00Hz，1H)2.26(m，2H)2.77(d，J＝7.15Hz，2H)2.83(d，J＝7.15Hz，1H)3.37(m，1H)3.78(s，1H)3.85(s，3H)5.30(t，J＝8.25Hz，1H)6.63(m，1H)6.81(m，1H)6.81(m，1H)7.19(m，4H)7.24(t，J＝7.42Hz，1H)7.28(m，3H)7.39(m，1H)7.76(s，1H)：MS 433.22(M+H)
+.
Listed embodiment 63-65 and 89 is by suitable applications embodiment 62 described methods or these methods are extended simply synthetic similarly by those skilled in the art in the table 2.
Embodiment 66
Trans-3-(2-((S)-1-(4-(amino methyl) hexanaphthene formamido group)-2-phenylethyl)-1H-imidazol-4 yl)-phenylformic acid, two-trifluoroacetate
(85mg is 0.18mmol) according to embodiment 26 described method hydrolysis with the product of embodiment 7.Crude product is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1), and be evaporated to driedly, obtain 86mg (71%) title compound.
1HNMR (500MHz, CDCl
3) δ 0.92 (m, 2H), 1.18 (m, 2H), 1.48 (m, 1H), 1.64 (d, J=12.60Hz, 1H), 1.77 (d, J=11.00Hz, 3H), 2.15 (t, J=12.10Hz, 1H), 2.61 (m, 2H), 3.23 (m, 1H), 3.42 (m, J=5.50Hz, 1H), 5.37 (bs, 1H), 7.21 (t, J=6.32Hz, 1H), 7.27 (m, 3H), 7.63 (t, J=7.42Hz, 1H), 8.00 (m, 3H), 8.15 (d, J=6.60Hz, 1H), 8.39 (s, 1H); C
26H
30N
4O
3HRMS (M+H)
+, the m/z calculated value: 447.2396, measured value: 447.2407.
Embodiment 67 and 68
4-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) methyl benzoate, two-trifluoroacetate (67) and 4-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene-formamido group)-2-phenylethyl)-1H-imidazol-4 yl) phenylformic acid, two-trifluoroacetate (68)
Steps A: (S)-4-(2-(1-(tertbutyloxycarbonyl)-2-phenylethyl)-1H-imidazol-4 yl) ethyl benzoate: product (8.5g, two step productive rates 97%) by the described condition of Application Example 1 steps A suitably by L-N-(Boc)-phenylalanine (3.99g, 20mmol), Cs
2CO
3(3.25g, 10mg), 4-(2-acetyl bromide) ethyl benzoate (5.4g, 20mmol) and ammonium acetate (31g, 400mmol) synthetic.MS 436.1(M+1)
+。
Step B:4-(2-((S)-1-(trans-4-(amino methyl) hexanaphthene formamido group)-2-styroyl)-1H-imidazol-4 yl) ethyl benzoate, two-trifluoroacetate: with the product (220mg of steps A, 0.48mmol) handle according to the method for embodiment 1 step B and embodiment 2 steps A and step B successively, obtain 200mg product (three step productive rates 56%).MS334.2(M-H)-。
Step C: embodiment 67 and 68: (200mg 0.28mmol) is dissolved in the MeOH/H that contains 0.1%TFA with the product of step B
2O (9: 1) (2ml) in.The pH of solution is adjusted to 12-14 with the NaOH aqueous solution of 1N.Reactant was at room temperature stirred 16 hours.Add TFA in solution, up to its pH=1, product separates by preparation HPLC, obtains 66mg embodiment 67 (34%) and 34mg embodiment 68 (18%).
The data of embodiment 67:
1H-NMR (500MHz, d
4-MeOH) δ 1.06 (m, 2H), 1.38 (m, 2H), 1.57 (m, 1H), 1.80 (d, J=11.55Hz, 1H), 1.86 (d, J=11.55Hz, 3H), 2.28 (tt, J=12.10,3.30Hz, 1H), 2.77 (d, J=6.60Hz, 2H), 3.33 (d, J=8.25Hz, 1H), 3.38 (dd, J=13.20,8.00Hz, 1H), 3.93 (s, 3H), 5.33 (t, J=8.25Hz, 1H), 7.18 (d, J=7.15Hz, 2H), 7.23 (t, J=7.15Hz, 1H), 7.29 (t, J=7.15Hz, 2H), 7.77 (d, J=8.80Hz, 2H), 7.89 (s, 1H), 8.11 (d, J=8.80Hz, 2H); C
27H
32N
4O
3HRMS (M+H)
+, the m/z calculated value: 461.2523, measured value: 461.2570.
The data of embodiment 68:
1H-NMR (500MHz, d
4-MeOH) δ 1.06 (m, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.80 (d, J=12.10Hz, 1H), 1.86 (d, J=11.55Hz, 3H), 2.28 (tt, J=12.10,3.30Hz, 1H), 2.77 (d, J=7.15Hz, 2H), 3.33 (d, J=8.25Hz, 1H), 3.39 (dd, J=13.50,8.25Hz, 1H), 5.33 (t, J=8.25Hz, 1H), 7.19 (d, J=7.15Hz, 2H), 7.24 (t, J=7.15Hz, 1H), 7.29 (t, J=7.15Hz, 2H), 7.76 (d, J=8.25Hz, 2H), 7.89 (s, 1H), 8.12 (d, J=8.80Hz, 2H); C
26H
30N
4O
3HRMS (M+H)
+, the m/z calculated value: 447.2396, measured value: 447.2397.
Embodiment 69
Trans-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl)-cyclohexane carboxamide, two-trifluoroacetate
(10mg 0.022mmol) is dissolved in the 1-butanols with the product of embodiment 65.Add hydrazine (66mg, 1.32mmol), with reaction mixture in sealed tube by carry out microwave radiation heating to 118 ℃, continue 4.5 hours.Reactant is cooled to room temperature, and restir 8 hours.Solvent removed in vacuo and excessive hydrazine.Product is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1).Solvent removed in vacuo obtains title compound (8.8mg, 59%).C
26H
31N
7The HRMS of O (M+H)
+, the m/z calculated value: 458.2668, measured value: 458.2650.
Embodiment 70
Trans-4-(amino methyl)-N-benzyl-N-((S)-2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate
Steps A: (S)-N-benzyl-2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethamine: with the product of embodiment 1 step B (33mg, 0.1mmol) and phenyl aldehyde (16mg 0.15mmol) is dissolved in CH
2Cl
2(4ml).Add NaBH (OAc)
3(32mg 0.15mmol), adds several HOAc again.Reactant was at room temperature stirred 48 hours.With reactant CH
2Cl
2Dilution, and water and salt water washing.It is used Na
2SO
4Drying is filtered and vacuum-evaporation, obtains the 42mg crude product.MS 354.5(M+H)
+。
Step B: trans-4-(amino methyl)-N-benzyl-N-((S)-2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) cyclohexane carboxamide, two-trifluoroacetate: according to the product of embodiment 70 steps A being changed into title compound with the described identical method of embodiment 2 steps A-B.
1H-NMR(500MHz，d
4-MeOH)δ0.95(m，2H)，1.25(m，1H)，1.60(m，3H)，1.80(m，3H)，2.49(t，J＝8.52Hz，1H)，2.72(d，J＝7.15Hz，2H)，3.53(d，J＝3.30Hz，2H)，4.80(m，2H)，6.14(t，J＝8.25Hz，1H)，7.00-7.53(m，16H).MS 493.20(M+H)
+.
Listed embodiment 71-74 and embodiment 85 extend simply embodiment 70 described methods by suitable applications embodiment 70 described methods or by those skilled in the art and synthesize in the table 5.
Embodiment 77
Trans-4-amino methyl-naphthenic acid [2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl)-ethyl]-acid amides, two-trifluoroacetate
Steps A: 4-[2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl)-ethylamino formyl radical]-cyclohexyl-methyl-phenyl carbamate with the product of embodiment 55 steps A (36mg, 0.1mmol) be dissolved in THF/DMF (2: 1,6ml) in, and be cooled to 0 ℃.(162mg 0.1mmol) joins in the solution with two cyclohexyls-carbodiimide.The gained mixture was stirred 1 hour down at 0 ℃.(33mg 0.1mmol), is warming up to 50 ℃ with reactant and kept 5 hours the product of adding embodiment 1 step B.Reactant is cooled to room temperature, and with the EtOAc dilution, Na is used in water and salt water washing (3 *)
2SO
4Drying is filtered and vacuum-drying.HPLC separates title compound by preparation, obtains 27mg (40%) colorless solid.MS 552.1(M+H)
+。
Step B:4-amino methyl-naphthenic acid [2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl)-ethyl]-acid amides: with the product (27mg of embodiment 77 steps A, 0.04mmol) adopt the method for embodiment 50 step C to change into final product (16mg, 75%).
1H-NMR(500MHz，d
4-MeOH)δ1.09(m，2H)，1.19(m，2H)，1.57(m，1H)，1.81(m，2H)1.92(m，2H)，2.76(d，J＝6.60Hz，2H)，3.25(m，1H)，3.35(m，2H)，5.21(t，J＝7.42Hz，1H)，7.16(d，J＝7.15Hz，2H)，7.24-7.29(m，3H)，7.44-7.49(m，3H)，7.65(d，J＝8.24Hz，2H)，7.72(s，1H).MS 418.1(M+1)
+.
Embodiment 82
(S)-and 4-[2-[1-[4-(amino methyl) hexanaphthene formamido group] amino]-the 2-styroyl]-4-(bromo-1H-imidazoles-5-yl)-benzamide
Steps A: (4-{1-[5-bromo-4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethylamino formyl radical }-cyclohexyl methyl)-t-butyl carbamate: (70mg 0.13mmol) is dissolved in CHCl with the product of embodiment 28 steps A
3(10ml), and with bromine (21mg 0.13mmol) handles.Stir after 16 hours, reactant vacuum-evaporation to doing, is obtained 93mg (＞99%) product.MS 625.3/627.3(1∶1；M+H)
+。
Step B:4-(2-{1-[(4-amino methyl-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-5-bromo-1H-imidazol-4 yl)-crude product (93mg of benzamide: embodiment 82 steps A, 0.13mmol) adopt the described method of embodiment 2 step B to change into title compound (35.8mg, 36%).
1H-NMR(500MHz，d
4-MeOH)δ1.38(m，1H)1.57(m，1H)1.76(d，J＝12.65Hz，1H)1.85(d，J＝9.90Hz，3H)2.23(dt，J＝12.10，3.30Hz，1H)2.77(d，J＝7.15Hz，2H)3.20(dd，J＝13.20，8.25Hz，1H)3.26(dd，J＝13.30，7.70Hz，1H)5.23(t，J＝7.97Hz，1H)7.17(d，J＝7.15Hz，2H)7.21(d，J＝7.15Hz，1H)7.26(t，J＝7.15Hz，2H)7.75(d，J＝8.80.Hz，2H)7.95(d，J＝8.80Hz，2H).MS 524.3/526.3(1∶1；M+H)
+.
Embodiment 107
(S)-4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-4-(trifluoromethyl)-1H-imidazoles-5-yl]-benzamide, two-trifluoroacetate
Steps A: trans-4-[(S)-1-(4-bromo-5-Trifluoromethyl-1 H-imidazoles-2-yl)-2-phenyl-ethylamino formyl radical]-cyclohexyl methyl-t-butyl carbamate: by successively suitably the method for Application Example 1 step B, embodiment 2 steps A and embodiment 82 steps A the product of embodiment 32 steps A is changed into title compound.MS：573.3/575.3(M+1)
+。
Step B: trans-(4-{ (S)-1-[4-(4-formamyl-phenyl)-5-Trifluoromethyl-1 H-imidazoles-2-yl]-2-phenyl-ethylamino formyl radical }-cyclohexyl methyl)-t-butyl carbamate: with the product (47mg of embodiment 107 steps A; 0.069mmol), 4-formamyl phenyl-boric acid (30mg, 0.18mmol), K
3PO
4(75mg, 0.35mmol) and Pd (PPh
3)
4(22mg) join 6ml 1 together, in the 4-dioxane.Mixture was heated 1.5 hours down at 110 ℃ with microwave in sealed tube.Remove and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and with purification by flash chromatography (silica gel, EtOAc/ hexane), obtains the required product of 25mg.MS：614.4(M+1)
+。
Step C: trans-4-(2-{ (S)-1-[(4-amino methyl-cyclohexyl-carbonyl)-amino]-2-phenyl-ethyl }-5-Trifluoromethyl-1 H-imidazol-4 yl)-benzamide, the product of two-trifluoroacetate: embodiment, 107 step B changes into embodiment 107 (15mg) by the described method of Application Example 2 step B suitably.
MS：514.3(M+1)
+.
1MR(400MHz，d
4-MeOH)δ1.04(m，2H)，1.39(m，2H)，1.57(m，1H)，1.82(m，4H)，2.21(m，1H)，2.76(d，J＝7.03Hz，2H)，3.20(m，2H)，5.25(m，1H)，7.20(m，5H)，7.50(d，J＝8.35Hz，2H)，7.93(d，J＝8.79Hz，2H).
Embodiment 108
N-{ (S)-1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-benzamide
Oxammonium hydrochloride (10 equivalent) is dissolved among the DMSO (1ml), adds triethylamine (10 equivalent).Mixture was stirred 5 minutes, remove by filter Triethylammonium chloride then.The compound (80mg) of embodiment 178 steps A is joined in the filtrate, mixture was heated 1-1.5 hour down at 65 ℃.Reactant is cooled to room temperature, uses about 10ml water dilution, collect the gained precipitation, wash with water and drying, obtain amidoxim intermediate (73mg, 84%).m/z 426.4(M+H)
+。This material is suspended in the methylene dichloride (10ml), adds diacetyl oxide (0.040ml).With mixture under argon gas in stirring at room 20 minutes, be evaporated to dried then.Residue is dissolved in the mixture of methyl alcohol/HOAc (10: 1), adds 10%Pd/C, with mixture at 1 normal atmosphere H
2Under stirred 2 hours.Remove by filter catalyzer, evaporated filtrate, residue obtains title compound two tfa salts (65mg, 60%) by preparation C18 HPLC purifying.
1HNMR(400MHz，MeOH-D4)δ3.41-3.59(m，2H)5.53(t，J＝8.13Hz，1H)7.20-7.31(m，5H)7.46(t，J＝7.69Hz，2H)7.56(t，J＝7.47Hz，1H)7.84(d，J＝7.03Hz，2H)7.87-7.95(m，5H)m/z 410.2(M+H)
+
Embodiment 109
Trans-5-(2-{ (S)-1-[(4-amino methyl-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)-2-cyano group-phenylformic acid, two-trifluoroacetate
Steps A: 5-ethanoyl-2-cyano group-methyl benzoate: with trifluoromethanesulfanhydride anhydride (10g, 35.4mmol) be added drop-wise to cold (40 ℃) 5-ethanoyl-2 hydroxybenzoic acid methyl esters (6.9g, 35.4mmol) and DIPEA (5.3g, CH 42.5mmol)
2Cl
2(100ml) in the solution.Reactant is warming up to-10 ℃, and stirred 16 hours.Again reactant is warming up to room temperature, vacuum-evaporation is dissolved among the EtOAc to doing again, and organic layer is washed with 1/2 saturated brine, uses MgSO
4Drying is filtered and vacuum-evaporation.(5.01g 15.3mmol) is dissolved among the DMF (40ml) with the thick triflate of part.With palladium (0) four (triphenylphosphine) (1.3g, 1.1mmol) and zinc cyanide (2.16g 18.4mmol) joins in the flask, and mixture heating up to 90 ℃ was kept 2.5 hours.Reactant is cooled to room temperature, and with 1: 1 dense NH
4The solution of OH and water (160ml) stirs together.The gained suspension is extracted with EtOAc.The organic extract that merges is washed with 1/2 saturated brine, use MgSO
4Drying is filtered and vacuum distilling.Title compound passes through SiO
2Chromatographic separation obtains 439mg (14%) white solid.MS 221.1(M+NH
4)
+。
Step B:5-(2-bromo-ethanoyl)-2-cyano group-methyl benzoate: (107mg 0.53mmol) is dissolved in CH with the product of embodiment 109 steps A
2Cl
2(5ml), and with bromine (84mg 0.53mmol) handles.After 3 hours, the color of solution is by the red yellowing of iron rust, shows that reaction finishes.With reactant CH
2Cl
2Saturated NaHCO is used in dilution
3Na is used in washing
2SO
4Drying is filtered and vacuum-evaporation, obtains 160mg (＞99%) colorless solid.
1HNMR(500MHz，CDCl
3)δ4.05(s，3H)4.47(s，2H)7.97(d，J＝7.70Hz，1H)8.26(m，1H)8.69(s，1H).
Step C:(S)-2-{[4-(tert-butoxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino }-3-phenyl-propionic acid: with 4-(tert-butoxycarbonyl amino-methyl)-naphthenic acid (1.7g, 6.6mmol) and ethylbenzene L-Ala hydrochloride (2.0g, 6.6mmol) be dissolved among the DMF (30ml), and with HOAt (0.5M is dissolved in the solution of DMF, 16ml, 8mmol) with 4-methylmorpholine (2.33g, 23mmol) chemical combination.In this mixture, add EDCI (1.76g, 9.2mmol).Reactant was at room temperature stirred 12 hours,, with the washing of 1/2 saturated brine several times, use MgSO with the EtOAc dilution
4Drying is filtered and vacuum-evaporation, obtains 2.8g (99%) colorless solid, it is dissolved among the MeOH (30ml), and at room temperature handled 3 hours with 1N NaOH (19ml).Vacuum is removed MeOH, and residue is soluble in water again.The aqueous solution is acidified to pH1 with 1N HCl, and extracts with EtOAc.With the organic extract MgSO that merges
4Drying is filtered and vacuum concentration, obtains 2.5g (95%) title compound free acid.MS 403.0(M+H+)。
Step D:5-[2-((S)-1-{[4-(tert-butoxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino }-2-phenyl-ethyl)-the 1H-imidazol-4 yl]-2-cyano group-ethyl benzoate: with the product (149mg of embodiment 109 step B, 0.53mmol) and the product (214mg of embodiment 109 step D, 0.53mmol) according to the described method chemical combination of embodiment 1 steps A, obtain 73.6mg (24%) title compound.MS 584.4(M-H
+)
-。
Step e: 5-(2-{ (S)-1-[(4-amino methyl-cyclohexyl-carbonyl)-amino]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)-2-cyano group-phenylformic acid: with the product (149mg of embodiment 109 step B, 0.53mmol) and the product (214mg of embodiment 109 step D, 0.53mmol) according to the described method chemical combination of embodiment 1 steps A, obtain 73.6mg (24%) title compound.MS 584.4(M-H
+)。
Step F: 5-(2-{ (S)-1-[(4-amino methyl-cyclohexyl-carbonyl)-amino]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)-2-cyano group-phenylformic acid: with the product (13mg of embodiment 109 step e, 0.022mmol) be dissolved among the anhydrous MeOH, and be cooled to 0 ℃.In solution, be blown into anhydrous ammonia gas about 15 minutes, and then reaction vessel covered tightly, and reactant was at room temperature stirred 24 hours.Blast nitrogen to reactant, and be evaporated to dried.Crude product is dissolved in the CH of 10%TFA
2Cl
2In the solution (v/v), and at room temperature stirred 16 hours.Vacuum evaporating solvent and TFA.Crude product is dissolved in again the MeOH/H that contains 0.1%TFA
2Among the O (9: 1).HPLC isolates title compound by preparation, is flint glass shape thing, obtains 2.0mg (19%).
1HNMR(500MHz，d
4-MeOH)□1.06(m，2H)1.39(m，2H)1.57(m，1H)1.79(d，J＝12.10Hz，1H)1.86(d，J＝12.10Hz，3H)2.26(m，1H)2.77(d，J＝6.60Hz，2H)3.33(d，J＝8.25Hz，2H)5.32(t，J＝7.97Hz，1H)7.1 9(d，J＝6.60Hz，2H)7.22(m，1H)7.28(t，J＝7.15Hz，3H)7.92(s，2H)8.09(d，J＝7.70Hz，1H)8.13(s，1H).MS 472.3(M+H
+)
+.
Embodiment 113
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-bromo-1H-imidazoles-2-yl]-the 2-styroyl]-4-(amino methyl)-trans-cyclohexane carboxamide, two-trifluoroacetate
Except method, by the synthetic embodiment 113 of Application Example 120 described methods suitably with the method alternative embodiment 120 step D of embodiment 82 steps A.
1HNMR(500MHz，d
4-MeOH)δ1.05(m，2H)1.39(m，2H)1.57(m，1H)1.75(bd，J＝12.10Hz，1H)1.85(bd，J＝13.20Hz，3H)2.22(m，1H)2.77(d，J＝7.15Hz，2H)3.16(dd，J＝13.20，8.25Hz，1H)3.24(dd，J＝13.20，7.40Hz，1H)5.21(t，J＝7.97Hz，1H)7.18(m，3H)7.25(t，J＝7.42Hz，2H)7.47(d，J＝9.90Hz，1H)7.70(s，1H)7.92(d，J＝8.25Hz，1H).MS：536(M+H+)+.
Embodiment 114
(S)-5-[4-(the formamyl phenyl]-2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-styroyl]-1H-imidazoles-4-methyl-formiate, two-trifluoroacetate
Steps A: 2-((S)-1-tert-butoxycarbonyl amino-2-phenyl-ethyl)-3H-imidazoles-4-methyl-formiate: (0.42g 1.07mmol) is dissolved among the MeOH (8ml), and adds TFA (0.8ml) with the compound of embodiment 32 step B.With reaction mixture under nitrogen in stirring at room 30 minutes.Add NaHCO
3The aqueous solution, and remove MeOH.With water CH
2Cl
2Extraction.With CH
2Cl
2MgSO is used in solution salt water washing
4Drying concentrates then, obtains yellow foam thing (0.40g).LC/MS：346.4(M+1)
+。
Step B:5-bromo-2-((S)-1-tert-butoxycarbonyl amino-2-phenyl-ethyl)-3H-imidazoles-4-methyl-formiate: (1.2g, purity 83% 0.28mmol) are dissolved in CHCl with the product of embodiment 114 steps A
3(20ml), and adding NBS (0.93g, 0.41mmol).With mixture under nitrogen in stirring at room 1.5 hours.It is used CHCl
3Dilution, and water and salt water washing.Then it is used MgSO
4Dry and concentrated, obtain white solid (0.79g).MS：424.4/426.2(M+1)
+。
Step C: trans-5-bromo-2-((S)-1-{[4-(tert-butoxycarbonyl amino-methyl)-hexanaphthene carbonyl]-amino }-2-phenyl-ethyl)-product of 3H-imidazoles-4-methyl-formiate: embodiment 114 step B is by Application Example 1 step B and the described method of embodiment 2 steps A change into title compound successively.LC/MS：563.3(M+1)
+。
Step D: trans-2-{ (S)-1-[(4-amino methyl-cyclohexyl-carbonyl)-amino]-2-phenyl-ethyl }-5-(4-formamyl-phenyl)-3H-imidazoles-4-methyl formate, the product of two-trifluoroacetate: embodiment, 114 step C is by Application Example 107 step B and the described method of embodiment 2 step B change into embodiment 114 successively.
1HNMR(400MHz，d
4-MeOH)δ1.05(m，2H)，1.39(m，2H)，1.57(m，1H)，1.81(m，4H)，2.23(m，1H)，2.77(d，J＝7.03Hz，2H)，3.24(m，2H)，3.82(s，3H)，5.28(t, J＝7.91Hz，1H)，7.21(m，5H)，7.76(d，J＝8.35Hz，2H)，7.94(d，J＝8.35Hz，2H).
Embodiment 117
(S)-N-[1-[4-[4-(formamyl) phenyl]-1H-imidazoles-2-yl]-the 2-styroyl]-4-(amino methyl)-benzamide
This compound is by Application Example 28 described method preparations suitably.
MS：440.2(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ3.53(m，2H)，4.19(s，2H)，5.55(m，1H)，7.27(m，5H)，7.57(m，2H)，7.77(m，2H)，7.80-8.02(m，5H).
Embodiment 118
4-amino methyl-N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-benzamide
Embodiment 118 is by Application Example 28 described method preparations suitably.
MS:458.2 (M+1)
+.
1HNMR (400MHz, d
4-MeOH) δ 3.47 (dd, J=13.84 and 8.13Hz, 2H), 4.18 (s, 2H), 5.59 (t, J=7.91Hz, 1H), 7.29 (m, 7H), 7.77 (m, 3H), 7.89 (s, 1H), 7.98 (d, J=8.79Hz, 2H).
Embodiment 119
Trans-2-{ (S)-1-[(4-amino methyl-cyclohexyl-carbonyl)-amino]-2-phenyl-ethyl }-5-(4-carboxyl-phenyl)-3H-imidazoles-4-formic acid, two-trifluoroacetate
The product of embodiment 114 is obtained embodiment 119 with the LiOH/THF hydrolysis.
MS:491.4 (M+1)
+.
1HNMR (400MHz, d
4-MeOH) δ 1.05 (dd, J=12.52 and 4.17Hz, 2H), 1.39 (m, 2H), 1.57 (m, 1H), 1.85 (m, 4H), 2.23 (m, 1H), 2.77 (d, J=7.03Hz, 2H), 3.23 (m, 2H), 5.29 (t, J=7.91Hz, 1H), 7.21 (m, 5H), 7.81 (d, J=8.35Hz, 2H), 8.06 (d, J=8.79Hz, 2H).
Embodiment 120
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-styroyl]-4-(amino methyl)-trans-cyclohexane carboxamide, two-trifluoroacetate
Steps A: 4-cyano group-3-fluorobenzoic acid: with 4-bromo-3-fluorobenzoic acid (7.5g, 0.034mol), Zn (CN)
2(4.0g, 0.034mol) and Pd (PPh
3)
4(3.95g 0.0034mol) joins among the 60ml DMF (degassing) together.Mixture was heated 3 hours in 90 ℃ under nitrogen.It is cooled to room temperature, and removes by filter insoluble inorganic salt (discarding).Filtrate water is diluted, and extract with EtOAc.With EtOAc mixture water, salt water washing, use MgSO
4Drying concentrates then, obtains 4.5g purity and be 90% required product.These materials are not further purified and are used for next step.
1H-NMR(500MHz，d
4-MeOH)δ7.82(m，1H)，7.90(m，3H)，7.56(d，J＝10.0Hz，1H)，7.68(s，1H)，7.96(d，J＝8.4Hz，1H).
Step B:4-(2-acetyl bromide)-2-fluorine benzonitrile: (material of 4.0g90% purity 0.02mol) is dissolved in CH with 4-cyano group-3-fluorobenzoic acid
2Cl
2(50ml).Through 15 fens clockwise wherein drip oxalyl chloride (2.3ml, 0.026mol).With reaction mixture under nitrogen in stirring at room 1 hour, reflux is 1 hour then.Remove and desolvate, residue is dissolved in CH again
3Among the CN (50ml).This solution is cooled to-15 ℃, and drips (trimethyl silyl) diazomethane (11.5ml 2.0M is in hexane) to it, carries out in 20 minutes.The gained mixture was stirred 1 hour in-15 ℃ under nitrogen.(4.25ml 33%wt), and stirs reaction mixture 20 minutes down at-15 ℃ to the HOAc solution that wherein dripped HBr through 20 minutes.Remove and desolvate, residue is dissolved among the EtOAc, MgSO is used in water, salt water washing
4Drying concentrates then, obtains the required product of 3.2g.
MS：240.1，242.1，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ2.42(s，2H)，7.76-7.85(m，3H).
Step C:(S)-1-(4-(4-cyano group-3-fluorophenyl)-1H-imidazoles-2-yl)-2-styroyl carboxylamine tertiary butyl ester: with 4-(2-acetyl bromide)-2-fluorine benzonitrile (3.2g, 0.013mol), the L-Boc-phenylalanine (3.5g, 0.013mol) and Cs
2CO
3(2.6g 0.008mol) joins among the DMF (20ml) together.The gained mixture was stirred 1 hour in 15 ℃ under nitrogen.It is diluted with 100ml EtOAc, and MgSO is used in water, salt water washing
4Drying concentrates, and by purification by flash chromatography (120g * 2 silica gel, the hexane solution of 10-55%EtOAc), obtains the required ester of 3.5g.LC/MS：425.3。Then with this material and ammonium acetate (12g) chemical combination, and be suspended in the dimethylbenzene (100ml).Mixture in being housed, was heated 2.5 hours in 150 ℃ under nitrogen by the flask of dean stark trap.Remove removal xylene.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and by purification by flash chromatography (120g * 2 silica gel, the hexane solution of 15-70%EtOAc), obtains the required imidazoles of 2.2g.
MS：407(M+H)
+.
1H-NMR(400MHz，CDCl
3)δ1.39(s，9H)，3.30(m，2H)，4.86(d，J＝6.59Hz，1H)，5.32(d，J＝7.47Hz，1H)，7.14-7.24(m，6H)，7.53-7.61(m，3H).
Step D:(S)-1-(5-chloro-4-(4-cyano group-3-fluorophenyl)-1H-imidazoles-2-yl)-2-styroyl carboxylamine tertiary butyl ester: with the product (2.2g of embodiment 120 step C, 5.4mmol) and N-chloro-succinimide (0.80g 6.7mmol) joins CH together
3Among the CN (100ml).With mixture reflux 7 hours under nitrogen.Remove and desolvate, residue is dissolved among the EtOAc.With its water, NaHCO
3MgSO is used in the aqueous solution and salt water washing
4Drying concentrates then, obtains the 2.4g foam.
MS：441.3，(M+H)
+.
1H-NMR(400MHz，CDCl
3)δ1.27(s，9H)，3.23(m，2H)，4.89(m，1H)，5.46(d，J＝7.03Hz，1H)，7.07(d，J＝6.15Hz，2H)，7.25-7.26(m，5H)，7.54(m，1H).
Step e: 4-(2-((S)-1-amino-2-styroyl)-5-chloro-1H-imidazol-4 yl)-2-fluorine benzonitrile: with the product of embodiment 120 step D (0.20g, 0.45mmol) under nitrogen with CH
2Cl
2(6ml) and TFA (1.5ml) stirred together 0.5 hour.Remove and desolvate.With residue vacuum-drying, obtain 0.26g two-tfa salt.
MS：340.94，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ3.33(m，2H)，4.56(dd，J＝8.57，6.37Hz，1H)，7.12(d，J＝6.59Hz，2H)，7.25-7.30(m，3H)，7.67(m，2H)，7.81(m，1H).
Step F: trans-(4-{ (S)-1-[5-chloro-4-(4-cyano group-3-fluorophenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl-carbamyl }-cyclohexyl methyl)-the carboxylamine tertiary butyl ester: with Boc-to aminomethyl hexahydrobenzoic acid (0.14g; 0.54mmol), Bop reagent (0.24g; 0.54mmol) and TEA (0.38ml 2.7mmol) joins among the 10ml THF together.With mixture under nitrogen in stirring at room 15 minutes, add then embodiment 120 step e product (0.26g, 0.45mmol).The gained mixture was heated 15 minutes in 75 ℃ under nitrogen.Reaction mixture is cooled to room temperature, and removes and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and by purification by flash chromatography (40g silica gel, the hexane solution of 10-100%EtOAc), obtains the required product of 0.21g.
MS：580.3，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ0.94(m，2H)，1.25-1.37(m，4H)，1.42(s，9H)，1.76-1.79(m，3H)，2.15(m，1H)，2.85(m，2H) 3.20-3.30(m，2H) 5.17(m，1H)，7.16-7.23(m，5H)，7.67-7.80(m，3H).
Step G: trans-4-amino methyl-naphthenic acid (S)-1-[5-chloro-4-(4-cyano group-3-fluorophenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl-acid amides: with the product of embodiment 120 step F (0.21g, 0.36mmol) under nitrogen with CH
2Cl
2(8ml) and TFA (2ml) stirred together 0.5 hour.Remove and desolvate.With residue vacuum-drying, obtain 0.25g two-tfa salt.MS：480.3，(M+H)
+。
Step H: trans-4-amino methyl-naphthenic acid [S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-acid amides, two-trifluoroacetate: with the product of embodiment 120 step G (0.21g, 0.36mmol) and hydrazine monohydrate (0.69ml) join together in the 8ml propyl carbinol.Mixture was heated 1 hour in 120 ℃ under nitrogen.Remove and desolvate.By the reversed-phase HPLC purifying, obtaining the 0.14g title compound is two-tfa salt with residue.
MS：492.3，(M+H)
+.
1H-NMR(400MHz，DMSO-d
6)δ0.82-0.84(m，2H)，1.11-1.22(m，2H)，1.36(m，1H)，1.52(m，1H)，1.61-1.70(m，3H)，2.02(m，1H)，2.52-2.61(m，2H)，2.94-3.09(m，2H)，5.15(m，1H)，7.13-7.20(m，5H)，7.77-8.27(m，3H).
Embodiment 121
N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl) benzamide, two-trifluoroacetate
Embodiment 121 makes by Application Example 120 described methods suitably, wherein uses Boc-in 4-((uncle-amino butoxy formyl radical) methyl) phenylformic acid alternate embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.
MS：486.3，(M+H)
+.
1HNMR(500MHz，d
4-MeOH)δ3.33-3.35(m，2H)，4.18(s，2H)，5.44(t，J＝7.42Hz，1H)，7.22-7.25(m，5H)，7.52-7.55(m，3H)，7.72(s，1H)7.88(d，J＝8.25Hz，2H)，7.97(d，J＝8.80Hz，1H).
Embodiment 122
3-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-1H-indazole-6-methane amide, two-trifluoroacetate
Steps A: (S)-(4-(3-amino-1H-indazole-6-yl }-S-chloro-1H-imidazoles-2-yl)-2-styroyl carboxylamine tertiary butyl ester: (0.52g 1.2mmol) changes into Aminoindazole by the described method of Application Example 120 step H suitably to the product of embodiment 120 step D to 1-.MS：453.3(M+H)
+。
Boc protecting group on step B:6-(2-((S)-1-amino-2-styroyl)-5-chloro-1H-imidazol-4 yl)-1H-indazole-3-amine: embodiment 122 steps A products is removed with TFA according to the described method of embodiment 120 step G.LC/MS：353.1(M-H)
+。
Step C:N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-4-cyano group-3-fluorobenzamide: the product of embodiment 122 step B is adopted the described method of embodiment 120 step F and 4-cyano group-3-fluorobenzoic acid coupling.MS：500.3(M+H)
+。
Step D:3-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-1H-indazole-6-methane amide, the product of two-trifluoroacetate: embodiment, 122 step C adopt the described method of embodiment 120 step H to change into embodiment 122.
MS：510.3(M-H)
-.
1HNMR(400MHz，d
4-MeOH)δ3.37(m，2H)，5.45(t，J＝7.42Hz，1H)，7.23-7.27(m，5H)，7.54-7.58(m，2H)，7.72(s，1H)，7.86(s，1H)，7.91-7.97(m，2H).
Embodiment 123
3-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl) different azoles of benzo [d]-6-methane amide, two-trifluoroacetate
The product of embodiment 122 step D changes into amino-benzene and different azoles with acetohydroxamic acid and salt of wormwood in DMF.
MS：513.1(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ3.37(m，2H)，5.44(t，J＝7.42Hz，1H)，7.23-7.27(m，5H)，7.54(d，J＝8.79Hz，1H)，7.68(d，J＝8.24Hz，1H)，7.72(8，1H)，7.82(d，J＝8.24Hz，1H)，7.83(s，1H)，7.97(d，J＝8.79Hz，1H).
Embodiment 124
N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-4-(amino methyl)-2-fluorobenzamide, two-trifluoroacetate
Embodiment 124 is by Application Example 120 described methods preparations suitably, wherein uses Boc-in 4-cyano group-2-fluorobenzoic acid alternate embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.Cyano group adopts (Boc)
2O/NiCl
2/ NaBH
4In MeOH, reduce down in 0 ℃.After the described method of Application Example 2 step B is carried out the TFA deprotection suitably, isolate title compound two-tfa salt.
MS:504.1, (M+H)
+.
1H-NMR (400MHz, d
4-MeOH) 63.34 (m, 2H), 4.18 (s, 2H), 5.44 (t, J=7.42Hz, 1H), 7.20-7.27 (m, 5H), 7.33-7.35 (m, 2H), 7.54 (dd, J=8.34Hz and 1.31Hz, 1H), 7.75 (m, 2H), 7.97 (d, J=9.22Hz, 1H).
Embodiment 128
N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-4-chloro-2-fluorobenzamide, two-trifluoroacetate
Embodiment 128 prepares similarly by the method for Application Example 120 suitably, wherein uses 4-chloro-2-fluorobenzoic acid to replace Boc-used in embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.
MS:509.3, (M+H)
+.
1H-NMR (500MHz, d
4-MeOH) δ 3.34 (m, 2H), 5.44 (t, J=7.42Hz, 1H), 7.21-7.34 (m, 7H), 7.53 (dd, J=8.79Hz and 1.1Hz, 1H), 7.66 (t, J=8.24Hz, 1H), 7.72 (s, 1H), 7.99 (d, J=8.79Hz, 1H).
Embodiment 129
N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-2-fluoro-5-methoxy benzamide, two-trifluoroacetate
Embodiment 121 prepares similarly by Application Example 120 described methods suitably, wherein uses 2-fluoro-5-methoxybenzoic acid to replace Boc-in embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.
MS:505.3, (M+H)
+.
1H-NMR (500MHz, d
4-MeOH) δ 334 (m, 2H), 3.78 (s, 3H), 5.44 (t, J=7.42Hz, 1H), 7.06 (m, 1H), 7.12 (m, 1H), 7.19 (m, 1H), 7.23-7.27 (m, 5H), 7.55 (dd, J=8.79Hz and 1.1Hz, 1H), 7.73 (s, 1H), 7.98 (d, J=8.79Hz, 1H).
Embodiment 130
(S)-4-[2-[(1-[4-(amino methyl) hexanaphthene formamido group]-the 2-styroyl]-4-chloro-1H-imidazoles-5-yl]-benzamide, two-trifluoroacetate
The described method of product Application Example 120 step D of embodiment 28 steps A is at room temperature used NCS/CHCl
3Carry out chlorination.Adopting the method for embodiment 2 step B to remove the Boc group then, obtain final product, is two-tfa salt.
MS：506.2(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ1.05(m，2H)，1.38(m，2H)，1.56(m，1H)，1.75(m，1H)，1.85(d，J＝10.55Hz，3H)，2.20(m，1H)，2.76(d，J＝7.03Hz，2H)，3.17(m，2H)，5.20(t，J＝7.91Hz，1H)，7.21(m，5H)，7.73(d，J＝8.79Hz，2H)，7.92(d，J＝8.79Hz，2H).
Embodiment 131
Trans-hexanaphthene-1,4-dioctyl phthalate 1-acid amides 4-((S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-acid amides), two-trifluoroacetate
Embodiment 131 prepares similarly by the method for Application Example 120 suitably, wherein use 4-trans-(methoxycarbonyl) naphthenic acid replaces Boc-in embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.The intermediate methyl esters changes into acid amides by the method for Application Example 26 steps A and embodiment 44 steps A successively.
MS：506.2，(M+H)
+。
1HNMR (500MHz, d
4-MeOH) δ 1.33-1.38 (m, 1H), 1.45-1.48 (m, 3H), 1.72 (m, 1H) 1.88 (m, 3H), 2.18-2.23 (m, 2H), 3.17 (m, 1H), 3.26 (m, 1H), 5.21 (t, J=7.42Hz, 1H), 7.19 (m, 3H), 7.25 (m, 2H), 7.52 (dd, J=8.24Hz and 1.1Hz, 1H), 7.70 (s, 1H), 7.99 (d, J=8.24Hz, 1H).
Embodiment 132
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-styroyl]-1,4-benzenedicarboxamide, two-trifluoroacetate
Embodiment 132 is by Application Example 120 described methods preparations suitably, wherein uses Boc-in 4-formamyl-phenylformic acid alternate embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.
MS:500.1, (M+H)
+.
1H-NMR (500MHz, d
4-MeOH) δ 3.34 (m, 2H), 5.44 (t, J=7.42Hz, 1H), 7.24-7.26 (m, 5H), 7.54 (dd, J=8.79 and 1.1Hz, 1H), 7.72 (s, 1H), 7.89 (d, J=8.3Hz, 2H), 7.95 (d, J=8.3Hz, 2H), 7.97 (d, J=8.79Hz, 1H).
Embodiment 135
(S)-4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-styroyl]-4-phenyl-1H-imidazoles-5-yl]-benzamide, two-trifluoroacetate
The product of embodiment 28 steps A by the method for Application Example 82 steps A suitably change into (4-{ (S)-1-[5-bromo-4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethylamino formyl radical-cyclohexyl methyl)-the carboxylamine tertiary butyl ester.Then this compound is passed through Application Example described condition of 107 step B and phenyl-boron dihydroxide coupling suitably.Adopting the method for embodiment 2 step B to remove the Boc blocking group with TFA, obtain embodiment 135, is two-tfa salt.
MS：522.4(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δδ1.07(m，2H)，1.42(m，2H)，1.59(m，1H)，1.85(m，4H)，2.30(m，1H)，2.78(d，J＝6.59Hz，2H)，3.41(m，2H)，5.32(t，J＝8.13Hz，1H)，7.29(m，7H)，7.44(m，2H)，7.90(d，J＝8.35Hz，2H).
Embodiment 136
1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-isoquinoline 99.9-6-methane amide, two-trifluoroacetate
This compound is by the 1-aminoisoquinoline-6-formic acid of the described method employing of Application Example 147 step F and embodiment 120 step F embodiment 147 step D and the product preparation of embodiment 120 step e successively.
MS：523.2(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ3.39(dd，J＝15.82，7.91Hz，2H)，5.48(t，J＝7.91Hz，1H)，7.25-7.27(m，6H)，7.52(d，J＝10.11Hz，1H)，7.61(d，J＝7.03Hz，1H)，7.72(s，1H)，7.96(d，J＝8.35Hz，1H)，8.08(dd，J＝8.79，1.76Hz，1H)，8.30(s，1H)，8.49(d，J＝8.79Hz，1H).
Embodiment 137
1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-5,6,7,8-tetrahydroisoquinoline-6-methane amide, two-trifluoroacetate
Embodiment 137 method by Application Example 120 step H suitably is by the product preparation of embodiment 147 step F.
MS：527.3(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ2.44(m，2H)，2.76(m，2H)，2.88(m，1H)，3.21(m，2H)，3.34(m，2H)5.29(m，1H)，6.66(t，J＝7.9Hz，1H)，7.24(m，5H)，7.56(m，2H)，7.73(s，1H)，7.97(d，J＝7.9Hz，1H).
Embodiment 138
2-(3-amino-1H-indazole-6-yl)-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl) ethanamide, two-trifluoroacetate
This compound wherein uses 2-(4-cyano group-3-fluorophenyl) acetate to be replaced by 4-cyano group-3-fluorobenzoic acid by Application Example 122 described method preparations suitably.
MS：526.3(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ3.17(m，1H)，3.26(m，1H)，3.69(d，J＝5.71Hz，2H)，5.26(t，J＝7.03Hz，1H)，7.02(d，J＝8.34Hz，1H)，7.16(m，5H)，7.26(s，1H)，7.52(d，J＝8.79Hz，1H)，7.71(s，1H)，7.81(d，J＝8.34Hz，1H)，7.97(d，J＝8.79Hz，1H).
Embodiment 139 trans-4-(2-{ (S)-1-[(4-amino methyl-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-5-bromo-1-methyl isophthalic acid H-imidazol-4 yl)-benzamide, two-trifluoroacetate
Product MeI/K with embodiment 82 steps A
2CO
3/ DMF methylates.Isolated main isomer is adopted the described method deprotection of embodiment 2 step B, obtain embodiment 139.
MS：538.2/540.2(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ1.04(m，2H)，1.39(m，2H)，1.56(m，1H)，1.80(m，4H)，2.20(m，1H)，2.76(d，J＝7.03Hz，2H)，3.27(m，2H)，3.41(s，3H)，5.35(t，J＝7.91Hz，1H)，7.22(m，5H)，7.96(m，4H).
Embodiment 140
4-amino methyl-N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-ethylamino-benzamide, two-trifluoroacetate
Steps A: 4-cyano group-2-fluorobenzoic acid tertiary butyl ester: (1.0g 6.1mmol) is dissolved among the trimethyl carbinol (9ml) and the THF (3ml) with 4-cyano group-2-fluorobenzoic acid.Add the Boc acid anhydrides (2.64g, 12.1mmol), add again DMAP (0.24g, 1.97mmol).With the gained mixture under nitrogen in stirring at room 12 hours.Remove and desolvate.Residue is dissolved among the EtOAc, and uses saturated NaHCO
3The aqueous solution and salt water washing.It is used MgSO
4Drying concentrates then, obtains oil, and it becomes solid (1.3g) under vacuum.
1HNMR (400MHz, d
4-MeOH) δ 1.59 (s, 9H), 7.44 (dd, J=25.71 and 9.01Hz, 2H), 7.95 (m, 1H).
Step B:4-cyano group-2-(ethylamino) phenylformic acid tertiary butyl ester: with the product of embodiment 140 steps A (0.30g, 1.36mmol) and ethylamine hydrochloride (0.22g 2.72mmol) joins among the 5ml DMF together.Mixture was heated 2 hours in 50 ℃ under nitrogen.Add entry, the gained mixture is extracted with EtOAc.With the salt water washing of EtOAc extract, use MgSO
4Drying concentrates then, and residue by purification by flash chromatography (silica gel, EtOAc/ hexane), is obtained the required product of 50mg.MS：247.3(M+1)
+。
Step C:4-cyano group-2-(ethylamino) phenylformic acid: (50mg is 0.20mmol) with 5ml TFA and 5ml CH with the product of embodiment 140 step B
2Cl
2Under nitrogen in stirring at room 1 hour, then at N
2Following reflux 1 hour.Remove and desolvate.With residue dried, obtain 45mg acid.
1HNMR(400MHz，d
4-MeOH)δ1.28(m，3H)，3.18(m，2H)，76.75(m，1H)，6.86(s，1H)，7.95(d，J＝7.91Hz，1H).
Step D:(S)-4-(2-(1-(1-(4-cyano group-2-(ethylamino) phenyl) vinyl amino)-2-styroyl)-1H-imidazol-4 yl) benzamide: with cyano group-2-(ethylamino) phenylformic acid (40mg of embodiment 140 step C, 0.2mmol), Bop reagent (108mg, 0.24mmol) and Et
3N (0.28ml) joins among the 5ml THF together.Mixture was at room temperature stirred 15 minutes; add (S)-4-(2-(1-amino-2-styroyl)-1H-imidazol-4 yl) benzamide (107mg then; 0.2mmol), it is by Application Example 1 steps A, embodiment 28 steps A and the described method of embodiment 1 step B are made by N-Boc-(L)-phenylalanine and 4-(2-bromo-ethanoyl)-benzonitrile successively.With gained mixture reflux 2 hours under nitrogen.Remove and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Dry, concentrate, and, obtain the required product of 50mg with ISCO purification by flash chromatography (silica gel, EtOAc/ hexane).LC/MS：479.3(M+1)
+。
Step e: 4-amino methyl-N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2 base]-2-phenyl-ethyl }-2-ethylamino-benzamide, two-trifluoroacetate: the product of embodiment 140 step D is dissolved in the dioxane solution of 10ml MeOH and 1ml 4N HCl.The Pd/C (10%) that adds catalytic amount.Mixture was placed the hydrogen balloon environment following 12 hours.It is filtered by Celite, concentrate, use the reversed-phase HPLC purifying then, obtain 24mg two-tfa salt.
LC/MS:483.4 (M+1)
+.
1HNMR (400MHz, d
4-MeOH) δ 1.22 (t, J=7.25Hz, 3H), 3.18 (q, J=7.03Hz, 2H), 3.47 (dd, J=32.52 and 8.35Hz, 2H), 4.05 (s, 2H), 5.50 (t, J=8.35Hz, 1H), 6.66 (d, J=7.91Hz, 1H), 6.77 (s, 1H), 7.26 (m, 5H), 7.70 (d, J=7.91Hz, 1H), 7.76 (d, J=8.35Hz, 2H), 7.88 (s, 1H), 7.98 (d, J=8.35Hz, 2H).
Embodiment 142
(S)-and N-(1-(4-(4-carbamyl phenyl)-1H-imidazoles-2-yl)-2-styroyl)-1,2,3,4-tetrahydroisoquinoline-6-methane amide
Embodiment 142 is by suitable applications embodiment 28 described method preparations.
MS：466.2(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ3.15(t，J＝6.37Hz，2H)，3.49(m，4H)，4.41(s，2H)，5.53(t，J＝8.35Hz，1H)，7.27(m，6H)，7.75(m，4H)，7.88(s，1H)，7.97(d，J＝8.79Hz，2H).
Embodiment 143
4-amino methyl-N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-the 2-styroyl }-2-ethyl-benzamide
Steps A: 4-bromo-2-chloro benzoic ether: (1.0g 4.25mmol) is dissolved among the 10ml MeOH with 2-bromo-4-chloro-benzoic acid.Mixture is cooled off in ice bath, again to thionyl chloride wherein (3.1ml, 42.5mmol).Remove cooling bath, with mixture under nitrogen in stirring at room 12 hours.Remove and desolvate, and vacuum-drying, the 1.0g water white oil obtained.LC/MS：251.1(M+1)
+。
Step B:2-chloro-4-cyano-benzoic acid methyl ester: with the product of embodiment 143 steps A (1.0g, 4.0mmol), Zn (CN)
2(0.52g, 4.8mmol), Pd (PPh
3)
4(0.23g 0.2mmol) joins among the 9ml DMF together.With the mixture degassing, heated 6 hours down at 90 ℃ then.Water and EtOAc are joined in the reaction mixture.With its filtration, remove inoganic solids.Layering is with EtOAc layer water and salt water washing.It is used MgSO
4Drying concentrates, and by purification by flash chromatography (silica gel, EtOAc/ hexane), obtains the required product of 0.28g.MS：196.1(M+1)
+。
Step C:4-cyano group-2-ethyl benzoate methyl esters: with the product of embodiment 143 step B (160mg, 0.82mmol), ethyl-boron dihydroxide (120mg, 1.64mmol), K
3PO
4(344mg, 1.64mmol) and Pd (PPh
3)
4(114mg 0.1mmol) joins among the 9ml DME together.Adopt microwave to heat 15 minutes down in mixture at 150 ℃.Remove DME, and add EtOAc.With its water and salt water washing, use MgSO
4Drying concentrates, and by purification by flash chromatography (silica gel, EtOAc/ hexane), obtains the required product of 100mg.MS:190.21 (M+H
+)
+With 222.3 (M+Na
+)
+
Step D:4-cyano group-2-ethyl benzoate: (100mg 0.53mmol) is dissolved among the 5ml EtOH, and adds the NaOH aqueous solution of 1ml 1N with the product of embodiment 143 step C.With reaction mixture under nitrogen in stirring at room 2 hours.The HCl aqueous solution that adds 1N is regulated pH to 4.Remove EtOH, mixture is diluted with EtOAc and water.Separates two.Water layer is extracted with EtOAc.With EtOAc solution with water and the salt water washing that merges, use MgSO
4Drying, and concentrate, the required acid of 90mg obtained.
1HNMR(400MHz，d
4-MeOH)δ1.22(m，3H)，3.00(m，2H)，7.71(m，1H)，7.67(s，1H)，7.92(d，J＝8.35Hz，1H).
Step e: N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-cyano group-2-ethyl-benzamide: with the product (90mg of embodiment 143 step D; 0.51mmol), Bop reagent (265mg; 0.61mmol) and triethylamine (0.42ml 1.5mmol) joins among the 5ml THF together.With mixture under nitrogen in stirring at room 15 minutes, (365mg, 0.51mg), it adopts embodiment 2 and 28 described methods preparations to add (S)-4-(2-(1-amino-2-styroyl)-1H-imidazol-4 yl) benzamide then.The gained mixture was heated 70 minutes down at 75 ℃.Remove THF, residue is dissolved among the EtOAc.With its water and salt water washing, use MgSO
4Drying concentrates, and by purification by flash chromatography (silica gel, EtOAc/ hexane), obtains the required product of 80mg.MS：464.4(M+1)
+。
Step F: 4-amino methyl-N-{ (S)-1-[4-(4-formamyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-ethyl-benzamide: (70mg 0.15mmol) is dissolved in the dioxane solution of 10ml MeOH and 1ml 4N HCl with the product of embodiment 143 step e.Add the Pd/C (10%) of catalytic amount, mixture was placed the hydrogen balloon environment following 6 hours.It is filtered by Celite, and wash with MeOH.Concentrated filtrate, and, obtain 75mg two-tfa salt by the reversed-phase HPLC purifying.
LC/MS：468.4(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ1.08(t，J＝7.47Hz，3H)，2.61(t，J＝7.47Hz，2H，)，3.44(dd，J＝13.62，8.35Hz，2H)，4.12(s，2H)，5.59(t，J＝8.35Hz，1H)，7.34(m，7H)，7.80(d，J＝8.35Hz，2H)，7.89(s，1H)，7.99(d，J＝8.35Hz，2H).
Embodiment 144
3-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-1-methyl isophthalic acid H-indazole-6-methane amide, two-trifluoroacetate
By the described method of Application Example 120 step H suitably the product of embodiment 122 step C is changed into required product, wherein substitute hydrazine with methyl hydrazine.MS：526.3(M+H)
+。
MS：526.3(M+H)
+.
1HHNMR(400MHz，d
4-MeOH)δ3.35(m，2H)，3.84(s，3H)，5.46(m，1H)，7.23(m，5H)，7.39(d，J＝8.35Hz，2H)，7.64(s，1H)，7.72(d，J＝8.35Hz，1H)，7.79(s，1H)，7.84(d，J＝7.91Hz，1H).
Embodiment 147
1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-5,6,7,8-tetrahydroisoquinoline-6-methane amide, two-trifluoroacetate
Steps A: (E)-2-(2-(dimethylamino) vinyl) terephthalonitrile: (1.42g, 1.0mmol) (3.5g 2.0mmol) heated 12 hours in 75 ℃ under nitrogen with 15mlDML with tert.-butoxy two (dimethylamine) methane with the methyl terephthalonitrile.Remove DMF, and add hexane.Filter out formed precipitation, and dry, obtain the required product of 1.85g.
MS：504.4，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ2.95(s，6H)，5.27(d，J＝13.62Hz，1H)，7.14(m，1H)，7.42(d，J＝13.18Hz，1H)，7.54(d，J＝7.91Hz，1H)，7.86(s，1H).
Step B:2-(2, the 4-dimethoxy-benzyl)-1-imino--1,2-dihydro-isoquinoline-6-nitrile: with the product of embodiment 147 steps A (1.85g, 9.38mmol) and 2, (2.6ml 15.03mmol) heated 3 hours in 140 ℃ under nitrogen with 5ml DMPU the 4-dimethoxybenzylamine.With the reaction mixture cooling, add EtOAc/ hexane (1: 2) then.Filter out formed precipitation, and vacuum-drying, the required product of 2.5g obtained.
1H-NMR(400MHz，DMSO-d
6)δ3.72(s，3H，3.81(s，3H)，4.95(s，2H)，6.10(d，J＝7.03Hz，1H，6.44(d，J＝7.91Hz，1H)，6.57(s，1H)，7.02(d，J＝8.35Hz，1H)，7.22(d，J＝6.15Hz，1H，)7.68(d，J＝7.91Hz，1H)，7.94(s，1H)，8.34(d，J＝7.91Hz，1H).
Step C:2-(2, the 4-dimethoxy-benzyl)-1-imino--1,2-dihydro-isoquinoline-6-formic acid: with the product of embodiment 147 step B (2.5g, 7.84mmol) with 40ml MeOH-15%NaOH (1: 1) under nitrogen in 90 ℃ of heating 1.5 hours.With the reaction mixture cooling and the dropping HCl aqueous solution, regulate pH to about 5.Remove methyl alcohol, add EtOAc/ hexane (1: 2) then.Filter out formed precipitation, and dry, obtain the required product of 2.42g.
LC/MS：339.2，(M+H)
+.
1HNMR(400MHz，d
4-MeOH)δ2.00(s，2H)，3.82(d，J＝9.67Hz，6H)，6.62(m，2H)，7.23(d，J＝7.91Hz，2H)，7.50(d，J＝7.03Hz，1H)，8.23(s，1H)，8.31(s，1H)，8.42(d，J＝8.79Hz，1H).
Step D:1-aminoisoquinoline-6-formic acid: with the product of embodiment 147 step C (2.12g, 6.28mmol) with 17ml methyl-phenoxide and 20ml TFA under nitrogen in 105 ℃ of heating 12 hours.Remove and desolvate, add EtOAc/ hexane (1: 2) then.Filter out formed precipitation, and dry, obtain the 1.77g tfa salt.
LC/MS：189.04，(M+H)
+.
1HNMR(400MHz，d
4-MeOH)δ7.34(d，J＝7.03Hz，1H)，7.62(d，J＝7.03Hz，1H)，8.30(d，J＝8.79Hz，1H)，8.51(d，J＝8.79Hz，1H)，8.56(s，1H).
Step e: 1-amino-5,6,7,8-tetrahydroisoquinoline-6-formic acid: with the product of embodiment 147 step D (1.0g, 3.31mmol) and platinum oxide (87mg 0.38mmol) joins among the 21mlTFA together.Reaction mixture is placed under the hydrogen balloon environment, be warming up to 60 ℃ then and continue 16 hours.Mixture is cooled to room temperature, removes by filter platinum oxide by Celite then.Remove and desolvate, residue obtains the required product of 0.21g by the reversed-phase HPLC purifying, is tfa salt.
LC/MS：193.1，(M+H)
+.
1HNMR(400MHz，d
4-MeOH)δ2.00(m，1H)，2.28(m，1H)，2.57(m，2H，)2.85(m，1H)，3.02(d，J＝7.03Hz，2H)，6.75(d，J＝6.59Hz，1H)，7.61(d，J＝6.59Hz，1H).
Step F: 1-amino-N-((S)-1-(4-chloro-5-(4-cyano group-3-fluorophenyl)-1H-imidazoles-2-yl)-2-styroyl)-5,6,7,8-tetrahydroisoquinoline-6-methane amide: with embodiment 147 step e (0.21g, 0.67mmol), Bop reagent (0.44g, 1.0mmol) and triethylamine (0.91ml 6.54mmol) joins among the 15ml THF together.With mixture under nitrogen in stirring at room 20 minutes, add then embodiment 120 step e product (0.41g, 0.90mmol).The gained mixture was heated 1 hour in 75 ℃ under nitrogen.With the reaction mixture cooling, and remove and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and by purification by flash chromatography (40g silica gel, the dichloromethane solution of 0-15%MeOH), obtains the required product of 0.31g.
LC/MS：515.4，(M+H)
+.
1HNMR(400MHz，d
4-MeOH)δ1.73(dd，J＝12.96，5.93Hz，1H)，2.10(m，1H)2.39(m，1H)，2.58(m，4H)，3.22(m，2H)，5.24(t，J＝7.69Hz，1H)，6.37(d，J＝5.27Hz，1H)，7.23(m，5H)，7.64(m，3H，)7.79(m，1H).
Step G: the chiral separation of step F product: the product of embodiment 147 step F is separated (OD post, 30%EtOH/MeOH (1: 1) and 70% contains the heptane of 0.15%DEA) by chirality preparation-HPLC, obtain diastereomer A and diastereomer B.
Step H:(S)-1-amino-5,6,7,8-tetrahydroisoquinoline-6-formic acid (S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-styroyl-acid amides: with the diastereomer A of embodiment 147 step G (0.10g, 0.19mmol) and hydrazine (0.50ml) join together in the 7ml propyl carbinol.Mixture was heated 1.5 hours in 120 ℃ under nitrogen.Remove and desolvate.Residue by the reversed-phase HPLC purifying, is obtained the required product of 0.10g, is two-tfa salt.
LC/MS：527.21，(M+H)
+.
1HNMR(400MHz，d
4-MeOH)δ1.84(m，1H)，2.14(m，1H)，2.51(m，2H)，2.72(m，3H)，3.19(m，2H)，5.24(m，1H)，6.66(d，J＝6.59Hz，1H)，7.24(m，5H)，7.49(d，J＝8.35Hz，1H)，7.59(d，J＝6.59Hz，1H)7.69(s，1H)，7.93(d，J＝9.23Hz，1H).
Embodiment 155
N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-1,2,3,4-tetrahydroisoquinoline-6-methane amide, two-trifluoroacetate
Embodiment 155 wherein uses 2-(tertbutyloxycarbonyl)-1,2,3 by the method preparation of Application Example 120 suitably, and 4-tetrahydroisoquinoline-6-formic acid replaces the Boc-of embodiment 120 step F to the aminomethyl hexahydrobenzoic acid.
MS：512.2，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ3.17(t，J＝6.37Hz，2H，3.35(m，2H)3.53(t，J＝6.37Hz，2H)，4.41(s，2H)，5.41(t，J＝7.91Hz，1H)，7.22(m，5H)，7.32(d，J＝8.35Hz，1H)，7.50(d，J＝10.11Hz，1H)7.71(m，3H)7.94(d，J＝8.35Hz，1H).
Embodiment 157
Trans-4-amino methyl-naphthenic acid (S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-propyl group }-acid amides, three-trifluoroacetate
Steps A: (S)-2-benzyloxycarbonyl amino-pentanedioic acid 5-tertiary butyl ester 1-[2-(4-cyano group-3-fluoro-phenyl)-2-oxo-ethyl] ester: with (S)-2-benzyloxycarbonyl amino-pentanedioic acid 5-tertiary butyl ester (674mg, 2mmol), Cs
2CO
3(326mg, 1mmol) and DMF (5ml) at room temperature stirred 0.5 hour.Adding 1 '-bromo-3-fluoro-4-cyano-acetophenone (484mg, DMF 2mmol) (5ml) solution.Continue to stir 16 hours.Reaction mixture is diluted with EtOAc (100ml).LiCl solution washing with 10% three times is used MgSO
4Drying is filtered and solvent removed in vacuo, obtains orange oil (900mg, productive rate 91%).
1H-NMR(CDCl
3，400MHz)：δ7.77(m，3H)，7.35(m，5H)，5.52(m，1H)，5.42(d，1H，J＝16)，5.25(d，1H，J＝16)，5.11(s，2H)，4.60(m，1H)，2.45(m，2H)，1.44(s，9H)；MS：497(M-H+)-.
Step B:(S)-4-benzyloxycarbonyl amino-4-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-tert-butyl acetate: with the intermediate of embodiment 157 steps A (900mg, 1.81mmol), NH
4OAc (1.54g, 20mmol) and dimethylbenzene (30ml) under reflux temperature, stirred 2.5 hours.Reaction mixture is cooled to envrionment temperature.Solvent removed in vacuo.With residue at EtOAc and saturated Na
2CO
3Distribute three times between the solution.With the organic layer MgSO that merges
4Drying is filtered then.Solvent removed in vacuo obtains orange red oil by behind the HPLC (0% to 100%EtOAc-hexane), obtains orange oil (400mg, productive rate 46%).
1H-MR(CDCl
3，400MHz)：δ10.3(s，1H)，7.59(m，4H)，7.35(m，5H)，5.83(s，1H)，5.13(m，2H)，4.79(m，1H)，2.53(m，1H)，2.34(m，3H)，1.45(s，9H)；MS：477(M-H+)-.
Step C:(S)-4-amino-4-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-tert-butyl acetate: with the intermediate of embodiment 157 step B (400mg, 0.84mmol), 10%Pd/C (40mg) and EtOH (4ml) stirred 2 hours under hydrogen atmosphere.Reaction mixture is filtered by Celite.Solvent removed in vacuo obtains oily matter.(0% to 10%MeOH-CH by HPLC
2Cl
2) after, obtain light yellow solid (189mg, productive rate 65%).
1H-NMR(CDCl
3，400MHz)：δ10.3(s，1H)，7.59(m，2H)，7.34(1，2H)，4.81(t，1H，J＝7)，2.59(m，2H)，2.28(m，2H)，1.42(s，9H)；MS：343(M-H
+)
-.
Step D: trans-(S)-4-{[4-(benzyloxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino-4-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-tert-butyl acetate: with N-CBz-to the aminomethyl hexahydrobenzoic acid (160mg, 0.66mmol), HOBtH
2O (82mg, 0.61mmol), EDCI (117mg, 0.61mmol), (i-Pr)
2NEt (388mg, 0.52ml, 3mmol) and DMF (1ml) at room temperature stirred 15 minutes.The intermediate (189mg, DMF 0.55mmol) (1ml) solution that add embodiment 157 step C.Continue to stir 24 hours.Reaction mixture is diluted with EtOAc (40ml).With organic mixture with 10% LiCl solution washing.Use MgSO
4Drying is filtered and solvent removed in vacuo, obtains brown solid (330mg, productive rate 97%).
1H-NMR (CDCl
3, 400MHz): δ 10.1 (s, 1H), 7.60 (m, 1H), 7.35 (m, 2H), 6.97 (d, 1H, J=8), 5.09 (s, 2H), 4.90 (d, 1H, J=8), 4.81 (m, 1H), 3.06 (t, 2H, J=7), 2.37 (m, 2H), 2.27 (m, 1H), 1.87 (m2H), 1.46 (s, 9H), 1.03 (m, 2H); HRMS (ES
+): C
34H
41FN
5O
5Calculated value: 618.3092, measured value: 618.3098 (M+H+)
+.
Step e: trans-(S)-4-{[4-(benzyloxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino-4-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-butyric acid: with the intermediate of embodiment 157 step D (330mg, 0.53mmol), TFA (0.5ml) and CH
2Cl
2(0.5ml) stir 2 hours at ambient temperature.Solvent removed in vacuo obtains brown solid (300mg, productive rate 100%).
1H-NMR (DMSO-d
6, 400MHz): δ 8.24 (m, 1H), 8.04 (s, 1H), 7.97 (m, 1H), 7.88 (d, 1H, J=9), 7.81 (d, 1H, J=9), 7.35 (m, 6H), 7.25 (m, 1H), 5.01 (s, 2H), 5.0 (m, 1H), 3.63 (m, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.31 (m, 2H), 2.15 (m, 2H), 2.04 (m1H), 1.75 (m, 2H), 1.27 (m, 5H), 0.88 (m, 1H); HRMS (ES
+): C
30H
33FN
5O
5Calculated value: 562.2466, measured value: 562.2453 (M+H)
+.
Step F: trans-(4-{ (S)-1-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-the propyl group formamyl }-cyclohexyl methyl)-the carboxylamine benzyl ester: with the intermediate (325mg of embodiment 157 step e; 0.53mmol),, HOBt-H
2O (81mg, 0.6mmol), EDC (115mg, 0.6mmol), (i-Pr)
2NEt (388mg, 0.52ml, 3.0mmol) and DMF (1ml) under nitrogen atmosphere in stirring at room 15 minutes.(65mg 0.6mmol), and continues to stir 88 hours to add the 2-aminomethyl pyridine.Reaction mixture with EtOAc (20ml) dilution, is washed organic mixture three times with 10% LiCl solution (5ml).With organic layer MgSO
4Drying is filtered then.Solvent removed in vacuo.(0% to 10%MeOH-CH by HPLC
2Cl
2) after, obtain light yellow solid (40mg, productive rate 12%).
1H-NMR (MeOH-d
4, 400MHz): δ 8.49 (m, 1H), 7.81 (t, 1H, J=8), 7.73 (m, 2H), 7.35 (m, 11H), 5.08 (s, 1H), 4.50 (s, 2H), 3.37 (m, 4H), 2.98 (d, 2H, J=7), 2.40 (m, 2H), 2.25 (m, 2H), 1.86 (m, 6H), 1.47 (m, 2H), 1.05 (m, 2H); HRMS (ES
+): C
36H
39FN
7O
4Calculated value: 652.3048, measured value: 652.3063 (M+H).
Step G: trans-4-amino methyl-naphthenic acid (S)-1-[5-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-propyl group }-acid amides; three-trifluoroacetate: with the intermediate (98mg of embodiment 157 step F; 0.15mmol) and the acetic acid solution of HBr (33%, 3ml) stir 21 hours at ambient temperature.Solvent removed in vacuo obtains oily matter.By reversed-phase HPLC (contain 0.1%TFA 0% to 100%CH
3CN-H
2O) after, obtain white solid (20mg, productive rate 39%).
1H-NMR (MeOH-d
4, 400MHz): δ 8.70 (d, 1H, J=5), 8.38 (t, 1H, J=8), 8.00 (s, 1H), 7.80 (m, 5H), 5.18 (t, 1H, J=6), 4.93 (m, 5H), 4.69 (d, 1H, J=16), 4.63 (d, 1H, J=16), 2.78 (d, 2H, J=7), 2.51 (m, 2H), 2.31 (m, 4H), 1.62 (m, 2H), 1.45 (m, 4H), 1.09 (m, 2H); HRMS (ES
+): C
28H
33FN
7O
2Calculated value: 518.2680, measured value: 518.2698 (M+H).
Step H: trans-4-amino methyl-naphthenic acid (S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-propyl group }-acid amides; three-trifluoroacetate: with the intermediate of embodiment 157 step F (20mg, 0.02mmol), hydrazine hydrate (0.5ml) and n-butanols (0.5ml) in microwave device in 120 ℃ of heating 15 minutes down.Solvent removed in vacuo obtains white solid (10mg, productive rate 49%).
1H-NMR (MeOH-d
4, 400MHz): δ 8.48 (d, 1H, J=2), 7.80 (t, 1H, J=8), 7.67 (m, 2H), 7.35 (m, 4H), 5.11 (t, 1H, J=7), 4.86 (m, 8H), 4.50 (s, 2H), 3.57 (t, 1H, J=7), 2.81 (d, 2H, J=7), 2.39 (m, 2H), 2.24 (m, 4H), 1.95 (m, 4H), 1.53 (m, 2H), 0.96 (t, 2H, J=7); HRMS (ES
+): C
28H
36N
9O
2Calculated value: 530.2992, measured value: 530.2991 (M+H)
Embodiment 158
Trans-4-amino methyl-naphthenic acid (S)-1-[5-phenyl-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-ethyl }-acid amides
This compound prepares according to embodiment 157 steps A to the described method of H.
1H-NMR (MeOH-d
4, 400MHz): δ 8.30 (d, 1H, J=8), 7.58 (d, 2H, J=8), 7.43 (t, 1H, J=8), 7.25 (m, 3H), 7.13 (m, 2H), 7.05 (d, 1H, J=8), 5.40 (t, 1H, J=7), 4.76 (m, 5H), 4.38 (d, 1H, J=16), 4.30 (d, 1H, J=16), 2.94 (dd, 1H, J=15,7), (2.84 dd, 1H, J=15,7), 2.43 (d, 2H, J=7), 2.10 (m, 1H), 1.77 (m, 4H), 1.34 (m, 4H), 0.89 (m, 1H); HRMS (ES
+): calculated value: C
26H
33N
6O
2: 461.2665, measured value: 461.2657 (M+H).
Embodiment 159
N-[2-(2S)-[2-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[is trans-[4-(amino methyl) hexanaphthene formamido group] ethyl] and phenyl]-phenylacetamide, two-trifluoroacetate
Steps A: trans-4-[(S)-1-[4-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-2-(2-nitrophenyl)-ethylamino formyl radical]-the hexanaphthene methyl }-t-butyl carbamate: with L-2-nitro-N-(Boc)-phenylalanine (2.24g; 7.23mmol) successively according to embodiment 1 steps A and step B and the described method processing of embodiment 2 steps A, obtain the required product of 3.0g (productive rate 98%).MS 450(M-H)
-。
Step B: trans-(4-{ (S)-2-(2-amino-phenyl)-1-[4-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-the ethylamino formyl radical }-the hexanaphthene methyl)-t-butyl carbamate: (284mg 0.48mmol) is dissolved in during acetate (3.5ml) and 5 drips with the product of embodiment 159 steps A.(273mg 4.8mmol) joins in the flask, reactant is heated to 50 ℃ kept 5 hours with iron powder.Reactant is cooled to room temperature, dilutes, and filter by Celite with 50ml MeOH.Solvent removed in vacuo obtains 265mg (productive rate 98%) crude benzol amine.MS 559(M-H)-。
Step C: trans-4-[(S)-1-[4-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-2-(2-phenyl acetylaminohydroxyphenylarsonic acid phenyl)-ethylamino formyl radical]-cyclohexyl methyl }-the carboxylamine tertiary butyl ester: with the product (132mg of embodiment 159 step B; 0.23mmol) and toluylic acid (40mg; 0.28mmol) be dissolved in pyridine (0.7ml, 0.71mmol) and 1.5ml DMF in.With HOBt (45mg, 0.3mmol) and EDCI (60mg 0.30mmol) joins in the flask, and reactant was at room temperature stirred 12 hours.Reactant is diluted with EtOAc,, use MgSO with 1/2 saturated brine extraction (4-6 time)
4Drying filters and is evaporated to dried, obtains required product 150mg (productive rate 95%).MS 677(M-H)-。
Step e: trans-4-amino methyl-naphthenic acid [(S)-1-[4-(4-cyano group-3-fluoro-phenyl)-1H-imidazoles-2-yl]-2-(2-phenyl acetylaminohydroxyphenylarsonic acid phenyl)-ethyl]-acid amides: with the product (150mg of embodiment 159 step C, 0.22mmol) under the described condition of embodiment 2 step B, handle, and by preparation HPLC purifying (MeOH/H
2O/0.1%TFA, gradient), obtain the required product of 18mg (productive rate 14%).MS 577(M-H)-。
Step F: trans-4-amino methyl-naphthenic acid [(S)-1-[4-(3-amino-1H-indazole-6 base)-1H-imidazoles-2-yl]-2-(2-phenyl acetylaminohydroxyphenylarsonic acid phenyl)-ethyl]-acid amides, two-trifluoroacetate: with the product (18mg of embodiment 159 step D, 0.03mol) under the described condition of embodiment 120 step H, handle, obtain the embodiment 159 of 2.3mg (productive rate 11%).
1HNMR (500MHz, MeOH-d4) δ 0.93-1.11 (m, 1H) 1.35 (ddd, J=58.97,12.78,3.57Hz, 1H) 1.48-1.62 (m, 1H) 1.59-1.73 (m, 1H) 1.74-1.92 (m, 2H) 2.10-2.31 (m, 1H) 2.76 (d, J=7.15Hz, 1H) 3.75 (q, J=13.75Hz, 1H) 5.24 (t, J=8.25Hz, 1H) 7.05-7.22 (m, 2H) 7.26-7.33 (m, 1H) 7.37 (t, J=6.60Hz, 2H) 7.63 (s, 1H) 7.78 (s, 1H) 7.88 (d, J=8.80Hz, 1H) HRMSm/z calculated value C
34H
39N
8O
2(M+H)
+: 591.3196 measured value 591.3221.
Embodiment 162
(S)-4-(amino methyl)-N-[1-[4-(4-amino-7-quinazolyl)-5-chloro-1H-imidazoles-2-yl]-the 2-styroyl]-trans-cyclohexane carboxamide, two-trifluoroacetate
Steps A: (4-{ (S)-1-[4-(4-amino-quinazolines-7-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethylamino formyl radical }-cyclohexyl methyl)-the carboxylamine tertiary butyl ester: with the product (0.53g of embodiment 120 step F; 0.9mmol) and the carbonamidine acetic ester (1.5g 14.4mmol) joins among the 20ml DMAC together.Mixture was heated 8 hours in 140 ℃ under nitrogen.Add again a carbonamidine (1.5g, 14.4mmol), with mixture reheat 12 hours.With the mixture cooling, and add entry.With mixture NaHCO
3The aqueous solution is transferred pH to 7, then it is extracted with EtOAc.With the EtOAc extract salt water washing that merges, use MgSO
4Drying concentrates, and by purification by flash chromatography (120g silica gel, the CH of 0-10%MeOH
2Cl
2Solution), obtain the required product of 80g.LC/MS：604.1，606.1，(M+H)
+。
Step B:4-amino methyl-naphthenic acid (S)-1-[4-(4-amino-quinazolines-7-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl-acid amides, two-trifluoroacetate: with the product of embodiment 162 steps A (80mg, 0.13mmol) and CH
2Cl
2(5ml) and TFA (2ml) under nitrogen, stirred 0.5 hour.Remove and desolvate.Residue by the reversed-phase HPLC purifying, is obtained the required product of 75mg, is two-tfa salt.
MS：504.4，(M+H)
+.
1H-NMR(400MHz，d
4-MeOH)δ1.02-1.06(m，2H)，1.34-1.47(m，2H)，1.55(bs，1H)，1.75-1.90(m，4H)，2.22(m，1H)，2.76(d，J＝7.03Hz，2H)，3.12-3.24(m，2H)，5.20(m，1H)，7.16-7.22(m，5H)，8.00(m，1H)，8.13(s，1H)，8.34(m，1H)，8.65(s，1H).
Embodiment 175
N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-[3-(difluoro-methoxy) phenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide, two-trifluoroacetate
Steps A: 2-(diphenylmethylene-amino)-3-(3-difluoro-methoxy-phenyl)-ethyl propionate: N-(diphenylmethylene) glycine ethyl ester (500mg, 1.87mmol), Tetrabutylammonium bromide (63mg, 0.187mmol) and 3-(difluoro-methoxy) bromotoluene (0.5ml 1.87mmol) places flask.Flask is vacuumized and recharges argon gas.Anhydrous methylene chloride is joined in the flask, reactant is cooled to-78 ℃ in dry ice acetone bath.Under argon gas, slowly add 2-tertbutylimido-2-diethylins-1 in-78 ℃, 3-dimethyl perhydro--carotene 1,3,2-diaza phospha benzene (diazaphosphorine) (0.7ml, 2.44mmol).To be reflected at-78 ℃ and stir 30 minutes down, and be warming up to room temperature then and kept 16 hours.Solvent removed in vacuo.Residue is adsorbed on the silicon-dioxide in advance, and product is separated by silicon-dioxide, obtain the 700mg light yellow oil.MS424.0(M+H)
+。
Step B:2-amino-3-(3-difluoro-methoxy-phenyl) ethyl propionate: (700mg 1.65mmol) places flask, and is dissolved in THF (30ml) with the product of embodiment 175 steps A.(aqueous solution 30ml), at room temperature stirred reactant 72 hours to add 30% (w/v) citric acid.Solution is extracted with ether (50ml), and water layer adopts saturated NaHCO
3Solution is regulated pH to 6.With aqueous solution dichloromethane extraction, use the salt water washing, use MgSO
4Drying is filtered and evaporation, obtains 420mg (productive rate 97%) transparent glass shape thing.MS 260(M+H)
+。
Step C: trans-2-{[4-(t-butoxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino }-3-(3-difluoro-methoxy-phenyl)-ethyl propionate: with the product (420mg of embodiment 175 step B, 1.62mmol) adopt the described method of embodiment 2 steps A to handle, obtain 800mg (productive rate 97%) white solid.MS 497(M-H)
-。
Step D: trans-2-{[4-(t-butoxycarbonyl amino-methyl)-cyclohexyl-carbonyl]-amino }-3-(3-difluoro-methoxy-phenyl) propionic acid: with the product (800mg of embodiment 175 step C, 1.6mmol) handle according to embodiment 26 described methods, obtain 750mg white sticky solid.MS 469(M-H+)
-。
Step e: trans-4-amino methyl-naphthenic acid [1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(3-difluoro-methoxy-phenyl)-ethyl]-acid amides, two-trifluoroacetate: with the product (284mg of embodiment 175 step D, 0.6mmol) handle according to the method for embodiment 1 steps A, embodiment 2 step B and embodiment 120 step H successively, behind preparation HPLC purifying, obtain the transparent glass shape thing of 1.1mg (productive rate 9%) title compound.
1HNMR (500MHz, MeOH-d4) δ 0.98-1.20 (m, 1H) 1.33 (s, 1H) 1.49-1.65 (m, 1H) 1.74-1.91 (m, J=11.55Hz, 1H) 2.25 (s, 1H) 2.77 (d, J=7.15Hz, 1H) 3.16 (s, 1H) 3.55-3.69 (m, 1H) 5.34 (t, J=7.97Hz, 1H) 6.77 (s, 1H) 7.00 (s, 1H) 7.06 (dd, J=24.74,8.25Hz, 1H) 7.33 (t, J=7.97Hz, 1H) 7.77 (d, J=8.25Hz, 1H) 7.84 (s, and 1H) 7.98 (d, J=8.80Hz, 1H); HRMSm/z calculated value C
27H
32N
5O
3F
2(M+H)
+: 512.2473 measured value 512.2485.
Embodiment 176
(S)-3-amino-N-[1-[4-[4-(carbamimidoyl) phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-1H-indazole-5-methane amide:
Steps A: 4-[2-((S)-1-amino-2-phenyl-ethyl)-1H-imidazol-4 yl] the benzonitrile dihydrochloride: will according to preparation as described in embodiment 28 steps A (S)-1-[4-(4-cyano-phenyl)-1H-imidazoles-2-yl]-the 2-phenylethyl t-butyl carbamate (1.0g, 2.57mmol) be dissolved in the dioxane solution (10ml) of dioxane (10ml) and 4N HCl, add the 5ml dioxane again.With the gained mixture under nitrogen in stirring at room 2-2.5 hour, dilute with ether then.The gained solid is ground with another part ether, and collect and leach thing, with ether and hexane wash, and dry, obtain the light green solid (0.89g, 96%) of amine dihydrochloride.
1HNMR(500MHz，DMSO-D6)δ3.25-3.32(m，1H)3.33-3.40(m，1H)4.60(s，1H)7.11(d，J＝7.15Hz，2H)7.16-7.29(m，3H)7.78-7.89(m，3H)7.95(d，J＝8.25Hz，2H)8.65(s，2H).m/z289.2(M+H)
+.
Step B:3-cyano group-N-{ (S)-1-[4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-fluoro-benzamide: with embodiment 176 steps A compound (100mg, 0.28mmol), 3-cyano group-4-fluorobenzoic acid (46mg, 0.28mmol), triethylamine (0.085ml, 0.61mmol) and be dissolved in THF (5ml) BOP (0.18g, mixture 0.4mmol) under nitrogen in stirred overnight at room temperature.With the reaction mixture dilute with water, and with EtOAc extraction 3 times.With the saturated NaHCO of extract that merges
3With the salt water washing, use anhydrous Na then
2SO
4Drying is filtered and evaporation.(behind the hexane/EtOAc), obtain amide product (88mg, 72%) by silica gel chromatography.
1HNMR(500MHz，CDCl
3)δ3.41(dd，J＝13.75，7.15Hz，1H)3.58(dd，J＝13.47，7.97Hz，1H)5.33(q，J＝7.70Hz，1H)7.01-7.09(m，1H)7.18-7.37(m，7H)7.66(d，J＝8.25Hz，2H)7.85(d，J＝8.25Hz，2H)7.89-7.96(m，1H)7.95-8.03(m，1H)9.74(s，1H).m/z 436.1(M+H)
+.
Step C:3-amino-1H-indazole-6-formic acid (S)-1-[4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl)-acid amides: with the compound (86mg of embodiment 176 step B, 0.20mmol) be dissolved in the propyl carbinol (2ml), add excessive hydrazine (0.1ml).In sealed tube, adopt microwave radiation to heat 10 minutes down in mixture in 160 ℃.Reaction mixture is cooled to room temperature, dilute with water, and with EtOAc extracts (2 *).With extract water and the salt water washing that merges, use Na
2SO
4Drying is filtered and evaporation.With thick Aminoindazole [m/z448.1 (M+H)
+] do not carry out purifying and be used for next step.
Step D:N-3-amino-1H-indazole-5-formic acid (S)-1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl } acid amides: the compound of embodiment 176 step C is dissolved in the ethanol (8ml), this solution is stirred in ice bath, simultaneously logical 10-15 minute HCl (g) in solution.Then that the flask lid is tight, and in refrigerator, place and spend the night.Flask is warming up to room temperature, inclusion was stirred 3-4 hour, then ethanol evaporation.The gained residue is developed with ether, obtained solid, filter and collect this solid, and vacuum-drying.The imines ester that so obtains is dissolved in the ethanol (5ml) again, and adds excessive volatile salt (0.2g).Mixture was stirred 48 hours under room temperature in covering tight flask.Reaction mixture is diluted with methyl alcohol, and decant also is evaporated to dried.Residue is dissolved in the methyl alcohol again, and, behind the evaporating solvent, obtains the pale solid (85mg, 61%) of title amidine product two tfa salts by preparation C18 HPLC purifying.
1HNMR(500MHz，DMSO-D6)δ3.35-3.47(m，2H)5.51(q，J＝7.15Hz，1H)7.18(t，J＝7.15Hz，1H)7.21-7.34(m，6H)7.80(d，J＝8.80Hz，1H)7.89(d，J＝8.25Hz，2H)7.99(d，J＝8.80Hz，2H)8.03-8.15(m，1H)8.32(s，1H)8.94(s，1H)9.03(s，2H)9.31(s，2H)11.86(s，1H).m/z 465.0(M+H)
+.
Embodiment 182
N-{ (S)-1-[4-(4-carbamimidoyl-phenyl)-1-ethyl-1H-imidazoles-2-yl]-the 2-styroyl }-benzamide
Steps A: N-{ (S)-1-[4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-the 2-styroyl }-benzamide: with the compound (0.15g of embodiment 176 steps A, 0.42mmol) adopt method and the phenylformic acid coupling of embodiment 176 step B, obtain title compound (0.12g, 76%).
1HNMR(400MHz，CDCl
3)δ3.45-3.65(m，2H)5.34(d，J＝8.35Hz，1H)6.82(d，J＝7.47Hz，1H)7.19-7.35(m，7H)7.40(t，J＝7.69Hz，2H)7.45-7.56(m，1H)7.64(d，J＝7.03Hz，4H)7.86(d，J＝8.35Hz，2H).m/z393.1(M+H)
+.
Step B:N-{ (S)-1-[4-(4-cyano group-phenyl)-1-ethyl-1H-imidazoles-2-yl]-2-phenyl-ethyl)-benzamide: with the compound (60mg of embodiment 182 steps A, 0.15mmol) be dissolved among the DMF (2.5ml), add salt of wormwood (32mg, 0.23mmol), add iodoethane (0.015ml again, 0.19mmol), the gained mixture at room temperature stirred spend the night.With the reaction mixture dilute with water, and with EtOAc extracts (3 *).With extract water and the salt water washing that merges, use Na then
2SO
4Drying is filtered and evaporation.Residue is separated by silica gel chromatography, obtain product (48mg, 76%).
1HNMR(400MHz，DMSO-D6)δ1.17(t，J＝7.25Hz，3H)3.34-3.48(m，2H)3.89-4.05(m，2H)5.46(d，J＝7.03Hz，1H)7.14(d，J＝7.03Hz，1H)7.21(t，J＝7.47Hz，2H)7.31(d，J＝7.47Hz，2H)7.41(t，J＝7.25Hz，2H)7.48(d，J＝7.03Hz，1H)7.76-7.84(m，3H)7.88(s，1H)7.94(d，J＝8.79Hz，2H)9.08(d，J＝8.35Hz，1H).m/z 421.2(M+H)
+.
Step C:N-{ (S)-1-[4-(4-carbamimidoyl-phenyl)-1-ethyl-1H-imidazoles-2-yl]-the 2-styroyl }-benzamide: the compound (17mg) of embodiment 182 step B is dissolved in the ethanol (2ml), add oxammonium hydrochloride (15mg then, 5 equivalents) and triethylamine (0.03ml, 5 equivalents).In sealed tube, adopt microwave radiation to heat 15 minutes down in mixture in 125 ℃.Add equal portions oxammonium hydrochloride and triethylamine again, and under 120 ℃ microwave radiation 10 minutes once more.Evaporating solvent is dissolved in residue in the acetate (2ml) again, handles with diacetyl oxide (0.015ml, 3 equivalents).Solution was at room temperature stirred 15 minutes, add zinc powder (25mg, 10 equivalents) and a small amount of MeOH then.Then mixture is at room temperature stirred and spend the night.Reactant is filtered by a slice Celite, solid is washed with MeOH.With the filtrate evaporation, residue obtains title compound two-tfa salt by preparation C18HPLC purifying, is white solid (16mg, 60%).
1HNMR(400MHz，DMSO-D6)δ1.20(t，J＝7.03 Hz，3H)3.33-3.52(m，2H)3.93-4.10(m，2H)5.49(d，J＝7.47Hz，1H)7.16(t，J＝7.47Hz，1H)7.23(t，J＝7.25Hz，2H)7.32(d，J＝7.03Hz，2H)7.43(t，J＝7.47Hz，2H)7.51(t，J＝7.47Hz，1H) 7.84(dd，J＝7.69，5.49Hz，4H)7.95(s，1H)8.00(d，J＝8.35Hz，2H)8.92(s，2H)9.12(d，J＝7.91Hz，1H)9.25(s，2H).m/z450.2(M+H)
+.
Embodiment 183
N
1-(S)-1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-terephthalamide
Steps A: ((S)-1-{4-[4-(5-methyl-[1,2,4] diazole-3-yl)-phenyl]-1H-imidazoles-2-yl-2-phenyl-ethyl)-t-butyl carbamate: will as preparation as described in embodiment 28 steps A (S)-1-[4-(4-cyano-phenyl)-1H-imidazoles-2-yl]-the 2-styroyl t-butyl carbamate (1.00 equivalents; 2.57 mmole; 1.00g) be dissolved among the 15ml EtOH, add oxammonium hydrochloride (12.87 mmoles then; 894.42mg) and triethylamine (12.87 mmoles; 1.79ml).With gained solution under the nitrogen in 80 ℃ of oil baths reflux spend the night.Reactant is cooled to room temperature, and EtOH is removed in evaporation.Residue is suspended in EtOAc/EtOH (about 10: the 1) mixture, removes by filter inoganic solids then.With filtrate reconcentration yellowly foam thing.Residue is dissolved among the 10mlHOAc again, and uses diacetyl oxide (4.23mmoles when under nitrogen, stirring; 400 μ l) handle.Solution was at room temperature stirred 20 minutes, and heating 2 hours in 80 ℃ of oil baths then is cooled to stir after the room temperature and spends the night.Remove most of HOAc by Rotary Evaporators,, and add saturated NaHCO carefully then with the residue dilute with water
3Be neutralized to pH and be about 8.Use CH
2Cl
2Extraction 3 *.With the extract salt water washing that merges, use MgSO then
4Red foam thing is filtered and be evaporated to drying.Residue by silica gel purification, is obtained pink brown foam product (590mg; 51.4%).
1HNMR(500MHz，CDCl
3)δ1.41(s，9H)2.65(s，3H)3.28-3.44(m，2H)4.88(d，J＝7.70Hz，1H)5.23(s，1H)7.13-7.36(m，5H)7.42-7.55(m，1H)7.88(d，J＝8.25Hz，2H)8.06(d，J＝8.25Hz，2H)9.67(s，1H).m/z446.1(M+H)
+.
Step B:(S)-1-{4-[4-(5-methyl-[1,2,4] diazole-3-yl)-phenyl]-1H-imidazoles-2-yl }-2-phenyl-ethamine dihydrochloride: the method for employing embodiment 176 steps A is removed the BOC group on the embodiment 183 steps A compounds, obtain the amine hydrochlorate brown solid, productive rate 46%.
1HNMR(500MHz，CDCl
3)δ2.67(s，3H)2.87(dd，13.75，9.35Hz，1H)3.44 dd，J＝13.75，4.40Hz，1H)4.44(dd，J＝9.35，4.40Hz，1H)7.20-7.31(m，5H)7.34(t，J＝7.42Hz，3H)7.85(s，1H)8.08(d，J＝8.80Hz，2H).m/z 346.0(M+H)
+，330.0(M+H-NH3)
+.
Step C:4-cyano group-2-fluoro-N-((S)-1-{4-[4-(5-methyl-[1,2,4] diazole-3-yl)-phenyl]-1H-imidazoles-2-yl }-2-phenyl-ethyl)-benzamide: the compound of embodiment 183 step B is adopted method and the 4-cyano group-2-fluorobenzoic acid coupling of embodiment 176 step B, obtain acid amides, productive rate 90%.
1HNMR(500MHz，CDCl
3)δppm 2.64(s，3H)3.43(dd，J＝13.75，7.15Hz，1H)3.58(dd，J＝13.75，7.70Hz，1H)5.38(q，J＝7.15Hz，1H)7.20-7.33(m，7H)7.42(d，J＝9.90Hz，1H)7.54(d，J＝8.25Hz，2H)7.86(s，1H)8.05(d，J＝8.25Hz，2H)8.14(t，J＝7.70Hz，1H)9.43(s，1H).m/z 493.1(M+H)
+.
Step D:2-fluoro-N
1-((S)-1-{4-[4-(5-methyl-[1,2,4] diazole-3-yl)-phenyl]-1H-imidazoles-2-yl }-2-phenyl-ethyl)-terephthalamide: with the compound (75mg of embodiment 183 step C, 0.15mmol), salt of wormwood (66mg, 3 equivalents) and the mixture of 30% hydrogen peroxide (0.055ml, 11 equivalents) solution that is dissolved in DMSO (2.5ml) in nitrogen in stirred overnight at room temperature.With reaction mixture water and EtOAc dilution, and be separated.Water is extracted (2 *) again with EtOAc.With organic phase water and the salt water washing that merges, use anhydrous Na
2SO
4Drying is filtered and distillation.The gained crude amide does not carry out purifying and directly uses.m/z 511.0(M+H)
+。
Step e: N
1-(S)-1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-terephthalamide: with compound (68mg) and the 10%Pd/C (35mg of embodiment 183 step D, moistening, Degussa) be suspended in methyl alcohol and triethylamine (4.5ml, 8: 1) mixture in, and at 1 normal atmosphere H
2Following stirring is spent the night.Remove by filter catalyzer by Celite, and wash with MeOH.Evaporated filtrate by preparation C18 HPLC purifying, obtains two tfa salts of title compound with residue, is white solid (48mg, 53%).
1HNMR(500MHz，DMSO-D6)δppm3.23-3.31(m，1H)3.41(dd，J＝13.75，6.60Hz，1H)5.43(q，J＝7.70Hz，1H)7.13-7.23(m，1H)7.23-7.31(m，5H)7.59-7.66(m，2H)7.67-7.77(m，2H)7.87(t，J＝7.70Hz，2H)7.99(d，J＝8.25Hz，3H)8.13(s，1H)8.95(s，2H)8.98-9.06(m，1H)9.27(s，2H).m/z471.0(M+H)
+.
Embodiment 188
N1-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-2-fluorine terephthalamide, two-trifluoroacetate
Embodiment 188 similarly prepares by the method for Application Example 120 suitably, and the Boc-that wherein uses 4-formamyl-2-fluorobenzoic acid alternate embodiment 120 step F is to the aminomethyl hexahydrobenzoic acid.
1H-MR(500MHz，DMSO-d6)δ3.16(dd，J＝13.75，8.80Hz，1H)，3.30(dd，J＝13.75，6.05Hz，1H)5.31-5.43(m，1H)，7.16-7.23(m，1H)，7.25-7.31(m，5H)，7.38(d，J＝8.80Hz，1H)，7.55(t，J＝7.42Hz，1H)，7.62(d，J＝5.50Hz，2H)，7.65-7.76(m，2H)，7.86(d，J＝8.80Hz，1H)，8.12(s，1H)，8.97(d，J＝8.25Hz，2H)，12.05(s，1H)，12.81(s，1H).
Embodiment 189
N1-((S)-1-(4-(4-amido quinazoline-7-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-2-fluorine terephthalamide, two-trifluoroacetate
Embodiment 189 is by the method preparation of Application Example 162 suitably, but removes embodiment 162 step G, and with the Boc-in 4-formamyl-2-fluorobenzoic acid alternate embodiment 120 step F methods to the aminomethyl hexahydrobenzoic acid.
MS：530.01，(M+H)
+.
1HNMR(500MHz，DMSO-d
6)δ3.14-3.24(m，1H)，3.25-3.35(m，1H，)5.31-5.44(m，1H)，7.15-7.24(m，1H)，7.24-7.33(m，5H)，7.54(t，J＝7.70Hz，1H)，7.64(s，1H)，7.66-7.76(m，3H)，7.99(d，J＝8.80Hz，1H)，8.13(s，2H)，8.46(d，J＝8.80Hz，1H)，8.80(s，1H)，9.07(d，J＝6.60Hz，1H)，13.20(s，1H).
Embodiment 190
1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-5,6,7,8-tetrahydroisoquinoline-6-methane amide, two-trifluoroacetate
The method of embodiment 190 by Application Example 147 step H suitably adopts and prepares like the diastereomer category-B of embodiment 147 step G.
1H-NMR(400MHz，d
4-MeOH)δ1.75(dd，J＝13.40，10.33Hz，1H)，2.01(m，1H)，2.45(t，J＝6.37Hz，2H)，2.73(m，1H)，2.90(m，2H)，3.20(m，2H)，5.28(m，1H)，6.69(d，J＝6.59Hz，1H)，7.25(m，5H)，7.51(d，J＝8.79Hz，1H)，7.59(d，J＝6.59Hz，1H)，7.71(s，1H)，7.95(d，J＝8.79Hz，1H).
Embodiment 191
1-amino-N-((S)-1-(4-(4-amido quinazoline-7-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-5,6,7,8-tetrahydroisoquinoline-6-methane amide, two-trifluoroacetate
Embodiment 191 is by the product preparation of the described method employing of Application Example 162 steps A embodiment 147 step F suitably.
LC/MS:539.2 (M+1)
+.
1HNMR (400 MHz, d
4-MeOH) δ 1.77 (m, 1H), 2.00 (d, J=3.95Hz, 1H) 2.45 (m, 2H), 2.74 (m, 2H) 2.91 (m, 1H), 3.21 (m, 2H), 5.26 (m, 1H), 6.67 (t, J=7.25Hz, 1H), 7.23 (m, 5H), 7.59 (t, J=6.59Hz, 1H), 8.02 (m, 1H), 8.16 (d, J=4.39Hz, 1H), 8.36 (dd, J=8.79 and 1.76Hz, 1H), 8.65 (s, 1H).
Embodiment 192
1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-3-methylisoquinolinium-6-methane amide, two-trifluoroacetate
Steps A: (Z)-3-(3-bromophenyl)-2-methacrylic acid: with 3-bromobenzaldehyde (benziladelhyde) (2.6g; 0.014mol) and (ethoxycarbonyl ethylidene) triphenylphosphine alkane (phosphorane) (5.6g 0.015mol) joins in the 30ml toluene together.With mixture under nitrogen in stirring at room 24 hours.Remove and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and by purification by flash chromatography (silica gel, hexane/EtOAc), obtain the required ester of 3.7g.MS：271.2/273.2(M+1)
+。Then this ester is dissolved in 30ml THF and the 10ml water.Adding LiOH (1.32g, 0.031mol).With mixture under nitrogen in stirring at room 72 hours.Remove THF.With gained mixture dilute with water, and with EtOAc extraction (discarding).With aqueous mixture HCl acidifying, and extract with EtOAc.With the salt water washing of EtOAc extract, use MgSO
4Drying, and concentrate, white solid (3.2g) obtained.
1HNMR(400MHz，CDCl
3)δ2.12(s，3H)，7.29(m，2H)，7.47(d，J＝7.91Hz，1H)，7.56(s，1H)，7.73(s，1H).
Step B:6-bromo-3-methylisoquinolinium-1 (2H)-ketone: with the product of embodiment 192 steps A (2.76g, 11.45mmol) and triethylamine (3.60ml 22.90mmol) joins in the 18ml acetone together.Mixture is cooled to 0 ℃, drip then Vinyl chloroformate (1.85ml, 17.17mmol).Reaction mixture was stirred 1 hour in 0-5 ℃ under nitrogen.To wherein adding sodiumazide (1.34g, 20.60mmol) slurries in 2ml water.With reaction mixture under nitrogen in stirred overnight at room temperature.Remove and desolvate.Residue is dissolved among the EtOAc, and water and salt water washing.It is used MgSO
4Drying concentrates, and vacuum-drying, obtains the required acyl azide of 3.4g80% purity.With Tributylamine (4.40ml, 18.49mmol) and the solution of ditane (15ml) be heated to 190 ℃.Wherein drip acyl azide (material of 3.4g 80% purity, ditane 10.3mmol) (12ml) solution through 12 fens clockwise.Mixture was stirred 2 hours in 220 ℃ under nitrogen.It is cooled to room temperature.Make crude product precipitation and filtration.It by purification by flash chromatography (120g silica gel, the dichloromethane solution of 0-10%MeOH), is obtained the required product of 0.43g.
MS：238.2，240.1(M+1)
+.
1HNMR(400MHz，DMSO-d
6)δ2.20(s，3H)，6.30(s，1H)，7.52(d，J＝8.79Hz，1H)，7.80(s，1H)，7.81(d，J＝8.35Hz，1H).
Step C:6-bromo-3-methylisoquinolinium-1-amine: (2.5ml) cools off in ice bath with phosphorus oxychloride, be added drop-wise to then embodiment 192 step B product (120mg, 0.5mmol) in.Mixture was heated 1.5 hours in 110 ℃ under nitrogen.With the reactant cooling, and water and MeOH cancellation.Add more water then.Filter out solid, and, obtain the 115mg solid with NaOH and the water washing of 1N.With the NH of gained solid (51mg) with 1ml 13-15%
3Ethylene glycol solution merge.In sealed tube, adopt microwave radiation to heat 20 minutes down in mixture at 170 ℃.To react cooling, and add entry.Cross filter solid, and by ISCO purification by flash chromatography (silica gel, CH
2Cl
2/ MeOH), obtain the required product of 12mg.
MS：237.1/239.1(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ2.39(s，3H)，6.76(s，1H)，7.53(m，1H)，7.81(d，J＝1.76Hz，1H)，7.98(d，J＝8.79Hz，1H).
Step D:1-amino-3-methylisoquinolinium-6-nitrile: with the product of embodiment 192 step C (22mg, 0.093mmol), Zn (CN)
2(12mg) and Pd (PPh
3)
4(8mg) join among the 2mlDMF.Mixture was heated 10 minutes down at 180 ℃ by microwave radiation in sealed tube.Mixture is filtered, and wash with EtOAc.Concentrated filtrate, and by purification by flash chromatography (silicon-dioxide, CH
2Cl
2/ MeOH), obtain the required product of 12mg.LC/MS：184.18(M+1)
+。
Step e: 1-amino-3-methylisoquinolinium-6-formic acid: the NaOH aqueous solution that in the product (35mg) of embodiment 192 step D, adds 4ml MeOH and 4ml 15%.Mixture was heated 2 hours down at 70-85 ℃.It is concentrated, and be acidified to pH=5 with HCl and TFA.Cross filter solid, and, obtain the 18mg tfa salt by anti-phase preparation-HPLC purifying.LC/MS：203.03(M+1)
+。
Step F: 1-amino-N-((S)-1-(4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl)-2-styroyl)-3-methylisoquinolinium-6-methane amide, two-trifluoroacetate: the method that adopts embodiment 120 step F and step H respectively changes into Aminoindazole then with the product of embodiment 192 step e and the product coupling of embodiment 120 step e.
MS：537.0(M+1)
+.
1HNMR(400MHz，d
4-MeOH)δ2.52(s，3H)，3.41(m，2H)，5.46(t，J＝7.91Hz，1H)，7.05(s，1H)，7.23(m，5H)，7.50(d，J＝8.79Hz，1H)7.71(s，1H)，7.98(m，2H)，8.19(s，1H)，8.43(d，J＝8.79Hz，1H).
Embodiment 200
4-amino methyl-naphthenic acid (S)-2-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-1-benzyl-ethyl]-acid amides, two-trifluoroacetate
This compound is according to embodiment 120 described method preparations.
1HNMR (500MHz, solvent) δ 0.90-1.01 (m, 2H), 1.18-1.24 (m, 2H), 1.42-1.50 (m, 1H), 1.50-1.62 (m, 2H), 1.68-1.79 (m, 2H), and 2.00-2.09 (m, 1H), 2.71 (d, J=7.15Hz, 2H), 2.94 (dd, J=13.00,8.80Hz, 2H), 3.02 (dd, J=13.00,6.04Hz, 2H), 3.13 (dd, J=15.12,10.17Hz, 1H), and 4.57-4.65 (m, 1H), 7.18-7.23 (m, 1H), and 7.26-7.30 (m, 4H), 7.47 (d, J=9.90Hz, 1H), 7.74 (s, 1H) 7.89 (s, 1H), 7.97 (d, J=8.25Hz, 1H) .HRMS (ES
+): C
27H
33N
7The calculated value of O: 471.2747, measured value: 472.2839 (M+H).
Following table 1-6 has gathered the preparation embodiment of compound among the present invention.
Table 1
Table 2
Table 3
Table 4
| The embodiment numbering | R 3a | Mass spectrum (m/z) (M+H) + |
| 42 | CO 2Et | 435.3 |
| 43 | CO 2H | 421.2 |
| 44 | CONH 2 | 420.2 |
| 45 | -CH 2CO 2Et | 463.4 |
| 46 | -CH 2CO 2H | 435.4 |
| 47 | -CH 2CONH 2 | 434.3 |
Table 5
Table 6
| The embodiment numbering | R 10 | Mass spectrum (m/z) (M+H) + |
| 70 | Bn | 493.20 |
Adopt the combination of technician's currently known methods in said synthesis route and experimental technique and organic synthesis field, can be prepared as follows other The compounds of this invention shown in the table 6.
Table 7
Practicality
The compounds of this invention is the inhibitor of factor XI, plasma thromboplastin antecedent a, is suitably used as the anti-coagulants for the treatment of or prevention mammal thrombus embolism class diseases (being factor XI, plasma thromboplastin antecedent a relevant disease). Usually, thrombotic disease is a kind of circulatory diseases that is caused by blood clot (namely relates to fibrinously form, the disease of platelet activation and/or platelet aggregation). Term used herein " thrombotic disease " comprises artery cardiovascular thromboembolic disease, vein is cardiovascular or cerebrovascular thrombotic disease and heart chamber in thrombotic disease. Term used herein " thrombotic disease " also comprises and is selected from but is not limited to following concrete illness: the thrombosis that the outbreak of property ischaemic, apoplexy, atherosclerotic, periphery obstructive arterial disease, phlebothrombosis formation, DVT formation, thrombophlebitis, arterial embolism disease, coronary artery thrombosis formation, cerebral artery thrombosis formation, cerebral embolism disease, renal embolism disease, pulmonary embolism disease and underlying cause cause is crossed in UA or other acute coronary syndromes, atrial fibrillation, first or Recurrent myocardial infarction, ischemic sudden death: (a) artificial valve or other implants, (b) inlying catheter, (c) Si Tante support, (d) cardiopulmonary bypass, (e) haemodialysis and (f) other make blood contact artificial surface to impel thrombotic operation. Should be noted that thrombosis comprises blocks disease (for example after using bypass) and blocks disease (for example, during percutaneous transluminal coronary angioplasty or afterwards) again. Thrombotic disease may come from including, but not limited to following illness: atherosclerotic, operation or operation complication, long-term bed, artery fibrillation, congenital thrombophilia, cancer, diabetes, medicine or hormonal action and complications of pregnancy. The anti-coagulants effect of the compounds of this invention is considered to because to the inhibitory action of the serine protease that participates in coagulation cascade and/or contact activation system, more particularly, be inhibitory action to following clotting factor: factor XI, plasma thromboplastin antecedent a, factor VIIa, factors IX a, factor Xa, plasma kallikrein or fibrin ferment.
The compounds of this invention also is the inhibitor of plasma kallikrein, is suitably used as the anti-inflammatory agent for the treatment of or the prevention disease relevant with the activation of contact activation system (being the plasma kallikrein associated conditions). Usually, a kind of activation by the blood on the artificial surface of contact activation system illness causes, comprises that artificial valve or other implants, inlying catheter, Si Tante support, cardiopulmonary bypass, haemodialysis, microorganism (for example bacterium, virus) or other make blood contact artificial surface promote operation, the blood clotting of contact activation effect determine (disease that namely relates to fibrin formation, platelet activation and/or platelet aggregation). It also comprises the defective of systemic inflammatory response syndrome, pyaemia, ARDS, hereditary angioedema or other heredity or posteriority contact activation effect component or its inhibitor (plasma kallikrein, Factor XIIa, high molecular weight kininogen, Cl-esterase inhibitor). It also can comprise the inflammation of acute and chronic joint, blood vessel or other mammalian organs.
The compounds of this invention can adopt respectively the associated serine protease of purifying and suitable synthetic substrate to measure as the effect of the inhibitor of plasma thromboplastin antecedent a, VIIa, IXa, Xa, plasma kallikrein or fibrin ferment. Under the condition that the compounds of this invention does not exist and exists, all carry out associated serine protease to the mensuration of colour developing or fluorogenic substrate hydrolysis rate. The hydrolysis of substrate causes the release of pNA (paranitroanilinum), its increase by absorptance under the spectrophotometry 405nm is monitored, perhaps cause the release of AMC (aminomethyl cumarin), its increase by the 460nm place luminance that fluorescence spectrophotometry 380nm excites is monitored. The minimizing that absorptance or fluorescence change in the presence of inhibitor shows the enzymeinhibition effect. This method is well known by persons skilled in the art. The result of this test is by suppressing constant KiExpression.
The 50mM that is determined at of factor XI, plasma thromboplastin antecedent a comprises 145mM NaCl, 5mM KCl and 0.1% PEG, 8000 (polyethylene glycol; JT Baker or Fisher Scientific) the HEPES buffer solution under 7.4 pH, carry out. Measuring and adopting ultimate density is the Purification of Human factor XI, plasma thromboplastin antecedent a (Haematologic Technologies) of 75-200pM and the synthetic substrate S-2366 (pyroGlu-Pro-Arg-pNA of 0.0002-0.00025M concentration; Chromogenix) carry out. Usually, for example the particular compound described in the above embodiment is identified has an activity for preferred the compounds of this invention, and demonstration is equal to or less than the K of 15 μ M in factor XI, plasma thromboplastin antecedent a testi, therefore confirmed the serviceability of the compounds of this invention as effective especially plasma thromboplastin antecedent a inhibitor. Preferred compound has and is equal to or less than 5 μ M, preferably is equal to or less than 1 μ M, more preferably is equal to or less than the K of 0.5 μ Mi。
Being determined in the HEPES buffer solution that 0.005M calcium chloride, 0.15M sodium chloride, 0.05M contains 0.5%PEG 8000 of factor VIIa carried out under 7.4 pH. Measuring and adopting final experimental concentration is Purification of Human factor VIIa (Haematologic Technologies) or recombined human factor VIIa (Novo Nordisk), the recombinant soluble tissue factor of 18-35nM concentration and the synthetic substrate H-D-Ile-Pro-Arg-pNA (S-2288 that concentration is 0.001M of 2-5nM; Chromogenix or BMPM-2; AnaSpec) carry out. Usually, in the factor VIIa test, be equal to or less than the K of 15 μ M when the test compounds demonstrationiThe time, it is considered to have activity.
Being determined among 0.005M calcium chloride, 0.1M sodium chloride, 0.05M TRIS alkali and the 0.5%PEG 8000 of factors IX a carried out under 7.4 pH. Measuring and adopting final experimental concentration is the Purification of Human factors IX a (Haematologic Technologies) of 20-100nM and synthetic substrate PCIXA2100-B (CenterChem) or the Pefafluor IXa3688 (H-D-Leu-Ph ' Gly-Arg-AMC that concentration is 0.0004-0.0005 M; CenterChem) carry out. Usually, in factors IX a test, be equal to or less than the K of 15 μ M when the test compounds demonstrationiThe time, it is considered to have activity.
Being determined in the 0.1M sodium phosphate buffer that contains 0.2M sodium chloride and 0.5%PEG 8000 of factor Xa carried out under 7.4 pH. Measuring and adopting final experimental concentration is the Purification of Human factor Xa (Haematologic Technologies) of 150-1000 pM and the synthetic substrate S-2222 (Bz-Ile-Glu (γ-OMe, 50%)-Gly-Arg-pNA that concentration is 0.0002-0.0003M; Chromogenix) carry out. Usually, in factor Xa test, be equal to or less than the K of 15 μ M when the test compounds demonstrationiThe time, it is considered to have activity.
Being determined in the 0.1M sodium phosphate buffer that contains 0.2M sodium chloride and 0.5%PEG 8000 of plasma kallikrein carried out under 7.4 pH. Measuring and adopting final experimental concentration is that 200pM Purification of Human kallikrein (Enzyme Research Laboratories) and concentration are the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA of 0.00008-0.0004M; Chromogenix) carry out. Calculating KiKmValue is 0.00005-0.00007M. Usually, in the plasma kallikrein test, be equal to or less than the K of 15 μ M when the test compounds demonstrationiThe time, it is considered to have activity.
Being determined in the 0.1M sodium phosphate buffer that contains 0.2M sodium chloride and 0.5%PEG 8000 of fibrin ferment carried out under 7.4 pH. Measure adopting final experimental concentration is the Purification of Human α fibrin ferment (Haematologic Technologies or Enzyme Research Laboratories) of 200-250pM) and concentration be synthetic substrate S-2366 (the pyroGlu-Pro-Arg-pNA of 0.0002M; Chromogenix) carry out. Usually, in crosby test, be equal to or less than the K of 15 μ M when the test compounds demonstrationiThe time, it is considered to have activity.
Usually, preferred the compounds of this invention has shown the K that is equal to or less than 15 μ M at least one above-mentioned testiValue, therefore confirm the serviceability of the compounds of this invention as the establishment agent of coagulation cascade and/or contact activation system, and can be used as the anti-coagulants of thrombotic disease in prevention or the treatment mammal and/or the anti-inflammatory agent of conduct prevention or treatment mammal inflammatory disease.
The Michaelis constant K of every kind of protease hydrolytic substratemAdopt the method for Lineweaver and Burk under 25 ℃, to carry out. KiValue is measured by the albumen enzyme-to-substrate is reacted in the presence of inhibitor. Make reaction carry out 20-180 minute (depending on protease) assaying reaction speed (speed of absorptance or change in fluorescence is to the time). Adopt following relational expression calculating KiValue: for the competitive inhibitor of a binding site, (vo-v
s)v
s＝I/K
i(1+S/K
m); Perhaps
v
s/v
o＝A+((B-A)/1+((IC
50/(I)
n))) and
For competitive inhibitor, Ki＝IC
50/(1+S/K
m)
Wherein:
v
oSpeed for the reference substance under the unrestraint agent existence;
v
sBe the speed in the presence of inhibitor.
I is the concentration of inhibitor.
Minimum active (usually be locked as zero) of A for keeping;
The maximum activity (usually be locked as 1.0) of B for keeping;
N is hill coefficient, is the number of potential inhibitor binding site and the tolerance of cooperative effect;
IC
50Inhibitor concentration during for generation 50% inhibition under experimental condition;
K
iBe enzyme: the dissociation constant of inhibitor complexes;
S is the concentration of substrate; And
K
mMichaelis constant for substrate.
The compounds of this invention can adopt relevant thrombus in vivo formation model to comprise that electricity is induced rabbit arteriovenous shut thrombotic model in arteria carotis thrombotic model and the body in the body as the effect of the inhibitor of plasma thromboplastin antecedent a, VIIa, IXa, Xa or fibrin ferment.
Electricity is induced the arteria carotis thrombotic model in the body:
The compounds of this invention antithrombotic formation effect can be induced in rabbit arteria carotis thrombosis (ECAT) model at electricity and be confirmed. In this model, rabbit is anaesthetized with the mixture of ketamine (50mg/kg i.m.) and xylazine (10mg/kg i.m.). Isolate femoral vein and femoral artery and insert conduit. And also isolate arteria carotis, its blood flow can be measured by the calibrated fluxes probe that is connected in flowmeter. Stainless steel double polar hook electrode is placed arteria carotis, and make it be positioned at afterbody as the device that applies electro photoluminescence with respect to the flow probe. In order to protect surrounding tissue, under electrode, place a slice Parafilm sealed membrane.
After thrombosis was induced in electro photoluminescence, based on the ability of keeping blood flow in the arteria carotis, it was effective that test compounds is considered to as anti-coagulants. Through femoral vein continuous vein input test compound or carrier, 1 hour begins input before carrying out electro photoluminescence, and lasts till that test finishes. Adopt constant current unit and direct current exciter, apply the Direct Current of 3 minutes 4mA for the outer arteries surface, induce thrombosis. Monitoring carotid artery flow and minute to block time of (blood flow is down to zero after inducing thrombosis) for unit record. Calculating observation to hemodynamic change as with respect to the percentage of inducing blood flow before the thrombosis, compare with the situation that does not give compound, provide the tolerance of test compounds effect. With this information evaluation ED50Be worth-make blood flow and be increased to 50% dosage of contrast (induce thrombosis before blood flow), and obtained by nonlinear least square regression.
Rabbit arteriovenous shut thrombotic model in the body:
The compounds of this invention antithrombotic forms effect and can confirm in rabbit arteriovenous (AV) bypass thrombotic model. The rabbit of heavy 2-3kg is anaesthetized with the mixture of xylazine (10mg/kg i.m.) and ketamine (50mg/kg i.m.). The AV shunting device that to concentrate salt solution on is connected between femoral artery and the femoral venous catheter. The AV shunting device is made of the long polyethylene pipe of the 6cm that contains a rhizoid line. Blood will flow to femoral vein from femoral artery through the AV-bypass. Blood flow contact silk thread will be induced the formation of remarkable thrombus. After 40 minutes, pull down bypass, the silk thread that covers thrombus is weighed. Before opening the AV bypass, give testing drug or carrier (i.v., i.p., s.c. or oral). Measure the thrombotic inhibition percentage of every test group. Adopt linear regression to estimate ID50Value (producing the dosage that 50% thrombosis suppresses).
The antiphlogistic effects of these compounds can ooze out in the test at the Evans blue dyestuff that adopts C1-esterase inhibitor deficient mice and confirm. In this model, give compound of the present invention to mouse, again by the tail vein injection Evans blue, by the seepage discharge of blue dyes in the spectrophotometry tissue extract.
The compounds of this invention alleviates or prevents the ability of SIRS, for example in the cardiovascular method of extracorporal circulatory system, observe, can in the ECP system, test, perhaps for comprising that than large mammals dog and baboon are by the test of cardiopulmonary bypass surgery method. The index of estimating the compounds of this invention beneficial effect comprises the minimizing of the minimizing of for example blood platelet loss, blood platelet/leucocyte compound, the reduction of blood plasma neutrophil elastin laminin enzyme level, minimizing and the activation of contact activation albumen (plasma kallikrein, factor XI, plasma thromboplastin antecedent I, factor XI, plasma thromboplastin antecedent, high molecular weight kininogen, C1-esterase inhibitor) and/or the minimizing of consumption of complement factor activation.
The compounds of this invention alleviates or prevents the serviceability of the pyaemia incidence of disease and/or the death rate can be by estimating to mammalian hosts bacterial injection or virus or its extract and the compounds of this invention. The typical index of this effect comprises LD50The variation of keeping with blood pressure.
The compounds of this invention can also be used as the inhibitor of other serine protease, particularly human thrombin, human plasma kallikrein and fibrolan. Because their inhibitory action shows that these compounds can be used for prevention or treatment physiological reaction, comprise blood clotting, fibrinolysis, blood pressure adjusting and inflammation and by above-mentioned enzymatic wound healing. Specifically, the compounds of this invention can be used as treatment is improved caused disease such as miocardial infarction by the thrombin activity of above-mentioned serine protease medicine, perhaps being that diagnosis or other commercial objects are prepared by blood in the process of blood plasma, be used as anti-coagulants reagent.
The compounds of this invention can be separately or with one or more other therapeutic combination administrations. These comprise other anti-freezings or Coagulative inhibitors medicine, antiplatelet or PID thing, anti-inflammatory agent, thrombin inhibitor or thrombolysis or fibrinolytic drug thing.
Compound gives mammal to treat effective amount. " treatment effectively amount " refers to: when separately or with combination with other therapeutic agents during to the mammal administration, to the amount of the effective the compounds of this invention for the treatment of of the treatment (namely prevent, suppress or improve) of host's thromboembolia type and/or inflammatory disease illness or disease progression.
Compound of the present invention preferably gives mammal to treat effective amount separately. Yet the compounds of this invention can also give mammal to treat effective amount with following defined other therapeutic combination. When combination medicine-feeding, the combinatorial optimization of compound but must not be synergistic combination. Such as for example Chou and Talalay, Adv.Enzyme Regul.1984, described in the 22:27-55, when the compound effect (being desired target target inhibitory action) of combination medicine-feeding is compared to the individually dosed compound of single dose and adds with better effects if, namely produced synergy here. Usually, synergy can show under the inferior good concentration of compound the most significantly. Synergy can be based on combination partner and compare the cytotoxicity of reduction, anti-freezing effect or other beneficial effects of increase with independent component.
" combination medicine-feeding " or " combined therapy " refers to that the compounds of this invention and one or more other therapeutic agents give the mammal for the treatment of simultaneously. When combination medicine-feeding, the at one time administration of each component, perhaps at different time points with any order successively administration. Like this, each component can be distinguished administration, but will be within the time that enough approaches, in order to produce required curative effect.
Can with the compound of the compounds of this invention combination medicine-feeding including, but not limited to anti-coagulants, antithrombotic drug, antiplatelet drug, fibrinolytic agent, lipid lowerers, antihypertensive and anti-ischemia medicine.
Can comprise with other anticoagulants (or Coagulative inhibitors agent) of the compounds of this invention composite reagent warfarin, heparin (obtainable low molecular weight heparin, for example LOVENOX on unfractionated heparin or any marketTM), Aprotinin, synthetic pentose class, direct acting thrombin inhibitor comprise hirudin and argatroban, and other factor VIIas known in the art, VIIIa, IXa, Xa, XIa, fibrin ferment, TAFI and fibrinogenic inhibitor.
Term antiplatelet drug (or platelet suppressant drug) used herein refers to for example suppress by suppressing platelet aggregation, adhesion or granule secretion the medicine of platelet function. These medicines such as aspirin, brufen, naproxen, sulindac, Indomethacin, mefenamic acid salt, former times health in the wrong, Diclofenac, sulfinpyrazone and piroxicam, comprise its pharmaceutically acceptable salt or prodrug including, but not limited to various known non-steroid anti-inflammatory drugs (NSAIDS). In NSAIDS, preferred aspirin (acetylsalicylic acid or ASA) and piroxicam. Other suitable platelet suppressant drugs comprise IIb/IIIa antagonist (for example tirofiban, Eptifibatide and Abciximab), thromboxane-A2-receptor antagonist (ifetroban), thromboxane-A2-synthetase inhibitors, phosphodiesterase-III (PDE-III) inhibitor (for example Dipyridamole, ground, western Lip river azoles) and PDEV inhibitor (such as silaenafil) and pharmaceutically acceptable salt or prodrug.
Term antiplatelet drug (platelet suppressant drug) meaning used herein also comprises ADP (adenosine diphosphate) receptor antagonist, preferred purinergic receptor P2Y
1And P2Y
12Antagonist, more preferably P2Y
12Antagonist. Preferred P2Y
12Receptor antagonist comprises Ticlopidine and clopidogrel, comprises its pharmaceutically acceptable salt or prodrug. Clopidogrel is preferred medicine. Ticlopidine and clopidogrel also are preferred compounds because known its be gentle to intestines and stomach in use. The compounds of this invention can also be taken with Aprotinin.
Term thrombin inhibitor (antithrombotic drug) used herein refers to the serine proteinases thrombin inhibitor. Pass through Trombin inhibiting, the process of various fibrin ferments-mediation, for example the platelet activation of fibrin ferment-mediation (that is to say the granule secretion of platelet aggregation for example and/or plasminogen activator inhibitor-1 and/or thrombocytin), activated endothelial cell, inflammatory reaction and/or fibrinous formation will be interfered. Many thrombin inhibitors are well known by persons skilled in the art, and these inhibitor are considered and are used in combination with the compounds of this invention. These inhibitor comprise but are not limited to boric acid arginine derivative, boric acid polypeptide, heparin, hirudin and argatroban, comprise its pharmaceutically acceptable salt and prodrug. Boric acid arginine derivative and boric acid polypeptide comprise N-acetyl group and the peptide derivant of boric acid, such as the α aminoboronic acid derivative of the lysine of C-end, ornithine, arginine, homoarginine and corresponding isothiuronium salts analog thereof. Term hirudin used herein comprises suitable derivative or the analog of hirudin, is referred to as hirudin analog (hirulogs) here, for example two sulfuric acid hirudins.
Term used herein thrombolytic (or fibrinolytic) medicine (or thrombolytic agent or fibrinolytic agent) refers to the medicine of dissolved blood clot (thrombus). These medicines comprise tissue plasmin activator (TPA; natural or recombinant) and reworked, Anistreplase, urokinase, streptokinase, TNK (TNK), lanoplase (lanoteplase; nPA), factor VIIa inhibitors, PAI-I inhibitor (being the inactivator of tissue plasmin activator inhibitor), α-2-antifibrinolysin inhibitor and anisoyl plasminogen streptokinase activator compound, comprise its pharmaceutically acceptable salt or prodrug. The terminology used here Anistreplase refers to the plasminogen streptokinase activator compound of anisoyl, and for example such as European Patent Application No. No.028, described in 489, its disclosed content is incorporated herein this paper as a reference. Term urokinase used herein represents two strands and single chain urokinase type plasminogen activator, and the latter is also referred to as at this and is prourokinase.
The example that is used for the suitable antiarrhythmic drug that is used in combination with the compounds of this invention comprises: I type medicine (such as Propafenone); II type medicine (such as Carvedilol and inderal); III type medicine (such as Sotalol, Dofetilide, amiodarone, azimilide and Ibutilide); IV type medicine (such as diltiazem and Verapamil); K+Channel opener such as IAchInhibitor and IKurInhibitor (for example, disclosed compound among the WO01/40231).
Term antihypertensive used herein comprises: the alpha-1 adrenergic blocking agent; The Beta-3 adrenergic blocking agent; Calcium channel blocker (for example diltiazem, Verapamil, Nifedipine, Amlodipine and mybefradil); Diuretics (for example chlorothiazide, Hydrochioro, flumethiazide, hydroflumethiazide, bendroflumethiazide, methychlothiazide, trichloromethiazide, many thiazines, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, frusemide, musolimine, bumetanide, triamtrenene, amiloride, antisterone); Blood vessel tension peptide protoenzyme inhibitor; Angiotensin-converting enzyme (ACE) inhibitor (for example, captopril, lisinopril, Fosinopril, enalapril, ceranopril, Cilazapril, Delapril, pentopril, quinapril, Ramipril, lisinopril); AngiotensionⅡ receptor antagonist (for example, irbestatin, Losartan, Valsartan); ET receptor antagonist (for example Sai Tashengtan (sitaxsentan), atrsentan and U.S. Patent number No.5,612,359 and 6,043,265 in disclosed compound); ET/A II dual antagonist (for example disclosed compound among the WO00/01389); Neutral endopeptidase (NEP) inhibitor; Vasopeptidase inhibitors (ACE/NEP double inhibitor, for example omapatrilat, gemopatrilat, nitrate); And beta blocker (for example inderal, Nadolol or Carvedilol).
The example that is used for the suitable cardiac glycoside that is used in combination with the compounds of this invention comprises digitalis and strophanthin.
The example that is used for the suitable mineralocorticoid receptor antagonists that is used in combination with the compounds of this invention comprises antisterone and eplirinone.
Be used for suitable norcholesterol/fat-reducing medicament of being used in combination with the compounds of this invention and the example of fat type therapeutic agent and comprise HMG-CoA reductase inhibitor (for example Pravastatin, Lovastatin, Atorvastatin, Simvastatin, Fluvastatin, NK-104 (a.k.a. itavastatin or itavastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin or atavastatin or visastatin)); Squalene synthetase inhibitor; The special class (fibrates) of shellfish; Bile acid sequestrant (such as cholestyramine); The ACAT inhibitor; The MTP inhibitor; Lipoxidase inhibitor; Cholesterol absorption inhibitor; And cholesteryl ester transfer protein matter inhibitor (for example CP-529414).
The example that is used for the suitable antidiabetic medicine that is used in combination with the compounds of this invention comprises: biguanides (for example melbine); Alpha-glucosidase inhibitors (for example acarbose); Insulin (comprising Insulin secretagogues or insulin sensitizer); Meglitinides (meglitinides) (for example Repaglinide); Sulfonylurea (for example Glimepiride, glibenclamide and Glipizide); Biguanides/glibenclamide compound medicine (for example compound metformin hydrochloride (glucovance)); Thiazolidinediones (for example troglitazone, Rosiglitazone and pioglitazone); The PPAR-alfa agonists; The PPAR-gamma agonist; PPAR-α/γ dual agonists, SGLT2 inhibitor; Those disclosed among fatty acid binding protein (aP2) inhibitor such as the WO00/59506, glucagon-like-peptide-1 (GLP-1); And DPP IV (DP4) inhibitor.
The example that is used for the suitable antidepressants that are used in combination with the compounds of this invention comprises Nefazodone and Sertraline.
The example that is used for the suitable anti-inflammatory agent that is used in combination with the compounds of this invention comprises: metacortandracin; Dexamethasone; Yi Tanxipu; Protein tyrosine kinase (PTK) inhibitor; Cyclooxygenase-2 inhibitor (comprising NSAIDs and COX-1 and/or cox 2 inhibitor); Aspirin; Indomethacin; Brufen; Piroxicam; Naproxen; Celecoxib; And/or rofecoxib.
The example that is used for the suitable anti-osteoporosis agents that is used in combination with the compounds of this invention comprises Alendronic Acid salt and Raloxifene.
The example that is used for the suitable HRT agent that is used in combination with the compounds of this invention comprises estrogen (for example CE) and estradiol.
The example that is used for the suitable antiadipositas drug thing that is used in combination with the compounds of this invention comprises orlistat and aP2 inhibitor (such as WO00/59506 those disclosed).
The example that is used for the suitable anxiolytic drugs that is used in combination with the compounds of this invention comprises diazepam, Lorazepam, buspirone and hydroxyzine pamoate.
The example that is used for the suitable anxiolytic drugs that is used in combination with the compounds of this invention comprises diazepam, Lorazepam, buspirone and hydroxyzine pamoate.
The example that is used for the suitable anti-proliferative drug that is used in combination with the compounds of this invention comprises cyclosporin A, taxol, adriamycin; Epothilone, cis-platinum and carboplatin.
Be used for the suitable antiulcer that is used in combination with the compounds of this invention and the medicine of gastroesophageal reflux disease and comprise famotidine, ranitidine and Omeprazole.
The compounds of this invention (i.e. the first therapeutic agent) preferably can produce than independent compound and the more virtuous advantage of medicine with at least a other therapeutic agent (i.e. the second therapeutic agent) combination medicine-feeding, and preferably each can be to use than low dosage. Can reduce to greatest extent potential side effect than low dosage, therefore have the margin of safety of raising. Preferred one of them kind therapeutic agent is with inferior therapeutic dose administration. More preferably all therapeutic agents are with inferior therapeutic dose administration. Inferior therapeutic dose refers to the amount of this therapeutic agent that a kind of therapeutic agent itself can not produce required curative effect to the illness for the treatment of or disease. Synergistic combination refers to that the viewed combined effect summation more individually dosed than single dose is better.
The compounds of this invention also can be used as standard items or reference compound, for example, and in the test or test of relevant Trombin inhibiting, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein, as quality standard or reference substance. These compounds can provide with the commercial reagents box, are used for for example pharmacy research of relevant fibrin ferment, factor VIla, IXa, Xa, XIa and/or plasma kallikrein. XIa. For example, the compounds of this invention can be used as in test reference, and the activity that it is known compares with unknown active compound. It can make the experimenter guarantee that test correctly carries out, and provides the basis that contrasts, and particularly is the situation of the derivative of reference compound for test compounds. When developing new test or scheme, can be used for its validity of test according to compound of the present invention.
The compounds of this invention can also be used for relating to the diagnostic test of fibrin ferment, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein. For example, the existence of fibrin ferment, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein in the unknown sample, can be by in a series of solution that contain specimen and optional wherein a kind of the compounds of this invention, adding relevant chromogenic substrate, for example for factor XI, plasma thromboplastin antecedent a, add S2366, and measure. If in containing the solution of specimen, observe the generation of pNA, nextly do not have and exist at the compounds of this invention, then can conclude the existence of factor XI, plasma thromboplastin antecedent a.
K
iValue is less than or equal to 0.001 μ M for the target enzyme, and to the very effectively and optionally the compounds of this invention of other protease more than or equal to 0.1 μ M, can also be used for relating to the quantitative Diagnosis test of blood serum sample fibrin ferment, factor VIIa, IXa, Xa, XIa and/or plasma kallikrein. For example, in the blood serum sample amount of factor XI, plasma thromboplastin antecedent a can by in the presence of the factor XI, plasma thromboplastin antecedent inhibitor of the present invention of relevant chromogenic substrate S2366 and a kind of efficient selective carefully the activity of titration protease measure.
The present invention also comprises a kind of goods. Goods used herein refer to including, but not limited to kit and package. Goods of the present invention comprise: (a) the first container; (b) place the pharmaceutical composition of the first container, wherein composition comprises the first therapeutic agent, comprises the compounds of this invention or its pharmaceutically acceptable salt form; And (c) this pharmaceutical composition of indication can be used for treating the package insert (insert) of thromboembolia type and/or inflammatory disease (as defined above). In another embodiment, package insert indicates this pharmaceutical composition to use (as defined above) with the second therapeutic combination, with treatment thromboembolia type and/or inflammatory disease. Goods can further comprise: (d) second container, wherein member (a) and (b) place second container, member (c) to be positioned within the second container or outside. Place refer in the first and second containers each container with each article container within its border.
The first container is be used to the storage that holds pharmaceutical composition (receptacle). This container can be for the manufacture of, storage, transportation and/or retail/wholesale sales. The first container comprise bottle, tank, little phial, arrow-necked bottle, syringe, test tube (for example being used for cream) or any other for the preparation of, hold, store or sell the container of medicine.
Second container is used for holding the first container and optional package insert. The example of second container is including, but not limited to box (for example cardboard case or plastic casing), crate, carton, sack (for example paper bag or polybag), pouch and sack. Package insert can physically be fixed on by adhesive tape, glue, nail or other fixing means the outside of the first container, and perhaps it can be positioned in the second container, and is not fixed on the first container by any physical method. Perhaps, package insert is positioned at the outside of second container. When being positioned at the outside of second container, the preferred packaging specification carries out physical property by adhesive tape, glue, nail or other fixing means to be fixed. Perhaps, it also can or contact with second container outside adjacency, does not fix and do not carry out physical property.
Package insert is the trade mark that records the information of closing the pharmaceutical composition be arranged in the first container, label, marker etc. The information of putting down in writing is determined by the management organization (for example, U.S. food and drug administration) of administration goods market usually. The preferred packaging specification is put down in writing the indication of the pharmaceutical composition of approved particularly. Package insert can be read wherein or any material manufacturing of information on it by people. The preferred packaging specification is a kind of printing material (for example, paper, plastics, cardboard, paillon foil, back side viscosity paper or plastics etc.) that forms information needed (for example printing or coating) thereon.
Dosage and preparation
The compounds of this invention can carry out administration with peroral dosage form such as tablet, capsule (both include sustained release or time release formulation), pill, pulvis, granule, elixir, tincture, suspension, syrup and emulsion. It also can be with intravenous (pill or transfusion), peritonaeum is interior, subcutaneous or form intramuscular is carried out administration, and the formulation of all uses all is that the pharmaceutical field those of ordinary skill is known. They can be individually dosed, but usually with the pharmaceutical carrier administration according to method of administration and standard pharmacy practice selection.
The dosage of the compounds of this invention is certainly according to known factor and difference, for example pharmacodynamic properties and mode of administration and the approach of concrete medicine; The kind of curer, age, sex, health status, medical condition and body weight; The nature and extent of symptom; The kinds of Diseases for the treatment of simultaneously; Therapeutic frequency; Method of administration, patient's kidney and liver function and the required effect that reaches. Doctor or animal doctor can determine and leave prevention, antagonism or stop the effective dose of the required medicine of thrombotic disease development.
According to general guidance, when being used for indicated effect, the day oral dose of every kind of active component is about 0.001 to 1000mg/kg body weight, preferred about 0.01 to 100mg/kg body weight every day, most preferably from about 1.0 to 20mg/kg/ days. For intravenously administrable, most preferred dosage is about 1 to about 10mg/kg/ minute during the constant speed transfusion. The compounds of this invention can be with single daily dose administration, and perhaps total daily dose can be with the divided dose administration of every day twice, three times or four times.
The compounds of this invention can with the form administration in the nose, perhaps adopt through the skin skin patch and pass through through the skin administration by the interior carrier of the suitable nose of local use. When with through skin medicine-releasing system form administration the time, dosage certainly in whole dosage be continue rather than be interrupted.
Compound mixes administration with suitable pharmaceutical diluents, excipient or carrier (being referred to as pharmaceutical carrier at this) usually, carrier is according to predetermined form of administration, be that oral tablet, capsule, elixir, syrup etc. are suitably selected, and meet conventional pharmacy practice.
For example, for with tablet or capsule form oral administration, active pharmaceutical ingredient can with the combinations such as oral, nontoxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose, dolomol, dicalcium phosphate, calcium sulfate, sweet mellow wine, D-sorbite. For with the liquid form oral administration, the oral drugs composition can with the combinations such as any oral, nontoxic, pharmaceutically acceptable inert carrier such as ethanol, glycerine, water. In addition, if needs or essential can also be incorporated into suitable adhesive, lubricant, disintegrant and colouring agent in the mixture. Suitable adhesive comprises starch, gelatin, natural sugar such as glucose or β-lactose, corn sweetener, natural and paragutta such as Arabic gum, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, wax etc. The lubricant that is used for these formulations comprises enuatrol, odium stearate, dolomol, Sodium Benzoate, sodium acetate, sodium chloride etc. Disintegrant includes but not limited to starch, methylcellulose, agar, bentonite, xanthans etc.
The compounds of this invention can also be with liposome medicine-releasing system form administration, for example small unilamellar vesicle, large unilamellar liposome and multilamellar liposome. Liposome can be formed by various phosphatide such as cholesterol, stearmide or phosphatid ylcholine.
The compounds of this invention can also be coupled with the soluble polymer as target medicine carrier. These polymer can comprise PVP, pyran co-polymer, poly-hydroxypropyl methyl acrylamide-phenol, poly-hydroxyethyl asparagine phenol or the polyethylene glycol oxide-polylysine that is replaced by the palmityl residue. In addition, the compounds of this invention can also be coupled with the biodegradable polymer of a class that is used for the release of realization control medicine, for example the copolymer of PLA, polyglycolic acid, PLA and polyglycolic acid, poly-δ caprolactone, poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate and crosslinked or ampholytic hydrogel block copolymer.
The every dosage unit of formulation (pharmaceutical composition) that is fit to administration can contain has an appointment 1 milligram to about 100 milligrams of active components. In these pharmaceutical compositions, based on the gross weight of composition, usually can have consumption is the active component of about 0.5-95% weight.
Gel capsule can contain active component and dust carrier such as lactose, starch, cellulose derivative, dolomol, stearic acid etc. Similarly diluent can be for the manufacture of compressing tablet. Tablet and Capsula can be made into the sustained release product, in order to the medicine of continuous release was provided within a few hours. Compressing tablet can carry out sweet tablet or film coating, to shield any undesirable taste and to prevent that tablet from contacting atmosphere, perhaps carries out enteric coating, is used for optionally disintegration in intestines and stomach.
Be used for oral liquid dosage form and can contain colouring agent and flavor enhancement, to promote patient's acceptance.
Usually, water, suitable oil, salt solution, dextrose (glucose) aqueous solution and associated sugars solution and glycols such as propane diols or polyethylene glycol are the suitable carriers of parenteral solution. The solution of parenteral preferably contain the water soluble salt of active component, suitable stabilizing agent and, if necessary, buffer substance. Antioxidant such as sodium hydrogensulfite, sodium sulfite or ascorbic acid independent or that mix are suitable stabilizing agents. Can also use citric acid and salt thereof and sodium ethylene diamine tetracetate. In addition, parenteral solution can contain anticorrisive agent such as benzalkonium chloride, methyl-or propyl group-metagin and chlorobutanol.
Suitable pharmaceutical carrier is recorded in Remington ' s Pharmaceutical Sciences, and among the Mack Publishing Company, it is the canonical reference book of this area.
In the situation of the compounds of this invention and the combination of other anti-coagulants, daily dose can be about 0.1 to 100 milligram of the compounds of this invention and about 1 to 7.5 milligram of every kg of patient body weight of the second anti-coagulants. For Tabules, the compounds of this invention can exist with about 5 to the 10 milligrams amount of every dosage unit usually, and the second anti-coagulants exists with the amount of the about 1-5 milligram of every dosage unit.
When the compounds of this invention and antiplatelet drug combination medicine-feeding, according to general guidance, daily dose can about 0.01 to 25 milligram of the compounds of this invention and about 50 to 150 milligrams of antiplatelet drugs, preferred about 0.1 to 1 milligram of the compounds of this invention and the every kg of patient body weight of about 1-3 milligram antiplatelet drug usually.
When the compounds of this invention and thrombolytic agent combination medicine-feeding, usually daily dose can be about 0.1 to 1 milligram of every kg of patient body weight of the compounds of this invention, for thrombolytic agent, the routine dose of individually dosed thrombolytic agent, with the compounds of this invention combination medicine-feeding time, can reduce about 70-80%.
When two or more above-mentioned second therapeutic agents during with the compounds of this invention administration, when considering the therapeutic combination administration add and or synergy, the conventional daily dose of every kind of component and the amount of regular dosage form can reduce usually with respect to the common dosage of individually dosed medicine.
Particularly when providing with single dose unit, has the chemically interactive possibility of generation between the active component of combination. Based on this reason, when formula I compound and the second therapeutic agent make up with single dose unit, although active component is blended in the single dose unit, they are made into to make the physical contact form of few (namely having reduced) as much as possible between the active component. For example, wherein a kind of active component can be enteric coating. By enteric coating a kind of active component wherein, not only being in contact with one another of mixed active composition can be reduced as far as possible, and the wherein release of a kind of component in intestines and stomach can be controlled, make wherein that a kind of composition does not discharge under one's belt, and in enteron aisle, discharge. Wherein a kind of active component also can coat a kind of material, achieves sustained release in whole intestines and stomach, and performance reduces the effect of the physical contact between the combined activity composition as far as possible. In addition, the sustained release component can also further be carried out enteric coating, so that this component only discharges in enteron aisle. The preparation of combination product also comprises other method, wherein a kind of component is coated with and continues and/or the interior release polymers of intestines, and other components also coat a kind of polymer, the for example hydroxypropyl methylcellulose of low viscosity grade (HPMC) or other suitable materials known in the art are with further isolation active component. Polymer coating is being brought into play the effect of additional mask and other component interactions.
In case learned disclosure of the present invention, these and other the method that reduces that is in contact with one another as far as possible that makes the combination product component of the present invention then, no matter with single formulation administration or the in an identical manner simultaneously administration of formulation to separate, all be apparent to those skilled in the art.
Claims (34)
1, formula (I) compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-10Carbocyclic ring comprises that perhaps carbon atom and 1-4 is selected from N, O and S (O)
pHeteroatomic 5-to 12-unit heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when comprising the heterocycle of one or more nitrogen-atoms, then A is not connected on the L by any nitrogen-atoms on the A ring;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-C
3Alkyl) ,-N (C
1-C
3Alkyl)
2,-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7CO
2R
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-C
3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8a), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
1And R
2When group was substituted on the adjacent annular atoms, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b,-(CH
2)
rSR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c,-C (O)-C
1-C
4Alkyl ,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3c,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
2-6Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring, perhaps 5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group was positioned on the adjacent atom, they can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
6Be H;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl or-(CH
2)
n-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When group was connected on the identical nitrogen-atoms, it was combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-4Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl and heteroaryl are optional by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the identical nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
d(the CH that replaces
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CR
14R
15)
r-C
3-10Carbocyclic ring or-(CR
14R
15)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
Perhaps, R
14With R
15In conjunction with formation=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heterocyclic group are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5-to 10-unit heteroaryl)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; And
S is selected from 1,2,3 and 4 at every turn when occurring;
Prerequisite is:
(a) when L be-during C (O) NH-, R
3Be not 2,4 dichloro benzene base, 4-nitrophenyl or pentafluorophenyl group;
(b) when L be-during C (O) NH-, R
11Be not-CH
2-(3-indyl) ,-(CH
2)
4NHCO
2(t-Bu) or-(CH
2)
4NH
2
2, according to the compound of claim 1, wherein:
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2CONR
10-or-NR
10COCH
2-;
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
r-CONR
8R
9, by 0-2 R
11aThe C that replaces
1-6Alkyl, by 0-2 R
11aThe C that replaces
2-6Thiazolinyl, by 0-2 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11B replaces-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace.
3, according to the compound of claim 1, wherein:
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-C (Me)
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aWith 0-1 R
3dThe naphthyl that replaces, by 0-2 R
3aWith 0-1 R
3dThe indanyl that replaces or-(CH
2)
r-5 to 10 yuan comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, CF
3, OMe, NH
2, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph; And
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace.
4, according to the compound of claim 1, wherein compound has structural formula (II):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NH-or-NHC (O)-;
R
1Be F, Cl, Me, Et ,-NH when occurring independently at every turn
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aThe phenyl that replaces, by 0-2 R
3aThe naphthyl that replaces, by 0-2 R
3aIndanyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aReplace;
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
4bReplace;
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or by 0-2 R
11bReplace-(CH
2)
r-5-to 10-unit heteroaryl, and be selected from thiazolyl, azoles base, triazolyl, tetrazyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indoline base, isoindoline base, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, tetrahydric quinoline group and tetrahydro isoquinolyl; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph, or Bn;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace.
5, according to the compound of claim 1, wherein compound has structural formula (II):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-CO
2Me-cyclohexyl, 4-CONH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl, phenyl, 4-Me-phenyl, 3-OMe-phenyl, 4-CH
2NH
2-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-amidino groups-phenyl, 4-amidino groups-phenyl, 2-F-4-Me-phenyl, 2-Bn-4-CH
2NH
2-phenyl, 4-SO
2NH
2-phenyl, 2-F-5-OMe-phenyl, 2-F-4-Cl-phenyl, 2-F-4-CH
2NH
2-phenyl, 2-F-4-CONH
2-phenyl, 2-Cl-4-CONH
2-phenyl, 2-Et-4-CH
2NH
2-phenyl, 2-NHEt-4-CH
2NH
2-phenyl, 2-OMe-4-CONH
2-phenyl, 3-OMe-4-CONH
2-phenyl, 1,2,3,4-naphthane-2-base, 3-Cl-thiophene-2-base, indoles-5-base, indoles-6-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-indazole-5-base, 1-Me-3-NH
2-indazole-6-base, 3-NH
2-benzisoxa azoles-6-base, 1,2,3,4-tetrahydroisoquinoline-6-base, 1,2,3,4-tetrahydroisoquinoline-3-base, 2-COPh-1,2,3,4-tetrahydroisoquinoline-3-base, 2-CO
2Bn-1,2,3,4-tetrahydroisoquinoline-3-base, 1,2,3,4-tetrahydroisoquinoline-1-ketone-6-base, 2H-isoquinoline 99.9-1-ketone-6-base, isoquinoline 99.9-6-base, 1-NH
2-isoquinoline 99.9-6-base, 1-NH
2-3-Me-isoquinoline 99.9-6-base, 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base, 4-NH
2-quinazoline-7-base, 3H-quinazoline-4-one-7-base,
R
3Be CO
2H, CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, phenyl, styroyl ,-(CH=CH)-and phenyl, 3-xenyl, 4-xenyl, 3,4-methylenedioxyphenyl, 1-naphthyl, 2-naphthyl, 3-NH
2-phenyl, 3-NMe
2-phenyl, 4-OPh-phenyl, 4-OBn-phenyl, 4-(t-fourth oxygen methyl)-phenyl, 4-SO
2Me-phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-F-phenyl, 4-F-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 3-Br-phenyl, 4-Br-phenyl, 3-OH-phenyl, 4-OH-phenyl, 2-OMe-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 3-CF
3-phenyl, 4-CF
3-phenyl, 3-CO
2H-phenyl, 4-CO
2H-phenyl, 3-CO
2Me-phenyl, 4-CO
2Me-phenyl, 3-CH
2CO
2H-phenyl, 4-CH
2CO
2H-phenyl, 4-CH
2CO
2Me-phenyl, 3-CH
2CO
2Et-phenyl, 4-CH
2CO
2Et-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-CH
2CONH
2-phenyl, 4-CH
2CONH
2-phenyl, 4-CONHMe-phenyl, 4-CONMe
2-phenyl, 4-amidino groups-phenyl, 3-NHCOMe-phenyl, 4-NHCOMe-phenyl, 4-NHCO
2Me-phenyl, 4-SO
2NH
2-phenyl, 3-NHSO
2Me-phenyl, 4-NHSO
2Me-phenyl, 2,4-two fluoro-phenyl, 3-F-4-CN-phenyl, 3-CN-5-F-phenyl, 3-F-4-CONH
2-phenyl, 3-CO
2H-4-CN-phenyl, 3-NMe
2-4-CN-phenyl, 3-Ph-4-CONH
2-phenyl, 4-(2-oxo-1-piperidino-(1-position only))-phenyl, thiazol-2-yl, 4-CO
2Me-thiazol-2-yl, 4-CONH
2-thiazol-2-yl, 1-Bn-pyrazoles-4-base, 5-Ph- azoles-2-base, 5-CONH
2-thiophene-2-base, 5-CO
2H-thiophene-2-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl, 6-NH
2-pyridin-3-yl, benzimidazolyl-2 radicals-Ji, 1-Me-benzimidazolyl-2 radicals-Ji, benzoxazol-2-base, benzothiazole-2-base, 3-NH
2-benzisoxa azoles-6-base, 3-NH
2-benzisoxa azoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base, 4-imino--3,4-dihydro-2H-phthalazines-1-ketone-7-base, 3-(5-tetrazyl)-phenyl, 2,3-dihydro-isoindole-1-ketone-6-base, quinoline-5-base, quinoline-6-base, quinoline-8-base, isoquinoline 99.9-5-base, 2H-isoquinoline 99.9-1-ketone-6-base, 2,4-diamino quinazoline-7-base or 4-NH
2-quinazoline-7-base;
R
4Be H, Me, Br, Cl, CF
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For Me, neo-pentyl, cyclohexyl methyl ,-CH
2CH
2CONHBn ,-CH
2CH
2CONH (CH
2CH
2Ph) ,-CH
2CH
2CON (Me) Bn, benzyl, styroyl, 2-Me-benzyl, 3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl, 4-Br-benzyl, 3-CF
3-benzyl, 4-CF
3-benzyl, 2-NH
2-benzyl, 3-NH
2-benzyl, 2-NO
2-benzyl, 3-NO
2-benzyl, 4-NO
2-benzyl, 3-OMe-benzyl, 4-OMe-benzyl, 3-OCF
2H-benzyl, 2-OCF
3-benzyl, 3-OCF
3-benzyl, 2-OPh-benzyl, 3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl, 3-CO
2H-benzyl, 3-CO
2Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl, 2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N (Me) COPh-benzyl, 3-(NHCOCH
2CH
2Ph)-benzyl, 2-NHSO
2Ph-benzyl, 3-NHSO
2Ph-benzyl, 3-[SO
2N (Me) Ph]-benzyl, 3-[N (Me) SO
2Ph]-benzyl, 3-[CONH (i-Bu)]-benzyl, 3-[CONH (t-Bu)-] benzyl, 3-[CONH (isopentyl)]-benzyl, 3-[CONH (2-Me-Ph)]-benzyl, 3-[CONH (3-Me-Ph)]-benzyl, 3-[CONH (4-Me-Ph)]-benzyl, 3-[CONH (4-F-Ph)]-benzyl, 3-[CONH (1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl, 3-[CONH (4-Cl-Bn)]-benzyl, 3-[CONH (4-OMe-Bn)]-benzyl, 3-[CONHCH
2CH
2Ph]-benzyl, 3-[CONHCH
2CH
2(4-OMe-Ph)]-benzyl, 3-[CONHCH
2CH
2(2-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(3-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(4-Cl-Ph)]-benzyl, 3-[CONH (CH
2)
3Ph]-benzyl, 3-[CONMe
2]-benzyl, 3-[CON (Me) are (Et)]-benzyl, 3-[CON (Me) (i-Pr)]-benzyl, 3-[CON (Me) (i-Bu)]-benzyl, 3-[CON (Me) Ph]-benzyl, 3-[CON (Me) (3-Me-Ph)]-benzyl, 3-[CON (Me) (4-Me-Ph)]-benzyl, 3-[CON (Me) Bn]-benzyl, 3-[CON (Me) (3-Cl-Bn)]-benzyl, 3-[CON (Me) (4-Cl-Bn)]-benzyl, 3-[CON (Me) (CH
2CH
2Ph)]-benzyl, 3-[CON (Et) Ph]-benzyl, 3-[CO (1-piperidino-(1-position only))]-benzyl, 3-[CO (4-Ph-1-piperidino-(1-position only))]-benzyl, 3-[CO (1,2,3,4-tetrahydroisoquinoline subbase)]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl, 4-Ph-benzyl, 3-styroyl-benzyl ,-CH
2OBn ,-CH
2SBn, 1-menaphthyl, 2-menaphthyl, thiazole-4-ylmethyl, pyridine-2-ylmethyl, pyridin-3-yl methyl, pyridin-4-yl methyl, 1-Bn-imidazol-4 yl methyl, benzothiazole-2-ylmethyl,
6, according to the compound of claim 1, wherein compound has structural formula (II):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
R
3Be 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-benzisoxa azoles-6-base, 3-NH
2-benzisoxa azoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base, isoquinoline 99.9-5-base, quinoline-5-base, quinoline-8-base, 2H-isoquinoline 99.9-1-ketone-6-base, 2,4-diamino quinazoline-7-base or 4-NH
2-quinazoline-7-base.
7, according to the compound of claim 6, wherein:
L is-C (O) NR
10-or-NR
10C (O)-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-C (Me)
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph;
R
11Be C
1-C
6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-1 comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4 for 0 yuan
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-N
8CO
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph or Bn.
8, according to the compound of claim 7, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl; And
R
10Be H.
9, compound according to Claim 8, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-CO
2Me-cyclohexyl, 4-CONH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl, phenyl, 4-Me-phenyl, 3-OMe-phenyl, 4-CH
2NH
2-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 3-amidino groups-phenyl, 4-amidino groups-phenyl, 2-F-4-Me-phenyl, 2-Bn-4-CH
2NH
2-phenyl, 4-SO
2NH
2-phenyl, 2-F-5-OMe-phenyl, 2-F-4-Cl-phenyl, 2-F-4-CH
2NH
2-phenyl, 2-F-4-CONH
2-phenyl, 2-Cl-4-CONH
2-phenyl, 2-Et-4-CH
2NH
2-phenyl, 2-NHEt-4-CH
2NH
2-phenyl, 2-OMe-4-CONH
2-phenyl, 3-OMe-4-CONH
2-phenyl, 1,2,3,4-naphthane-2-base, 3-Cl-thiophene-2-base, indoles-5-base, indoles-5-base, indazole-5-base, indazole-6-base, 3-NH
2-indazole-6-base, 3-NH
2-indazole-5-base, 1-Me-3-NH
2-indazole-6-base, 3-NH
2-benzisoxa azoles-6-base, 1,2,3,4-tetrahydroisoquinoline-6-base, 1,2,3,4-tetrahydroisoquinoline-3-base, 2-COPh-1,2,3,4-tetrahydroisoquinoline-3-base, 2-CO
2Bn-1,2,3,4-tetrahydroisoquinoline-3-base, 1,2,3,4-tetrahydroisoquinoline-1-ketone-6-base, 2H-isoquinoline 99.9-1-ketone-6-base, isoquinoline 99.9-6-base, 1-NH
2-isoquinoline 99.9-6-base, 1-NH
2-3-Me-isoquinoline 99.9-6-base, 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base, 4-NH
2-quinazoline-7-base, 3H-quinazoline-4-one-7-base,
R
4Be H, Me, Br, Cl, CF
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For Me, neo-pentyl, cyclohexyl methyl ,-CH
2CH
2CONHBn ,-CH
2CH
2CONH (CH
2CH
2Ph) ,-CH
2CH
2CON (Me) Bn, benzyl, styroyl, 2-Me-benzyl, 3-Me-benzyl, 4-Me-benzyl, 2-F-benzyl, 3-F-benzyl, 4-F-benzyl, 2-Cl-benzyl, 3-Cl-benzyl, 4-Cl-benzyl, 2-Br-benzyl, 3-Br-benzyl, 4-Br-benzyl, 3-CF
3-benzyl, 4-CF
3-benzyl, 2-NH
2-benzyl, 3-NH
2-benzyl, 2-NO
2-benzyl, 3-NO
2-benzyl, 4-NO
2-benzyl, 3-OMe-benzyl, 4-OMe-benzyl, 3-OCF
2H-benzyl, 2-OCF
3-benzyl, 3-OCF
3-benzyl, 2-OPh-benzyl, 3-OPh-benzyl, 2-OBn-benzyl, 3-OBn-benzyl, 4-OBn-benzyl, 4-COPh-benzyl, 3-CO
2H-benzyl, 3-CO
2Me-benzyl, 3-NHAc-benzyl, 2-NHCOPh-benzyl, 2-NHCOBn-benzyl, 3-NHCOBn-benzyl, 3-N (Me) COPh-benzyl, 3-(NHCOCH
2CH
2Ph)-benzyl, 2-NHSO
2Ph-benzyl, 3-NHSO
2Ph-benzyl, 3-[SO
2N (Me) Ph]-benzyl, 3-[N (Me) SO
2Ph]-benzyl, 3-[CONH (i-Bu)]-benzyl, 3-[CONH (t-Bu)]-benzyl, 3-[CONH (isopentyl)]-benzyl, 3-[CONH (2-Me-Ph)]-benzyl, 3-[CONH (3-Me-Ph)]-benzyl, 3-[CONH (4-Me-Ph)]-benzyl, 3-[CONH (4-F-Ph)]-benzyl, 3-[CONH (1-naphthyl)]-benzyl, 3-(CONHBn)-benzyl, 3-[CONH (4-Cl-Bn)]-benzyl, 3-[CONH (4-OMe-Bn)]-benzyl, 3-[CONHCH
2CH
2Ph]-benzyl, 3-[CONHCH
2CH
2(4-OMe-Ph)]-benzyl, 3-[CONHCH
2CH
2(2-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(3-Cl-Ph)]-benzyl, 3-[CONHCH
2CH
2(4-Cl-Ph)]-benzyl, 3-[CONH (CH
2)
3Ph]-benzyl, 3-[CONMe
2]-benzyl, 3-[CON (Me) are (Et)]-benzyl, 3-[CON (Me) (i-Pr)]-benzyl, 3-[CON (Me) (i-Bu)]-benzyl, 3-[CON (Me) Ph]-benzyl, 3-[CON (Me) (3-Me-Ph)]-benzyl, 3-[CON (Me) (4-Me-Ph)]-benzyl, 3-[CON (Me) Bn]-benzyl, 3-[CON (Me) (3-Cl-Bn)]-benzyl, 3-[CON (Me) (4-Cl-Bn)]-benzyl, 3-[CON (Me) (CH
2CH
2Ph)]-benzyl, 3-[CON (Et) Ph]-benzyl, 3-[CO (1-piperidino-(1-position only))]-benzyl, 3-[CO (4-Ph-1-piperidino-(1-position only))]-benzyl, 3-[CO (1,2,3,4-tetrahydroisoquinoline subbase)]-benzyl, 2-Ph-benzyl, 3-Ph-benzyl, 4-Ph-benzyl, 3-styroyl-benzyl ,-CH
2OBn ,-CH
2SBn, 1-menaphthyl, 2-menaphthyl, thiazole-4-ylmethyl, pyridine-2-ylmethyl, pyridin-3-yl methyl, pyridin-4-yl methyl, 1-Bn-imidazol-4 yl methyl, benzothiazole-2-ylmethyl,
10, compound according to Claim 8, wherein:
A is 4-CH
2NH
2-cyclohexyl, 4-NHCO
2(t-Bu)-cyclohexyl, 4-NHCO
2Bn-cyclohexyl or 1-NH
2-5,6,7,8-tetrahydroisoquinoline-6-base;
L is-C (O) NH-or NHC (O)-;
R
3Be indazole-5-base, indazole-6-base, 3-NH
2-indazole-5-base, 3-OH-indazole-5-base, 3-NH
2-indazole-6-base, 3-NH
2-4-F-indazole-6-base, 3-NH
2-5-F-indazole-6-base, 3-NH
2-7-F-indazole-6-base or 4-NH
2-quinazoline-7-base;
R
4Be H, Me, F, Br, Cl or CF
3And
R
11For by 0-2 R
11bThe benzyl that replaces.
11, according to the compound of claim 10, wherein:
A is 4-CH
2NH
2-cyclohexyl;
L is-C (O) NH-; And
R
3Be 3-NH
2-indazole-6-base or 4-NH
2-quinazoline-7-base.
12, according to the compound of claim 1, wherein compound has structural formula (II):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is by 0-2 R
1With 0-1 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NR
10-or-NR
10C (O)-;
R
3For-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, OMe, NH
2, CF
3, CO
2H, CO
2Me, CO
2Et ,-CONR
8R
9, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace; And
R
11For by 0-2 R
11bThe benzyl that replaces.
13, according to the compound of claim 1, wherein compound has structural formula (II):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NR
10-or-NR
10C (O)-;
R
3For by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl or by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl;
R
4Be H, Me, Br, Cl, CF when occurring independently at every turn
3, CO
2H, CO
2Me, CO
2Et, phenyl, 3-F-4-CN-phenyl or 3-NH
2-6-indazolyl; And
R
11For by 0-2 R
11bThe benzyl that replaces.
14, according to the compound of claim 1, wherein compound has structural formula (III):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, Me, CN, OH, NH
2, OMe, O (t-Bu), OBn, CF
3, CO
2H, CO
2Me ,-CH
2CO
2H ,-CH
2CO
2Me ,-CH
2CO
2Et ,-NHCOMe ,-CONH
2,-CH
2CONH
2,-CONHMe ,-CONMe
2,-C (=NH) NH
2,-NR
7R
8,-SO
2Me ,-SO
2NH
2, Ph or 2-oxo-piperidines-1-base;
R
3dBe H or C
1-4Alkyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
r-CONR
8R
9, by 0-2 R
11aThe C that replaces
1-6Alkyl, by 0-2 R
11aThe C that replaces
2-6Thiazolinyl, by 0-2 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
15, according to the compound of claim 14, wherein:
R
1When occurring be independently-NH at every turn
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH (Me) NH
2,-C (Me)
2NH
2, or-CH
2CH
2NH
2
R
10Be H, Me, benzyl or styroyl; And
R
11For Me, by 0-1 R
11bReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heteroaryl, wherein said heterocycle is by 0-1 R
11bReplace.
16, according to the compound of claim 1, wherein compound has structural formula (IV):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate are wherein:
A is by 1 R
1The cyclohexyl that replaces, by 1 R
1The phenyl that replaces, by 1 R
1The pyridyl that replaces, by 1 R
1The naphthyl that replaces, by 1 R
1The benzisoxa azoles base that replaces or by 0-1 R
1The isoquinolyl that replaces;
L is-C (O) NH-,-C (O) NMe-,-C (O) N (benzyl)-,-C (O) N (styroyl)-,-NHC (O)-,-CH
2C (O) NH-,-NHC (O) CH
2-,-C (O) NHCH
2-or-NHC (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-C (=NH) NH
2,-C (O) NH
2, or-CH
2NH
2
R
3aBe F, Cl, Br, Me, CN, OMe, CF
3, CO
2H, CO
2Me, CO
2Et ,-CH
2CO
2H ,-CH
2CO
2Me ,-CH
2CO
2Et, CONH
2,-CONHMe ,-CON (Me)
2,-CH
2CONH
2, or-C (=NH) NH
2
R
6Be H;
R
10Be H, Me, benzyl or styroyl; And
R
11For Me, by 0-1 R
11bReplace-(CH
2)
r-phenyl or by 0-1 R
11bReplace-(CH
2)
r-5-10 unit heteroaryl, and be selected from thiazolyl, imidazolyl, pyridyl and benzothiazolyl.
17, according to the compound of claim 16, wherein:
A is 4-CH
2NH
2-cyclohexyl or 4-amidino groups-phenyl; And
R
3aBe CO when occurring independently at every turn
2H, CO
2Me ,-CH
2CO
2H ,-CH
2CO
2Et ,-CONH
2, or-CH
2CONH
2
18, formula V compound:
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-10Carbocyclic ring or 5-to 12-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring;
X
1, X
2, and X
3Be CR independently
3, CR
4, CR
4R
5, O, S (O)
p, N, NR
3, NR
6, or C (O); Prerequisite is not have S-S, S-O or O-O key on the ring;
Prerequisite is
Be not
Z is-C (R
11) (R
12)-,-C (R
11) (R
12)-(CH
2)-,-NR
13-or-NR
13CH
2-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-,-NR
10C (O) CH
2-,-S (O)
2NR
10-,-NR
10S (O)
2-,-CH
2S (O)
2NR
10-,-CH
2NR
10S (O)
2-,-S (O)
2NR
10CH
2-,-NR
10S (O)
2CH
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2NR
7-,-NR
7CH
2-,-CH
2CH
2NR
7-,-NR
7CH
2CH
2,-CH
2NR
7CH
2-,-CH
2O-,-OCH
2-,-CH
2S (O)
p-,-S (O)
pCH
2-,-CH
2CH
2O-,-OCH
2CH
2-,-CH
2OCH
2-,-CH
2CH
2S (O)
p-,-S (O)
pCH
2CH
2-,-CH
2S (O)
pCH
2-,-CH
2C (O) ,-CH
2C (O) CH
2-,-CH
2CH
2C (O)-,-C (O) CH
2CH
2-, or-C (O) CH
2-;
R
1When occurring be independently-NH at every turn
2,-NH (C
1-3Alkyl) ,-N (C
1-3Alkyl)
2,-C (=NH) NH
2,-C (O) NR
8R
9,-S (O)
pNR
8R
9,-(CH
2)
rNR
7R
8,-(CH
2)
rNR
7C (O) OR
a,-CH
2NH
2,-CH
2NH (C
1-3Alkyl) ,-CH
2N (C
1-3Alkyl)
2,-CH
2CH
2NH
2,-CH
2CH
2NH (C
1-3Alkyl) ,-CH
2CH
2N (C
1-3Alkyl)
2,-CH (C
1-4Alkyl) NH
2,-C (C
1-4Alkyl)
2NH
2,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,=NR
8,-NR
8CR
8(=NR
8a), F, Cl, Br, I, OCF
3, CF
3,-(CH
2)
rOR
a,-(CH
2)
rSR
a, CN, 1-NH
2-1-cyclopropyl or by 0-1 R
1aThe C that replaces
1-6Alkyl;
R
1aFor H ,-C (=NR
8a) NR
7R
8,-NHC (=NR
8a) NR
7R
8,-NR
8CH (=NR
8a) ,-NR
7R
8,-C (O) NR
8R
9, F, OCF
3, CF
3, OR
a, SR
a, CN ,-NR
9SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
2When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CHF
2, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
2aThe C that replaces
1-6Alkyl, by 0-2 R
2aThe C that replaces
2-6Thiazolinyl, by 0-2 R
2aThe C that replaces
2-6Alkynyl, by 0-3 R
2bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
2bReplace;
R
2aWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, OCF
3, CF
3, OR
a, SR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c,-S (O) R
c, or-S (O)
2R
c
R
2bWhen occurring at every turn independently for H, F, Cl, Br, I ,=O ,=NR
8, CN, NO
2, OR
a, SR
a,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy;
In addition, work as R
1And R
2When group was substituted on the adjacent ring atom, they can form 5-to 7-unit with the annular atoms that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 0-4
pHeteroatomic carbocyclic ring or heterocycle, wherein said carbocyclic ring or heterocycle are by 0-2 R
2bReplace;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2)
sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
3aWhen occurring at every turn independently for=O, F, Cl, Br, I, OCF
3, CF
3, NO
2, CN ,-(CH
2)
rOR
3b,-(CH
2)
rSR
3b,-(CH
2)
rNR
7R
8, C (=NR
8a) NR
8R
9,-NHC (=NR
8a) NR
7R
8,-NR
8CR
8(=NR
8a) ,-(CH
2)
rNR
8C (O) R
3b,=NR
8,-(CH
2)
rNR
8C (O) R
3b,-(CH
2)
rNR
8C (O)
2R
3b,-(CH
2)
rS (O)
pNR
8R
9,-(CH
2)
rNR
8S (O)
pR
3c,-S (O)
pR
3c,-S (O)
pR
3c,-C (O)-C
1-4Alkyl ,-(CH
2)
rCO
2R
3b,-(CH
2)
rC (O) NR
8R
9,-(CH
2)
rOC (O) NR
8R
9,-NHCOCF
3,-NHSO
2CF
3,-SO
2NHR
3b,-SO
2NHCOR
3c,-SO
2NHCO
2R
3c,-CONHSO
2R
3c,-NHSO
2R
3c,-CONHOR
3b, C
1-4Haloalkyl-, C
1-4Halogenated alkoxy-, by R
3dThe C that replaces
1-6Alkyl, by R
3dThe C that replaces
2-6Thiazolinyl, by R
3dThe C that replaces
2-6Alkynyl, by 0-1 R
3dThe C that replaces
3-6Cycloalkyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
In addition, as two R
3aWhen group was positioned on the adjacent atom, they can form with the atom that it connected by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
3bWhen occurring at every turn independently for H, by 0-2 R
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3cBe by 0-2 R independently when occurring at every turn
3dThe C that replaces
1-6Alkyl, by 0-2 R
3dThe C that replaces
2-6Thiazolinyl, by 0-2 R
3dThe C that replaces
2-6Alkynyl, by 0-3 R
3dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3dReplace;
R
3dWhen occurring at every turn independently for H ,=O ,-(CH
2)
rOR
a, F, Cl, Br, CN, NO
2,-(CH
2)
rNR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7C (O) R
b,-C (O) NR
8R
9,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2R
c,-S (O)
pR
c,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl, by 0-2 R
eThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-3 R
4bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
4aWhen occurring at every turn independently for H, F ,=O, C
1-6Alkyl, OR
a, SR
a, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
4bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
In addition, work as R
3And R
4When group is positioned on the adjacent atom, can form together by 0-2 R
3dThe C that replaces
3-10Carbocyclic ring, perhaps 5-to 10-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3dReplace;
R
5Be H, F, OCF when occurring independently at every turn
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c,-S (O) 2R
c, by 0-2 R
5aThe C that replaces
1-6Alkyl, by 0-2 R
5aThe C that replaces
2-6Thiazolinyl, by 0-2 R
5aThe C that replaces
2-6Alkynyl, by 0-3 R
5bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
5bReplace;
R
5aWhen occurring at every turn independently for H ,=O, OR
a, SR
a, F, Cl, Br, I, CF
3, OCF
3, CN, NO
2,-NR
7R
8,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-NR
8S (O)
2R
c,-S (O) R
c, or-S (O)
2R
c
R
5bWhen occurring at every turn independently for H ,=O ,=NR
8, F, Cl, Br, I, OR
a, SR
a, CN, NO
2, CF
3,-SO
2R
c,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
2NR
8R
9,-S (O)
2R
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl or C
1-4Halogenated alkoxy-;
R
6Be H, C when occurring independently at every turn
1-6Alkyl, C
1-4Haloalkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c,-S (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
7Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-C
3-10Carbocyclic ring ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-CHO ,-C (O)
2R
c,-S (O)
2R
c,-CONR
8R
c,-OCONHR
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said alkyl, carbocyclic ring, heteroaryl and aryl are optional by 0-2 R
fReplace;
R
8Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
r-phenyl or-(CH
2)
n-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle; Wherein said alkyl, phenyl and heterocycle are optional by 0-2 R
fReplace;
In addition, work as R
7And R
8When being connected on the same nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
8aBe H, OH, C when occurring independently at every turn
1-6Alkyl, C
1-6Alkoxyl group, (C
6-10Aryl)-C
1-4Alkoxyl group ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O)
2R
c,-C (O) O-(C
1-4Alkyl) OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl) OC (O)-(C
6-10Aryl); Wherein said phenyl, aryl and heteroaryl are optional by 0-2 R
fReplace;
R
9Be H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl; Wherein said alkyl and phenyl are optional by 0-2 R
fReplace;
R
9aBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
In addition, work as R
8And R
9When being connected on the identical nitrogen-atoms, it is combined together to form 5-to 10-unit and comprises carbon atom and 0-2 other N, O and the S (O) of being selected from
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
10aThe C that replaces
2-6Thiazolinyl, by 0-3 R
10aThe C that replaces
2-6Alkynyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
10aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, SR
a, F, CF
3, CN, NO
2,-C (O) OR
a,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8SO
2R
c-,-S (O) R
c, or-S (O)
2R
c
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CR
14R
15)
r-C
3-10Carbocyclic ring or
-(CR
14R
15)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
R
11aWhen occurring at every turn independently for H ,=O, C
1-4Alkyl, OR
a, CF
3, SR
a, F, CN, NO
2, NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-C (O) R
a,-C (O) OR
a,-S (O)
pR
c, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-to 1 0-unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
dReplace;
R
11bWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, CN, NO
2, CF
3, OCF
3, OCHF
2,-C (O) R
a,-C (O) OR
a,-SOR
c,-SO
2R
c,-NR
7R
8,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
1-4Haloalkyl, C
1-4Halogenated alkoxy-, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace;
R
12Be H, F or C when occurring independently at every turn
1-4Alkyl;
R
13Be H, C when occurring independently at every turn
1-6Alkyl ,-(CH
2)
n-phenyl ,-(CH
2)
n-(5-10 unit heteroaryl) ,-C (O) R
c,-C (O) OR
c,-CONR
8R
c,-OCONR
8R
c,-S (O)
2R
c,-C (O) O-(C
1-4Alkyl)-OC (O)-(C
1-4Alkyl) or-C (O) O-(C
1-4Alkyl)-OC (O)-(C
6-10Aryl); Wherein said alkyl, phenyl, heteroaryl, aryl are chosen wantonly by 0-2 R
fReplace;
R
14And R
15Be H, F or C when occurring independently at every turn
1-4Alkyl;
R in addition
14Can with R
15Be combined together to form=O;
R
aBe H, CF when occurring independently at every turn
3, C
1-6Alkyl ,-(CH
2)
r-C
3-7Cycloalkyl ,-(CH
2)
r-C
6-10Aryl or-(CH
2)
r-5-to 10 yuan comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said cycloalkyl, aryl and heteroaryl groups are optional by 0-2 R
fReplace;
R
bBe CF when occurring independently at every turn
3, OH, C
1-4Alkoxyl group, C
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace;
R
cBe CF when occurring independently at every turn
3, by 0-2 R
fThe C that replaces
1-6Alkyl, by 0-2 R
fThe C that replaces
3-6Cycloalkyl, C
6-10Aryl, 5-to 10-unit heteroaryl, (C
6-10Aryl)-C
1-4Alkyl or (5-to 10-unit heteroaryl)-C
1-4Alkyl, wherein said aryl and heteroaryl groups are optional by 0-3 R
fReplace;
R
dWhen occurring at every turn independently for H ,=O ,=NR
8, OR
a, F, Cl, Br, I, CN, NO
2,-NR
7R
8,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9,-NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, by 0-2 R
eThe C that replaces
1-6Alkyl, by 0-2 R
eThe C that replaces
2-6Thiazolinyl or by 0-2 R
eThe C that replaces
2-6Alkynyl;
R
eWhen occurring be independently=O, OR at every turn
a, F, Cl, Br, I, CN, NO
2,-NR
8R
9,-C (O) R
a,-C (O) OR
a,-OC (O) R
a,-NR
8C (O) R
a,-C (O) NR
7R
8,-SO
2NR
8R
9, NR
8SO
2NR
8R
9,-NR
8SO
2-C
1-4Alkyl ,-NR
8SO
2CF
3,-NR
8SO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl or-(CF
2)
rCF
3
R
fWhen occurring at every turn independently for H ,=O ,-(CH
2)
r-OR
g, F, Cl, Br, I, CN, NO
2,-NR
9aR
9a,-C (O) R
g,-C (O) OR
g,-NR
9aC (O) R
g,-C (O) NR
9aR
9a,-SO
2NR
9aR
9a,-NR
9aSO
2NR
9aR
9a,-NR
9aSO
2-C
1-4Alkyl ,-NR
9aSO
2CF
3,-NR
9aSO
2-phenyl ,-S (O)
2CF
3,-S (O)
p-C
1-4Alkyl ,-S (O)
p-phenyl ,-(CF
2)
rCF
3, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl or-(CH
2)
n-phenyl;
R
gBe H, C when occurring independently at every turn
1-6Alkyl or-(CH
2)
n-phenyl;
N is selected from 0,1,2,3 and 4 at every turn when occurring;
P is selected from 0,1 and 2 at every turn when occurring;
R is selected from 0,1,2,3 and 4 at every turn when occurring; And
S is selected from 1,2,3 and 4 at every turn when occurring;
Prerequisite is:
(a) work as group
For
I. and when L be-NHC (O)-time, R
14Not with R
15Be combined together to form=O;
Ii. and when L is phenyl for-C (O) NH-and A, R
1Be not-NHC (O) H;
(b) work as group
Be
I. and as L be-NHC (O)-and R
3With R
4During in conjunction with formation and thiazole condensed phenyl ring, this phenyl ring is by at least one R
3aReplace;
Ii. and as L be-C (O) NH-, and A is when being phenyl R
1Be not-NHC (O) H; And
(c) A is not for replacing or unsubstituted azoles quinoline ketone, thiophene, diazole or furans.
19, according to the compound of claim 18, wherein:
A is by 0-1 R
1With 0-3 R
2The C that replaces
3-8Cycloalkyl, by 0-1 R
1With 0-3 R
2The C that replaces
4-8Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring;
Z is-C (R
11) (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2)
sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-C
3-8Cycloalkyl, by 0-3 R
3aAnd R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
4Be H, F, Cl, Br, I, OCF
3, CF
3, OR
a, SR
a, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
4bReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace;
20, according to the compound of claim 18, wherein:
A is by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkyl, by 0-1 R
1With 0-2 R
2The C that replaces
5-6Cycloalkenyl group, by 0-1 R
1With 0-3 R
2The phenyl that replaces, by 0-1 R
1With 0-3 R
2Naphthyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-1 R
1With 0-3 R
2Replace; Prerequisite be when A be when containing the heterocycle of one or more nitrogen-atoms, A is not connected on the L by any nitrogen-atoms on the A ring;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2) sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace; With
R
6Be H or C when occurring independently at every turn
1-6Alkyl.
21, according to the compound of claim 18, wherein,
Group
Be selected from:
22, according to the compound of claim 18, wherein,
Group
Be selected from:
23, according to the compound of claim 18, wherein,
A is by 0-1 R
1With 0-2 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
Group
Be selected from:
Z is-CH (R
12)-;
L is-C (O) NR
10-,-NR
10C (O)-,-CH
2C (O) NR
10-,-CH
2NR
10C (O)-,-C (O) NR
10CH
2-or-NR
10C (O) CH
2-;
R
3When occurring be independently-(CH at every turn
2)
rC (O) NR
8R
9,-(CH
2)
rC (O) NR
8(CH
2)
sCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-naphthyl, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
3aWith 0-1 R
3dReplace;
R
4When occurring at every turn independently for H ,=O, F, Cl, Br, I, OCF
3, CF
3, CN, NO
2,-C (O) R
a,-C (O) OR
a,-NR
7R
8,-C (O) NR
8R
9,-NR
7C (O) R
b,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-S (O) R
c,-S (O)
2R
c, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4aThe C that replaces
2-6Thiazolinyl, by 0-2 R
4aThe C that replaces
2-6Alkynyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-3 R
4bReplace;
R
6Be H, C
1-6Alkyl or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-2 R
10aThe C that replaces
1-6Alkyl, by 0-2 R
dReplace-(CH
2)
r-phenyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
dReplace; And
R
12Be H, F or Me when occurring independently at every turn.
24, according to the compound of claim 18, wherein compound has structural formula (VI):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate, in the scope aspect the 18, wherein:
R
3For-(CH
2)
rC (O) NR
8R
9,-(CH
2)
sC (O) NR
8(CH
2)
rCO
2R
3b,-(CH
2)
rCO
2R
3b, by 0-3 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aReplace-(CH
2)
r-naphthyl, by 0-2 R
3aReplace-(CH
2)
r-indanyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
3aWith 0-1 R
3dReplace;
R
6Be H, C when occurring independently at every turn
1-6Alkyl ,-CH
2OR
a,-C (O) R
c,-C (O)
2R
c, or by 0-3 R
dReplace-(CH
2)
r-phenyl;
R
10When occurring at every turn independently for H, by 0-3 R
10aThe C that replaces
1-6Alkyl, by 0-3 R
dReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
dReplace; And
R
11Be C
1-4Haloalkyl ,-(CH
2)
rC (O) NR
8R
9, by 0-3 R
11aThe C that replaces
1-6Alkyl, by 0-3 R
11aThe C that replaces
2-6Thiazolinyl, by 0-3 R
11aThe C that replaces
2-6Alkynyl, by 0-3 R
11bReplace-(CH
2)
r-C
3-10Carbocyclic ring or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-3 R
11bReplace.
25, according to the compound of claim 24, wherein:
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aWith 0-1 R
3dReplace-(CH
2)
r-phenyl, by 0-2 R
3aWith 0-1 R
3dThe naphthyl that replaces, by 0-2 R
3aWith 0-1 R
3dThe indanyl that replaces or-(CH
2)
r-5 to 10-units comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aWith 0-1 R
3dReplace;
R
6Be H;
R
10When occurring at every turn independently for H, Me, benzyl, styroyl ,-CH
2CH
2CO
2H ,-CH
2CH
2CO
2Me ,-CH
2CH
2CO
2Et ,-CH
2CH
2CONH
2, or-CH
2CH
2CONHCH
2CH
2Ph; And
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or-(CH
2)
r-5-10 unit comprises carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
11bReplace.
26, according to the compound of claim 18, wherein compound has structural formula (VII):
Perhaps its steric isomer, tautomer, pharmacy acceptable salt or solvate,
A is by 0-2 R
1With 0-1 R
2Replace, and be selected from: C
3-7Cycloalkyl, phenyl, naphthyl, 1,2,3,4-tetralyl, pyridyl, indazolyl, benzimidazolyl-, benzisoxa azoles base, isoquinolyl, 5,6,7,8-tetrahydro isoquinolyl, 1,2,3,4-tetrahydro isoquinolyl, quinazolyl, 1H-quinazoline-4-one base, 2H-isoquinoline 99.9-1-ketone group, 3H-quinazoline-4-one base, 3,4-dihydro-2H-isoquinoline 99.9-1-ketone group, 2,3-xylylenimine quinoline ketone group and phthalazinyl;
L is-C (O) NH-or-NHC (O)-;
R
1When occurring at every turn independently for F, Cl, Me, Et ,-NH
2,-C (=NH) NH
2,-C (O) NH
2,-CH
2NH
2,-CH
2NHCO
2Bn ,-CH
2NHCO
2(t-Bu) ,-CH (Me) NH
2,-CMe
2NH
2,-NHEt ,-NHCO
2(t-Bu) ,-NHCO
2Bn ,-SO
2NH
2, OR
a, or-CH
2R
1a
R
3For-CO
2H ,-CO
2Me ,-C (O) NHCH
2CO
2H ,-C (O) NHCH
2CO
2Et ,-C (O) NH
2,-C (O) NHMe ,-C (O) NHBn, by 0-2 R
3aThe phenyl that replaces, by 0-2 R
3aThe naphthyl that replaces, by 0-2 R
3aIndanyl that replaces or 5-to 10-unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-2
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
3aReplace;
R
4Be H, F, Cl, Br, CF
3, CO
2H, CO
2Me, CO
2Et, by 0-2 R
4aThe C that replaces
1-6Alkyl, by 0-2 R
4bPhenyl that replaces or 5-10 unit comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, wherein said heterocycle is by 0-2 R
4bReplace;
R
11Be C
1-6Alkyl ,-CH
2CONR
8R
9,-CH
2CH
2CONR
8R
9,-CH
2OBn ,-CH
2SBn, by 0-2 R
11bReplace-(CH
2)
r-C
3-7Cycloalkyl, by 0-2 R
11bReplace-(CH
2)
r-phenyl, by 0-2 R
11bReplace-(CH
2)
r-naphthyl or by 0-2 R
11bReplace-(CH
2)
r-5-to 10-unit heteroaryl, and be selected from thiazolyl, azoles base, triazolyl, tetrazyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indyl, pseudoindoyl, indoline base, isoindoline base, benzimidazolyl-, benzothiazolyl, quinolyl, isoquinolyl, tetrahydric quinoline group and tetrahydro isoquinolyl; And
R
11bBe H, F, Cl, Br, CF when occurring independently at every turn
3, OMe, OEt, O (i-Pr), OCF
3, OCHF
2, CN, OPh, OBn, NO
2,-NH
2,-C (O) R
a,-C (O) OR
a,-C (O) NR
7R
8,-NR
7C (O) R
b,-NR
8C (O)
2R
c,-S (O)
pNR
8R
9,-NR
8S (O)
pR
c,-SO
2R
c, C
1-C
4-alkyl, Ph or Bn;
In addition, as two R
11bWhen group was the substituting group that is positioned on the adjacent atom, they can form 5-to 7-unit with the atom that it connected and comprise carbon atom and individual N, O and the S (O) of being selected from of 1-4
pHeteroatomic heterocycle, and by 0-2 R
gReplace.
27, according to the compound of claim 26, wherein:
A is 4-CH
2NH
2-cyclohexyl or 4-amidino groups-phenyl; And
R
3Be phenyl, 3-CN-phenyl, 4-CN-phenyl, 3-Br-phenyl, 4-Br-phenyl, 3-OMe-phenyl, 4-OMe-phenyl, 3-CF
3-phenyl, 4-CF
3-phenyl, 3-CO
2H-phenyl, 4-CO
2H-phenyl, 4-CO
2Me-phenyl, 4-CH
2CO
2H-phenyl, 4-CH
2CO
2Me-phenyl, 3-CONH
2-phenyl, 4-CONH
2-phenyl, 4-CONHMe-phenyl, 4-CON (Me)
2-phenyl, 4-CH
2CONH
2-phenyl, 4-amidino groups-phenyl or 2,4-two fluoro-phenyl.
28, compound, it is selected from following compounds:
(S)-4-carbamimidoyl-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl) benzamide,
(S)-4-(amino methyl)-N-(2-phenyl-1-(4-phenyl-1H-imidazoles-2-yl) ethyl)-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-{1-[4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-{1-[4-(4-bromo-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-{1-[4-(4-methoxyl group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(1-benzyl-1H-imidazol-4 yl)-1-(4-phenyl-1H-imidazoles-2-yl)-ethyl]-trans-cyclohexane carboxamide,
(S)-3-(2-{1-[is trans-(4-amino methyl)-hexanaphthene formamido group]-2-phenyl-ethyl }-the 1H-imidazol-4 yl }-methyl benzoate,
(S)-4-(amino methyl)-N-{1-[4-(3-fluoro-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-{1-[4-(3-bromo-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(3-chloro-phenyl-)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(4-chloro-phenyl-)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[1-(4-phenyl-1H-imidazoles-2-yl)-2-(2-pyridyl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-phenyl-1-(4-thiazol-2-yl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-phenyl-1-(4-pyridine-2-base-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-[4-(2-{1-[is trans-(4-amino methyl)-hexanaphthene formamido group]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)-phenyl]-acetate,
(S)-4-(amino methyl)-N-{1-[(4-carbamyl ylmethyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-[4-(2-{1-[(4-amino methyl)-hexanaphthene formamido group]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)]-benzamide,
(S)-[3-(2-{1-[(4-amino methyl)-hexanaphthene formamido group]-2-phenyl-ethyl }-the 1H-imidazol-4 yl)]-benzamide,
(S)-4-(2-(1-trans-(4-amino methyl)-hexanaphthene formamido group)-2-phenylethyl)-1H-imidazol-4 yl)-N, the N-dimethyl benzamide,
(S)-2-(1-is trans-(4-amino methyl)-hexanaphthene formamido group }-the 2-phenylethyl)-1H-benzo [d] imidazoles-5-methane amide,
N-(4-carbamimidoyl phenyl)-3-phenyl-2-(4-phenyl-1H-imidazoles-2-yl) propionic acid amide,
4-(2-(1-(4-carbamimidoyl phenyl amino)-1-oxo-3-phenyl third-2-yl)-1H-imidazol-4 yl) benzamide,
4-(2-(1-(1-aminoisoquinoline-6-base is amino)-1-oxo-3-phenyl third-2-yl)-1H-imidazol-4 yl) benzamide,
4-(2-(4-(4-carbamimidoyl phenyl)-1H-imidazoles-2-yl)-3-phenyl propionamido) benzamide,
(S)-4-(amino methyl)-N-{1-[4-(2,4-two fluoro-phenyl }-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-{1-[4-(4-fluoro-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
(S)-3-(2-(1-trans-(4-amino methyl)-hexanaphthene formamido group)-2-phenylethyl)-1H-imidazol-4 yl)-phenylformic acid,
(S)-N-(1-(4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl)-2-phenylethyl)-4-(amino methyl)-trans-cyclohexane carboxamide,
4-[2-[1-[4-[4-(the carbamimidoyl phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-the 1H-imidazol-4 yl]-benzamide,
(S)-4-(amino methyl)-N-[1-(4-phenyl-1H-imidazoles-2-yl)-2-(4-pyridyl) ethyl]-trans-cyclohexane carboxamide,
(S)-and 4-[2-[1-[4-(amino methyl) hexanaphthene formamido group] amino]-the 2-phenylethyl]-4-(bromo-1H-imidazoles-5-yl)-benzamide,
(S)-3-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-the 1H-imidazol-4 yl]-toluylic acid,
(S)-3-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-the 1H-imidazol-4 yl]-phenylacetamide,
(S)-4-(amino methyl)-N-[1-[4-(3-hydroxy phenyl)-1H-imidazoles-2-yl]-the 2-phenylethyl]-trans-cyclohexane carboxamide,
(S)-3-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-the 1H-imidazol-4 yl]-Phenylacetic acid ethylester,
2-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-3, N-phenylbenzene-propionic acid amide,
(S)-4-(amino methyl)-N-[2-(4-fluorophenyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-[4-(benzyloxy) phenyl]-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(4-benzoyl phenyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-and 4-(amino methyl)-N-[1-(4-phenyl-1H-imidazoles-2-yl)-2-[3-(trifluoromethyl) phenyl] ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[-2-(3-nitrophenyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(2-chloro-phenyl-)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(1-naphthyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[2-(2-naphthyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-and 4-(amino methyl)-N-[-1-[4,5-two (3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-the 2-phenylethyl]-trans-cyclohexane carboxamide,
(S)-4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-4-(trifluoromethyl)-1H-imidazoles-5-yl]-benzamide,
(S)-N-[1-[4-[4-(carbamimidoyl) phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-benzamide,
(S)-4-(amino methyl)-N-[2-(2-bromophenyl)-1-(4-phenyl-1H-imidazoles-2-yl) ethyl]-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-bromo-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-5-[4-(the formamyl phenyl]-2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-1H-imidazoles-4-methyl-formiate,
4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-2-[2-(trifluoromethoxy) phenyl] ethyl]-the 1H-imidazol-4 yl]-benzamide,
4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-2-[2-(difluoro-methoxy) phenyl] ethyl]-the 1H-imidazol-4 yl]-benzamide,
(S)-N-[1-[4-[4-(formamyl) phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-benzamide,
(S)-N-[1-[4-[4-(formamyl) phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-2-fluoro-benzamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-styroyl]-4-(amino methyl)-benzamide,
(S)-3-amino-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-1H-indazole-6-methane amide,
(S)-3-amino-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-1,2-benzisoxa azoles-6-methane amide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-2-fluoro-benzamide,
(S)-N-[1-[4-[4-(carbamimidoyl) phenyl]-1-(2-phenylethyl)-1H-imidazoles-2-yl]-the 2-phenylethyl]-benzamide,
(S)-N-[1-[4-[4-(carbamimidoyl) phenyl]-1-methyl isophthalic acid H-imidazoles-2-yl]-the 2-phenylethyl]-benzamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-2-fluoro-5-methoxyl group-benzamide,
(S)-4-[2-[(1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-4-chloro-1H-imidazoles-5-yl]-benzamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-1, the 4-benzenedicarboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(2,2-dimethyl-1,3-benzo dioxole-4-yl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-2-[3-(difluoro-methoxy) phenyl] ethyl]-the 1H-imidazol-4 yl]-benzamide,
(S)-4-[2-[1-[4-(amino methyl) hexanaphthene formamido group]-the 2-phenylethyl]-4-phenyl-1H-imidazoles-5-yl]-benzamide,
(S)-1-amino-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-6-isoquinoline 99.9 methane amide,
(S)-1-amino-N-[1-[4-{3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-5,6,7,8-tetrahydrochysene-6-isoquinoline 99.9 methane amide,
N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(3-Phenoxyphenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(2-Phenoxyphenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
1-amino-N-[(1 S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-5,6,7, the 8-tetrahydrochysene-(6S)-6-isoquinoline 99.9 methane amide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(2-nitrophenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[-1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(3-nitrophenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(2-aminophenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(3-aminophenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[1,1 '-biphenyl]-2-base ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[1,1 '-biphenyl]-3-base ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-1,2,3,4-tetrahydrochysene-6-isoquinoline 99.9 methane amide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-the 2-[3-[(benzenesulfonyl) amino] phenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
N-[2-(2S)-[2-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[[is trans-[4-(amino methyl) hexanaphthene formamido group] ethyl] and phenyl]-phenylacetamide,
N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[(2S)-and 2-methyl-2-(2-phenylethyl)-1,3-benzo dioxole-4-yl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[(2R)-and 2-methyl-2-(2-phenylethyl)-1,3-benzo dioxole-4-yl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-4-(amino methyl)-N-[1-[4-(4-amino-7-quinazolyl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-trans-cyclohexane carboxamide,
N-[2-[(2S)-2-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[[[is trans-4-(amino methyl) hexanaphthene formamido group] and ethyl] phenyl]-hydrocinnamamide,
(S)-N-1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-the 2-[2-[(benzenesulfonyl) amino] phenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[2-(phenyl methoxyl group) phenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
N-[2-[(2S)-2-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-[[[is trans-4-(amino methyl) hexanaphthene formamido group] and ethyl] phenyl]-benzamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl }-1H-imidazoles-2-yl]-2-(2-bromophenyl) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-and N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3, the 3-dimethylbutyl]-4-(amino methyl)-, it is trans-cyclohexane carboxamide,
(R)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-2-(phenyl methoxyl group) ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(R)-N-[1-[4-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-the 2-[(phenyl methyl) sulfenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-and N-[1-[4-(3-amino-4-fluoro-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl] the 2-phenylethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-N-[1-[4-(3-amino-5-fluoro-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
3-[2-[4-[4-(aminocarboxyl) phenyl]-1H-imidazoles-2-yl]-2-[[[is trans-4-(amino methyl) hexanaphthene formamido group] and ethyl]-methyl benzoate,
N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-[3-(difluoro-methoxy) phenyl] ethyl]-4-(amino methyl)-trans-cyclohexane carboxamide,
(S)-3-amino-N-[1-[4-[4-(carbamimidoyll) phenyl]-1H-imidazoles-2-yl]-the 2-phenylethyl]-1H-indazole-5-methane amide,
3-[2-[4-[4-(aminocarboxyl) phenyl]-1H-imidazoles-2-yl]-2-[[[is trans-4-(amino methyl) hexanaphthene formamido group] and ethyl]-phenylformic acid,
(S)-3-amino-N-{1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-1H-indazole-6-methane amide,
(S)-N-{1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-1H-indazole-6-methane amide,
(S)-N-{1-[4-(4-carbamimidoyl-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-1H-indoles-6-methane amide,
(S)-N-{1-[4-(4-carbamimidoyl-phenyl)-1-ethyl-1H-imidazoles-2-yl]-2-phenyl-ethyl }-benzamide,
N
1-(S)-1-[4-{3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-terephthalamide,
N
1-(S)-1-[4-(4-amino-quinazolines-7-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-terephthalamide,
1-amino-N-[(1S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-the 2-phenylethyl]-5,6,7, the 8-tetrahydrochysene-(6R)-6-isoquinoline 99.9 methane amide,
(S)-1-amino-N-{1-[4-(4-amino-quinazolines-7-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
(S)-1-amino-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-3-methyl-isoquinoline 99.9-6-methane amide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-piperidines-1-carbonyl)-phenyl]-ethyl }-1 H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(neighbour-tolyl formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(methyl-phenyl-formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(benzylamino formyl radical)-phenyl]-ethyl }-the 1H-imidazol-4 yl }-benzamide,
(S)-N-{1-[4-(3-amino-7-fluoro-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
(S)-N-{1-[4-(3-amino-1H-indazole-5-yl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
(S)-N-{1-[4-(3-hydroxyl-1H-indazole-5-yl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
(S) 4-amino methyl-N-[1-(4-biphenyl-4-base-1H-imidazoles-2-yl)-2-phenyl-ethyl]-trans-cyclohexane carboxamide,
(S)-4-amino methyl-N-[1-(4-benzo [1,3] dioxole-5-base-1H-imidazoles-2-yl)-2-phenyl-ethyl]-cyclohexane carboxamide,
(S)-4-amino methyl-N-[1-(4-naphthalene-2-base-1H-imidazoles-2-yl)-2-phenyl-ethyl]-trans-cyclohexane carboxamide,
N
4-(S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-methoxyl group-terephthalamide,
(S)-4-amino methyl-N-{1-[4-(3-amino-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-cyclohexane carboxamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-isobutyl--formamyl-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(3-methyl-butyl formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-tertiary butyl formamyl-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(4-chloro-benzylamino formyl radical)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamyl]-2-[3-(4-chloro-benzylamino formyl radical)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamyl]-2-[3-(4-methoxyl group-benzylamino formyl radical)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamyl]-2-[3-styroyl formamyl-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamyl]-2-[3-[2-(4-chloro-phenyl)-ethylamino formyl radical]-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-[2-(4-methoxyl group-phenyl)-ethylamino formyl radical]-phenyl]-ethyl }-the 1H-imidazol-4 yl }-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(3-phenyl-propyl group formamyl)-phenyl]-ethyl)-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(benzyl-methyl-formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(methyl-styroyl-formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-m-tolyl-formamyl-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-p-methylphenyl-formamyl-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(4-fluoro-phenyl amino formyl radical)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(naphthalene-1-base formamyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(4-phenyl-piperidines-1-carbonyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-trans-hexanaphthene formamido group]-2-[3-(3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl)-phenyl]-ethyl }-the 1H-imidazol-4 yl)-benzamide,
(S)-N-[1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-(3-phenylsulfonamido-phenyl)-ethyl]-4-amino methyl-trans-cyclohexane carboxamide,
(S)-N-{1-[4-(4-benzyloxy-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
(S)-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-1-oxo-1,2-dihydro-isoquinoline 99.9-6-methane amide,
(S)-N-{1-[5-chloro-4-(2,4-diamino-quinazoline-7-yl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
(S)-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-3-amino-1H-indazole-5-methane amide,
4-(2-{ (S)-1-[(4-amino methyl-trans-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-5-bromo-1H-imidazol-4 yl)-2-fluoro-benzamide,
4-(2-{ (S)-1-[(4-amino methyl-trans-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-5-chloro-1 H-imidazol-4 yl)-2-fluoro-benzamide,
(S)-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-1-oxo-1,2,3,4-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
(S)-N-[1-(5-methyl-4-phenyl-1H-imidazoles-2-yl)-2-phenyl-ethyl]-4-amino methyl-trans-cyclohexane carboxamide,
4-(2-{ (S)-1-[(4-amino methyl-trans-hexanaphthene carbonyl)-amino]-2-phenyl-ethyl }-5-methyl isophthalic acid H-imidazol-4 yl)-benzamide,
(S)-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-trans-cyclohexane carboxamide,
1-amino-N-{ (S)-1-[4-(4-formamyl-phenyl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
1-amino-N-{ (S)-1-[4-(4-formamyl-phenyl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-carboxylic acid,
1-amino-N-{ (S)-1-[4-(4-formamyl-phenyl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
1-amino-N-{ (S)-1-[4-(4-formamyl-phenyl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-carboxylic acid,
4-amino methyl-N-{ (S)-1-[4-(6-amino-pyridine-3-yl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
4-amino methyl-N-{ (S)-1-[4-(3-chloro-phenyl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
5-(2-{ (S)-1-[(4-amino methyl-hexanaphthene formamido group]-2-phenyl-ethyl }-5-methyl isophthalic acid H-imidazol-4 yl)-thiophene-2-carboxylic acid,
5-(2-{ (S)-1-[(4-amino methyl-hexanaphthene formamido group]-2-phenyl-ethyl }-5-methyl isophthalic acid H-imidazol-4 yl)-thiophene-2-carboxamide derivatives,
N
4-(S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-phenoxymethyl-terephthalamide,
N-{ (S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-amino methyl-2-benzyl-benzamide,
6 (S)-1-amino-N-{ (S)-1-[5-chloro-4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
6 (R)-1-amino-N-{ (S)-1-[5-chloro-4-(4-cyano group-phenyl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
N-{ (S)-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-4-methyl-benzamide,
4-(2-{ (S)-2-(3-acetylaminohydroxyphenylarsonic acid phenyl)-1-[(4-amino methyl-hexanaphthene formamido group]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-amino methyl-N-{ (S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-[(5-methyl-pyrazine-2-ylmethyl)-formamyl]-propyl group }-cyclohexane carboxamide,
The 4-amino methyl-N-[(S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-(benzyl-methyl-formamyl)-propyl group]-cyclohexane carboxamide,
The 4-amino methyl-N-[(S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-(benzyl-formamyl)-propyl group]-cyclohexane carboxamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(ethyl-methyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(isopropyl-methyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(isobutyl--methyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(methyl-phenyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(ethyl-phenyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(methyl-m-toluyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(methyl-p-toluyl-formamyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[(3-chloro-benzyl)-methyl-formamyl]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[(4-chloro-benzyl)-methyl-formamyl]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[2-(2-chloro-phenyl) ethylamino formyl radical]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[2-(3-chloro-phenyl) ethylamino formyl radical]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[2-(4-chloro-phenyl) ethylamino formyl radical]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-amino methyl-N-{ (S)-1-[4-(4-methanesulfonamido-phenyl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
The 4-amino methyl-N-[(S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-(cyclopropyl methyl-formamyl)-propyl group]-trans-cyclohexane carboxamide,
The 4-amino methyl-N-[(S)-1-[5-(3-amino-1H-indazole-6-yl)-1H-imidazoles-2-yl]-3-(2-(phenyl) ethyl-formamyl)-propyl group]-trans-cyclohexane carboxamide,
4-amino methyl-N-{ (S)-1-[4-(4-acetylaminohydroxyphenylarsonic acid phenyl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
4-amino methyl-N-{ (S)-1-[4-(4-hydroxyl-phenyl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
4-[2-(1-[(4-amino methyl-hexanaphthene formamido group]-2-{3-[methyl-(2-pyridine-2-base-ethyl)-formamyl]-phenyl }-ethyl)-5-chloro-1H-imidazol-4 yl]-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(2,3-dihydro-indoles-1-carbonyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(1,3-dihydro-isoindole-2-carbonyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(2,3-dihydro-1,4-benzoxazine-4-carbonyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-(2-{1-[(4-amino methyl-hexanaphthene formamido group]-2-[3-(6-methyl-3,4-dihydro-2H-quinoline-1-carbonyl)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-amino methyl-N-{ (S)-1-[4-(1H-indazole-6-yl)-S-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
1-amino-N-{ (S)-1-[4-(3-amino-7-fluoro-1H-indazole-6-yl }-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-5,6,7,8-tetrahydrochysene-isoquinoline 99.9-6-methane amide,
4-amino methyl-N-{1-[4-(1H-indazole-6-yl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
4-amino methyl-N-{1-[4-(3-acetylaminohydroxyphenylarsonic acid phenyl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
5-(2-{1-[is trans-4-amino methyl-hexanaphthene formamido group]-2-phenyl-ethyl }-5-chloro-1H-imidazol-4 yl)-thiophene-2-carboxylic acid,
N
1-1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-chloro-terephthalamide,
4-amino methyl-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-3-[(thiazol-2-yl methyl)-formamyl]-propyl group }-trans-cyclohexane carboxamide,
4-amino methyl-N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-3-[(pyridine-2-ylmethyl)-formamyl]-propyl group }-trans-cyclohexane carboxamide,
4-amino methyl-N-{1-[5-methyl-4-(3-oxo-2,3-dihydro-1H-isoindole-5-yl)-1H-imidazoles-2-yl]-2-phenyl-ethyl }-trans-cyclohexane carboxamide,
[4-(2-{1-[is trans-4-amino methyl-hexanaphthene formamido group]-2-phenyl-ethyl }-5-methyl isophthalic acid H-imidazol-4 yl)-phenyl]-Urethylane,
4-(2-{1-[is trans-4-amino methyl-hexanaphthene formamido group]-2-[3-(methyl-phenyl-sulfamyl }-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-{2-[1-[is trans-4-amino methyl-hexanaphthene formamido group]-2-(3-benzenesulfonyl-methyl-amino-phenyl)-ethyl]-5-chloro-1H-imidazol-4 yl }-benzamide,
4-(2-{1-[is trans-4-amino methyl-hexanaphthene formamido group]-2-[3-(benzoyl-methyl-amino)-phenyl]-ethyl }-5-chloro-1H-imidazol-4 yl)-benzamide,
4-amino methyl-N-{1-[4-(1-imino--4-oxo-1,2,3,4-tetrahydrochysene-phthalazines-6-yl)-5-methyl isophthalic acid H-imidazoles-2-yl]-2-phenyl-ethyl)-trans-cyclohexane carboxamide,
4-amino methyl-N-(1-{5-methyl-4-[3-(2H-tetrazolium-5-yl }-phenyl]-1H-imidazoles-2-yl }-2-phenyl-ethyl)-trans-cyclohexane carboxamide,
N-{1-[4-(3-amino-1H-indazole-6-yl)-5-chloro-1H-imidazoles-2-yl]-2-phenyl-ethyl }-2-fluoro-4-methyl-benzamide,
Or its steric isomer, tautomer, pharmacy acceptable salt or solvate.
29, a kind of pharmaceutical composition, it comprises: any one compound among the claim 1-28 of pharmaceutically acceptable carrier and treatment significant quantity.
30, a kind of method for the treatment of thromboembolic states or inflammatory diseases, this method comprise any one compound in the claim 1-28 of patient's drug treatment significant quantity of this treatment of needs.
31, according to the method for the treatment thrombotic disease of claim 30, wherein thrombotic disease is selected from the thrombotic disease in artery cardiovascular thromboembolic disease, vein cardiovascular thromboembolic disease and the heart chamber.
32, according to the method for claim 31, wherein thrombotic disease is selected from: unstable angina, acute coronary syndrome, auricular fibrillation, first myocardial infarction, the recidivity myocardial infarction, the ischemic sudden death, one property crossed local asphyxia outbreak, apoplexy, atherosclerosis, periphery occlusive artery disease, venous thrombosis, venous thrombosis, thrombophlebitis, arterial thrombosis disease, Coronary thrombosis, cerebral artery thrombosis forms, cerebral embolism disease, renal infarction disease, the thrombosis that pulmonary infarction disease and underlying cause cause: (a) artificial valve or other implants, (b) inlying catheter, (c) Si Tante support, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other make blood in artificial surface to impel thrombotic operation.
33, any one compound among the claim 1-28, it is used for the treatment of.
34, each compound is used to prepare the purposes of the medicine that is used for the treatment of thromboembolic states or inflammatory diseases among the claim 1-28.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US57963804P | 2004-06-15 | 2004-06-15 | |
| US60/579,638 | 2004-06-15 | ||
| US68412705P | 2005-05-24 | 2005-05-24 | |
| US60/684,127 | 2005-05-24 | ||
| US11/151,667 | 2005-06-13 | ||
| US11/151,667 US7453002B2 (en) | 2004-06-15 | 2005-06-13 | Five-membered heterocycles useful as serine protease inhibitors |
| PCT/US2005/021212 WO2005123050A2 (en) | 2004-06-15 | 2005-06-14 | Five-membered heterocycles useful as serine protease inhibitors |
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| Publication Number | Publication Date |
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| CN101006063A true CN101006063A (en) | 2007-07-25 |
| CN101006063B CN101006063B (en) | 2013-07-17 |
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| CN200580027843.XA Expired - Fee Related CN101006063B (en) | 2004-06-15 | 2005-06-14 | Five-membered heterocycles useful as serine protease inhibitors. |
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| ZA (1) | ZA200610586B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973809A (en) * | 2010-02-11 | 2018-05-01 | 百时美施贵宝公司 | Big ring class as factor XI, plasma thromboplastin antecedent A inhibitor |
| CN110511213A (en) * | 2018-05-22 | 2019-11-29 | 成都先导药物开发股份有限公司 | A kind of immunomodulator |
| CN112341446A (en) * | 2019-08-09 | 2021-02-09 | 成都先导药物开发股份有限公司 | Immunomodulator |
-
2005
- 2005-06-14 CN CN200580027843.XA patent/CN101006063B/en not_active Expired - Fee Related
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2006
- 2006-12-15 ZA ZA200610588A patent/ZA200610586B/en unknown
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973809A (en) * | 2010-02-11 | 2018-05-01 | 百时美施贵宝公司 | Big ring class as factor XI, plasma thromboplastin antecedent A inhibitor |
| US11136327B2 (en) | 2010-02-11 | 2021-10-05 | Bristol-Myers Squibb Company | Macrocycles as factor XIA inhibitors |
| CN107973809B (en) * | 2010-02-11 | 2023-06-30 | 百时美施贵宝公司 | Macrocyclic compounds as factor XIA inhibitors |
| CN110511213A (en) * | 2018-05-22 | 2019-11-29 | 成都先导药物开发股份有限公司 | A kind of immunomodulator |
| CN112341446A (en) * | 2019-08-09 | 2021-02-09 | 成都先导药物开发股份有限公司 | Immunomodulator |
| WO2021027722A1 (en) * | 2019-08-09 | 2021-02-18 | 成都先导药物开发股份有限公司 | Immunomodulator |
| CN112341446B (en) * | 2019-08-09 | 2022-06-17 | 成都先导药物开发股份有限公司 | Immunomodulator |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200610586B (en) | 2008-12-31 |
| CN101006063B (en) | 2013-07-17 |
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