CN101374839A - Azaindoles useful as inhibitors of janus kinases - Google Patents

Azaindoles useful as inhibitors of janus kinases Download PDF

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Publication number
CN101374839A
CN101374839A CNA2007800032602A CN200780003260A CN101374839A CN 101374839 A CN101374839 A CN 101374839A CN A2007800032602 A CNA2007800032602 A CN A2007800032602A CN 200780003260 A CN200780003260 A CN 200780003260A CN 101374839 A CN101374839 A CN 101374839A
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compound
dmso
disease
500mhz
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Inventor
L·法莫
G·马蒂内兹-伯塔拉
A·皮尔斯
F·萨利特罗
王健
M·沃纳姆科
王天生
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

Description

Be suitable for the Azaindoles of making the Zhan Nasi kinase inhibitor
Technical field
The present invention relates to be suitable for the compound of making Zhan Nasi (Janus) kinases (JAK) inhibitor.The present invention also provides pharmaceutically acceptable composition that comprises The compounds of this invention and the method that said composition is used for the treatment of various disease.
Background technology
Zhan Nasi kinases (JAK) is gang's Tyrosylprotein kinase, and it is made up of JAK1, JAK2, JAK3 and TYK2.JAK plays keying action in the cytokine signaling conduction.The downstream substrate of JAK family kinase comprises signal transduction and transcriptional activation (STAT) albumen.The JAK/STAT signal transduction relates to many abnormal immune reactions as transformation reactions, asthma, autoimmune disease such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia and lymphadenomatous mediation.JAK2 also relates to myeloproliferative disorder, and it comprises polycyth(a)emia, essential thrombocythemia, chronic spontaneous myelofibrosis, with the life of marrow alienation, chronic myelocytic leukemia, chronic myelomonocytic leukemia, chronic acidophil leukecythemia, hypereosinophilic syndrome and the systemic mast cell disease of myelofibrosis.
Therefore, be starved of exploitation and be suitable for the compound of making kinases inhibitor.Especially, the suitable compound of making the JAK family kinase inhibitors of exploitation will be desirable.
Summary of the invention
Have now found that compound of the present invention and pharmaceutically acceptable composition thereof are effectively as kinases inhibitor, are effective as the JAK family kinase inhibitors especially.These compounds have general formula I:
Figure A200780003260D00131
Or its pharmacy acceptable salt, wherein X 1, R 1, R 2And R 3As defined herein.
These compounds and its pharmacy acceptable salt can be used for treating patient's multiple disease or alleviate its severity, and described disease comprises proliferative disease, heart disease, neurodegenerative disease, autoimmune disorder, situation, inflammatory diseases or the immune-mediated disease relevant with organ transplantation.
These compounds provided by the invention and composition also can be used for the research of jak kinase in biology and the pathology phenomenon; Research by the kinase mediated intracellular signal transduction approach of this class; And the comparative evaluation of Azaindole kinase inhibitors.
Definition and general terms
Except as otherwise noted, otherwise should be suitable for used herein to give a definition.With regard to purpose of the present invention, chemical element is according to the periodic table of elements, CAS version and Handbook of Chemistryand Physics, the 75th edition, 1994 evaluations.In addition, vitochemical rule is at " Organic Chemistry ", Thomas Sorrell, University Science Books, Sausalito:1999, " March ' s Advanced Organic Chemistry ", the 5th edition, Smith, M.B. and March, J. compile John Wiley ﹠amp; Sons describes among the New York:2001, and their full content is all incorporated this paper by reference into.
As described herein, compound of the present invention can be chosen wantonly by one or more substituting groups and replace, and these substituting groups are above general illustrational, or illustrational by the concrete class of the present invention, subclass and kind.Should understand, phrase " optional replacement " can exchange with phrase " replacement or unsubstituted " and use.Usually, term " replacement ", no matter whether the front has added " choosing wantonly ", all is meant with the one or more hydrogen groups in the specified substituent group replacement known structure.Except as otherwise noted, but the optional group that replaces can have substituting group at each the position of substitution of group.When an available more than substituting group that is selected from designated groups replaced a more than position in any known structure, each locational substituting group can be identical or different.
As described herein, in the time of before term " optional replacement " is positioned at list, described term is meant the replaced group of all back in this list.If substituting group group or structure are not determined or are defined as " optional replacement ", then this substituting group group or structure are unsubstituted.For example, if X is a halogen, the optional C that replaces 1-3Alkyl or phenyl; X can be optional alkyl that replaces or the optional phenyl that replaces.Equally, except as otherwise noted, if term " optional replacement " is followed after list, then described term also refers to all the replaced groups before list.For example: if X is halogen, C 1-3Alkyl or phenyl, wherein X is optional by J XReplace, then C 1-3Alkyl and phenyl all can be chosen wantonly by J XReplace.To not comprise as H, halogen, NO 2, CN, NH 2, OH or OCF 3Deng group, because they are not commutable groups, this is obvious for the one of ordinary skilled in the art.
The substituting group combination of the present invention's expection preferably can form those substituting groups of stable or chemically feasible compound.As used herein, term " stable " is meant and allows their production, detection when experience, and when preferably allowing their recovery, purifying and being used for the condition of one or more purposes disclosed herein, basically the compound that can not change.In some embodiments, stable compound or chemically feasible compound are under the condition that does not have moisture or other chemical reactivity condition to exist, when under 40 ℃ or lower temperature, keeping at least one week, and the compound that can not change basically.
As used herein, term " aliphatic series " or " aliphatic group " expression straight chain (promptly unbranched) or side chain, replacement or unsubstituted hydrocarbon chain, it is saturated fully or comprises one or more unsaturated units.Except as otherwise noted, aliphatic group comprises 1-20 aliphatic carbon atom.In some embodiments, aliphatic group comprises 1-10 aliphatic carbon atom.In other embodiments, aliphatic group comprises 1-8 aliphatic carbon atom.In other embodiments, aliphatic group comprises 1-6 aliphatic carbon atom, and in other embodiments, aliphatic group comprises 1-4 aliphatic carbon atom.Suitable aliphatic group include, but not limited to line style or side chain, replacement or unsubstituted alkyl, alkenyl or alkynyl.The further example of aliphatic group comprises methyl, ethyl, propyl group, butyl, sec.-propyl, isobutyl-, vinyl and sec-butyl.
Term " alicyclic " (or " carbocyclic ring " or " cycloalkyl ") is meant hydrocarbon saturated or that comprise one or more unsaturated units fully, but it is not fragrant, have the single point that links to each other with the molecule remainder, and the arbitrary independent ring in the wherein said bicyclic system has 3-7 unit.Except as otherwise noted, term " alicyclic " is meant monocyclic C 3-C 8The C of hydrocarbon or dicyclo 8-C 12Hydrocarbon.Suitable alicyclic group includes, but not limited to cycloalkyl, cycloalkenyl group or cycloalkynyl radical.The further example of alicyclic group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl and cycloheptenyl.
As used herein, term " heterocycle ", " heterocyclic radical " or " heterocyclic " are meant that wherein one or more ring memberses are independent heteroatomic monocycle, dicyclo or three-loop systems of selecting, and this system is saturated fully or comprises one or more unsaturated units, but it is not fragrant, has the single point that links to each other with the molecule remainder.In some embodiments, " heterocycle ", " heterocyclic radical " or " heterocyclic " group have 3-14 ring members, wherein one or more ring memberses are the heteroatomss that are independently selected from oxygen, sulphur, nitrogen or phosphorus, and each ring in the system comprises 3-7 ring members.
The heterocyclic example comprises, but be not limited to following monocycle: the 2-tetrahydrofuran base, the 3-tetrahydrofuran base, the 2-tetrahydro-thienyl, the 3-tetrahydro-thienyl, the 2-morpholino, the 3-morpholino, the 4-morpholino, 2-thiomorpholine generation, 3-thiomorpholine generation, 4-thiomorpholine generation, the 1-pyrrolidyl, the 2-pyrrolidyl, the 3-pyrrolidyl, 1-tetrahydrochysene piperazinyl, 2-tetrahydrochysene piperazinyl, 3-tetrahydrochysene piperazinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 1-pyrazolinyl, the 3-pyrazolinyl, the 4-pyrazolinyl, the 5-pyrazolinyl, piperidino, the 2-piperidyl, the 3-piperidyl, the 4-piperidyl, the 2-thiazolidyl, the 3-thiazolidyl, the 4-thiazolidyl, the 1-imidazolidyl, the 2-imidazolidyl, the 4-imidazolidyl, the 5-imidazolidyl; With following dicyclo: 3-1H-benzimidazolyl-2 radicals-ketone, 3-(1-alkyl)-benzimidazolyl-2 radicals-ketone, indolinyl, tetrahydric quinoline group, tetrahydro isoquinolyl, benzo thiacyclopentane, benzo dithian and 1,3-dihydro-imidazol--2-ketone.
One or more oxygen, sulphur, nitrogen, phosphorus or silicon represented in term " heteroatoms ", the any oxidised form that comprises nitrogen, sulphur, phosphorus or silicon, the quaternized form of any basic nitrogen, or heterocyclic can replace nitrogen, for example N (as 3, the N in the 4-dihydro-2 h-pyrrole base), NH (as the NH in the pyrrolidyl) or NR +(as the NR in the pyrrolidyl of N-replacement +).
As used herein, term " undersaturated " represents that certain part has one or more unsaturated units.
Use or be used as major part separately and be meant to have monocycle, dicyclo and the three ring carbon-loop systems that amount to 6-14 ring members as term " aryl " a part of in " aralkyl ", " aralkoxy " or " aryloxy alkyl ", wherein at least one ring in the system is fragrant, wherein the ring of each in the system all comprises 3-7 ring members, and has the single point that links to each other with the molecule remainder.Term " aryl " can exchange with term " aryl rings " and use.The example of aryl rings will comprise phenyl, naphthyl and anthracene.
Use or be used as major part separately and be meant to have monocycle, dicyclo and the three-loop system that amounts to 5-14 ring members as term " heteroaryl " a part of in " heteroaralkyl " or " heteroaryl alkoxyl group ", wherein at least one ring in the system is fragrant, at least one ring in the system comprises one or more heteroatomss, wherein the ring of each in the system comprises 3-7 ring members, and has the single point that links to each other with the molecule remainder.Term " heteroaryl " can exchange with term " heteroaryl ring " or term " assorted fragrance " and use.
The further example of heteroaryl ring comprises following monocycle: the 2-furyl, the 3-furyl, the TMSIM N imidazole base, the 2-imidazolyl, the 4-imidazolyl, the 5-imidazolyl, the 3-isoxazolyl, the 4-isoxazolyl, the 5-isoxazolyl, the 2-oxazolyl, the 4-oxazolyl, the 5-oxazolyl, the N-pyrryl, the 2-pyrryl, the 3-pyrryl, the 2-pyridyl, the 3-pyridyl, the 4-pyridyl, the 2-pyrimidyl, the 4-pyrimidyl, the 5-pyrimidyl, pyridazinyl (for example 3-pyridazinyl), the 2-thiazolyl, the 4-thiazolyl, the 5-thiazolyl, tetrazyl (for example 5-tetrazyl), triazolyl (for example 2-triazolyl and 5-triazolyl), the 2-thienyl, the 3-thienyl, pyrazolyl (for example 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazole base, 1,2,5-oxadiazole base, 1,2,4-oxadiazole base, 1,2, the 3-triazolyl, 1,2, the 3-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, pyrazinyl, 1,3,5-triazinyl and following dicyclo: benzimidazolyl-, benzofuryl, benzothienyl, indyl (for example 2-indyl), purine radicals, quinolyl (2-quinolyl for example, the 3-quinolyl, the 4-quinolyl) and isoquinolyl (1-isoquinolyl for example, 3-isoquinolyl or 4-isoquinolyl).
In some embodiments, aryl (comprising aralkyl, aralkoxy, aryloxy alkyl etc.) or heteroaryl (comprising heteroaralkyl and heteroaryl alkoxyl group etc.) group can comprise one or more substituting groups.Suitable substituting group on the unsaturated carbon atom of aryl or heteroaryl is selected from R hereinafter 2And R 4Listed substituting group in the definition.Other suitable substituting group comprises: halogen ,-R o,-OR o,-SR o, 1,2-methylene-dioxy, ethylenedioxy, the optional R that uses oThe phenyl (Ph) that replaces, the optional R that uses oReplace-O (Ph), the optional R that uses oReplace-(CH 2) 1-2(Ph), the optional R that uses oReplace-CH=CH (Ph) ,-NO 2,-CN ,-N (R o) 2,-NR oC (O) R o,-NR oC (S) R o,-NR oC (O) N (R o) 2,-NR oC (S) N (R o) 2,-NR oCO 2R o,-NR oNR oC (O) R o,-NR oNR oC (O) N (R o) 2,-NR oNR oCO 2R o,-C (O) C (O) R o,-C (O) CH 2C (O) R o,-CO 2R o,-C (O) R o,-C (S) R o,-C (O) N (R o) 2,-C (S) N (R o) 2,-OC (O) N (R o) 2,-OC (O) R o,-C (O) N (OR o) R o,-C (NOR o) R o,-S (O) 2R o,-S (O) 3R o,-SO 2N (R o) 2,-S (O) R o,-NR oSO 2N (R o) 2,-NR oSO 2R o,-N (OR o) R o,-C (=NH)-N (R o) 2Or-(CH 2) 0-2NHC (O) R oEach self-existent R wherein oBe selected from hydrogen, the optional C that replaces 1-6Aliphatic group, unsubstituted 5-6 unit's heteroaryl ring or heterocycle, phenyl ,-O (Ph) or-CH 2(Ph), perhaps two self-existent R on identical substituting group or different substituents oWith each R oThe atom that group connected is combined together to form 5-8 unit heterocycle, aryl rings or heteroaryl ring or 3-8 unit cycloalkyl ring, and wherein said heteroaryl ring or heterocycle have 1-3 heteroatoms that is independently selected from nitrogen, oxygen or sulphur.R oAliphatic group on optional substituting group be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo C 1-4Aliphatic group, wherein each aforementioned R oC 1-4Aliphatic group all is unsubstituted.
In some embodiments, aliphatic series or heterolipid family group, or nonaromatic heterocycles can comprise one or more substituting groups.Suitable substituting group on the saturated carbon of aliphatic series or heterolipid family group or nonaromatic heterocycles is selected from above about those listed substituting groups of the unsaturated carbon of aryl or heteroaryl, and comprise in addition following substituting group :=O ,=S ,=NNHR *,=NN (R *) 2,=NNHC (O) R *,=NNHCO 2(alkyl) ,=NNHSO 2(alkyl) or=NR *, each R wherein *Be independently selected from hydrogen or the optional C that replaces 1-6Aliphatic group.R *Substituting group optional on the aliphatic group is selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo (C 1-4Aliphatic group), each aforementioned R wherein *C 1-4Aliphatic group all is unsubstituted.
In some embodiments, the optional substituting group on the nitrogen of nonaromatic heterocycles comprises-R +,-N (R +) 2,-C (O) R +,-CO 2R +,-C (O) C (O) R +,-C (O) CH 2C (O) R +,-SO 2R +,-SO 2N (R +) 2,-C (=S) N (R +) 2,-C (=NH)-N (R +) 2Or-NR +SO 2R +R wherein +Be hydrogen, the optional C that replaces 1-6Aliphatic group, the optional phenyl that replaces, optional replace-O (Ph), optional replace-CH 2(Ph), optional replace-(CH 2) 1-2(Ph), optional replace-CH=CH (Ph), or have 1-4 heteroatomic unsubstituted 5-6 unit's heteroaryl ring or heterocycle that is independently selected from oxygen, nitrogen or sulphur; Two self-existent R on perhaps identical substituting group or the different substituents +With each R +The atom that group connected is combined together to form 5-8 unit heterocycle, aryl rings or heteroaryl ring or 3-8 unit cycloalkyl ring, and wherein said heteroaryl ring or heterocycle have 1-3 heteroatoms that is independently selected from nitrogen, oxygen or sulphur.R +Aliphatic group or the optional substituting group on the phenyl ring be selected from NH 2, NH (C 1-4Aliphatic group), N (C 1-4Aliphatic group) 2, halogen, C 1-4Aliphatic group, OH, O (C 1-4Aliphatic group), NO 2, CN, CO 2H, CO 2(C 1-4Aliphatic group), O (halo C 1-4Aliphatic group) or halo (C 1-4Aliphatic group), each aforementioned R wherein +C 1-4Aliphatic group all is unsubstituted.
As mentioned above, in some embodiments, two self-existent R ° of (or R +Or any other variable of the similar definition of this paper) can be combined together to form 5-8 unit heterocycle, aryl rings or heteroaryl ring or 3-8 unit cycloalkyl ring with the atom that is connected with each variable.Two self-existent R o(or R +, or any other variable of the similar definition of this paper) formed exemplary ring includes, but are not limited to following when combining with the atom that is connected with each variable: a) two self-existent R o(or R +, or any other variable of the similar definition of this paper) combine with same atoms, and be combined together to form ring, for example N (R with this atom o) 2, wherein existing two R oBe combined together to form piperidines-1-base, piperazine-1-base or morpholine-4-base group with nitrogen-atoms; B) two self-existent R o(or R +, or any other variable of the similar definition of this paper) with different atom combinations, and be combined together to form ring with those atoms, for example wherein phenyl by existing two OR oReplace
Figure A200780003260D00181
Existing these two R oWith with their bonded Sauerstoffatoms common form one thick and 6-unit ether ring:
Figure A200780003260D00182
Should be appreciated that as two self-existent R o(or R +, or any other variable of the similar definition of this paper) when the atom that is connected with each variable combines, can form various other rings, and think that the example of above-detailed is not restriction.
In some embodiments, alkyl chain or aliphatic chain can be chosen wantonly by another atom or group and be interrupted.The MU (methylene unit) of this expression alkyl chain or aliphatic chain is optional to be substituted by described other atom or group.This class atom or examples of groups include, but not limited to-NR-,-O-,-S-,-CO 2-,-OC (O)-,-C (O) CO-,-C (O)-,-C (O) NR-,-C (=N-CN) ,-NRCO-,-NRC (O) O-,-SO 2NR-,-NRSO 2-,-NRC (O) NR-,-OC (O) NR-,-NRSO 2NR-,-SO-or-SO 2-, wherein R is as defined herein.Except as otherwise noted, the Ren Xuan chemically stable compound of alternative formation.Optional interruption can occur within the chain and at arbitrary end of chain, promptly at tie point and/or also endways.Two optional substituting also can adjoin each other within chain, as long as it forms chemically stable compound.Except as otherwise noted, occur in end if substitute or be interrupted, then substitution atoms is connected in terminal H.For example, if-CH 2CH 2CH 3Optional usefulness-O-is interrupted, and the compound that then obtains can be-OCH 2CH 3,-CH 2OCH 3Or-CH 2CH 2OH.
As described herein, from a substituting group to multi-loop system in the key (as follows) that ring central authorities are drawn, but the replacement at any the position of substitution place in expression substituting group any one ring in multi-loop system.For example, the possible replacement in the arbitrary position shown in the figure a presentation graphs b.
Figure A200780003260D00191
Figure a figure b
This also be applied to optional loop systems (it dots) thick and multi-loop system.For example, among the figure c, X encircles the optional substituting group that A also is ring B.
Figure A200780003260D00192
Figure c
Yet except as otherwise noted, if two rings in the multi-loop system respectively have the different substituting groups that draws from each ring center, each substituting group only is illustrated in connected substitution in ring.For example, in figure d, Y only is the optional substituting group of ring A, and X only is the optional substituting group of ring B.
Figure d
Except as otherwise noted, structure described herein also means all isometrys (for example, enantiomerism, diastereo-isomerism and geometrical isomer (or conformer)) form that comprises this structure; For example, the R of each asymmetric center and S configuration, double bond isomer (Z) and (E), and (Z) and conformer (E).Therefore, the single stereoisomers of The compounds of this invention and enantiomorph, diastereomer and geometrical isomer (or conformer) mixture within the scope of the present invention.
Except as otherwise noted, all tautomeric forms of The compounds of this invention all within the scope of the present invention.In addition, except as otherwise noted, structure as herein described also means and comprises that difference only is to exist the compound of one or more isotopic enrichment atoms.For example, have the structure of the present invention except that deuterium or tritium instead of hydrogen, or have and remove 13C-or 14The compound of the structure of the present invention that the alternative carbon of the carbon of C-enrichment is outer all within the scope of the present invention.This compounds can be used as analysis tool or the probe in the biological example assay method.
The description of The compounds of this invention
The present invention relates to formula I compound:
Figure A200780003260D00201
Or its pharmacy acceptable salt, wherein
R 3Be H, Cl or F;
X 1Be N or CR 4
R 2Be H, F, R ', OH, OR ', COR ', COOH, COOR ', CONH 2, CONHR ', CON (R ') 2Or CN;
R 4Be H, F, R ', OH, OR ', COR ', COOH, COOR ', CONH 2, CONHR ', CON (R ') 2Or CN;
Perhaps R 2And R 4Be combined together to form optional by 1-4 R 10The 5-7 unit's aryl rings or the heteroaryl ring that replace;
R ' is optional by 1-4 R 5The C that replaces 1-3Aliphatic group;
Each R 5Be independently selected from halogen, CF 3, OCH 3, OH, SH, NO 2, NH 2, SCH 3, NCH 3, CN or unsubstituted C 1-2Aliphatic group, perhaps two R 5Group forms cyclopropyl rings or C=O jointly with its carbon that is connected;
Each R 10Be independently selected from halogen, OCH 3, OH, NO 2, NH 2, SH, SCH 3, NCH 3, CN or unsaturated C 1-2Aliphatic group;
R 1Be Or
R " be H or optional by 1-3 R 11Replace-C 1-2Aliphatic group;
Each R 11Be independently selected from halogen, OCH 3, OH, SH, NO 2, NH 2, SCH 3, NCH 3, CN, CON (R 15) 2Or unsubstituted C 1-2Aliphatic group, perhaps two R 11Group forms cyclopropyl rings or C=O jointly with its carbon that is connected;
R 6Be optional by 1-5 R 12The C that replaces 1-4Aliphatic group;
Each R 12Be independently selected from halogen, OCH 3, OH, NO 2, NH 2, SH, SCH 3, NCH 3, CN or unsubstituted C 1-2Aliphatic group, perhaps two R 12Group forms cyclopropyl rings jointly with its carbon that is connected;
Ring A is the saturated azo-cycle that contains of 4-8 unit, and this ring comprises two extra heteroatomss that are selected from N, O or S at the most, and optional by 1-4 R 13Replace;
Each R 13Be independently selected from halogen, R ', NH 2, NHR ', N (R ') 2, SH, SR ', OH, OR ', NO 2, CN, CF 3, COOR ', COOH, COR ', OC (O) H, OC (O) R ', CONH 2, CONHR ', CON (R ') 2, NHC (O) R ' or NR ' C (O) R ', perhaps any two R on identical substituting group or different substituting group 13Group and each R 13The atom that group connected forms 3-7 unit carbocyclic ring or heterocycle saturated, undersaturated or fractional saturation jointly, and this carbocyclic ring or heterocycle are optional by 1-3 R 5Replace;
R 8Be optional by 1-5 R 12The C that replaces 1-4Aliphatic group;
R 9Be C 1-2Alkyl; Perhaps
R 8And R 9Be combined together to form optional by 1-5 R 12The 3-7 unit's carbocyclic ring saturated rings or the heterocycle saturated rings that replace;
R 14Be H or unsubstituted C 1-2Alkyl;
R 15Be H or unsubstituted C 1-2Alkyl; And
R 7Be optional quilt 6 C that F replaces at the most 2-3Aliphatic series or alicyclic group.
In one embodiment, compound of the present invention has one of formula I-A or I-B:
Figure A200780003260D00221
In one embodiment, R 3Be H or Cl.In another embodiment, R 3Be Cl.In another embodiment, R 3Be H.
In one embodiment, R 2Be H, F, R ', OH or OR '.In another embodiment, R 2Be H or F.
In one embodiment, described compound is formula I-A compound and R 4Be H, F, R ', OH or OR '.In another embodiment, R 4Be H or F.In another embodiment, R 4Be F and R 2Be H.In another embodiment, R 2Be F and R 4Be H.In another embodiment, R 2And R 4All be H.In another embodiment, R 3Be Cl.In alternative embodiment, R 3Be H.
In another embodiment, this compound is formula I-A compound and R 2And R 4Be combined together to form 6-unit aryl rings.In another embodiment, R 3Be Cl.In alternative embodiment, R 3Be H.
In another embodiment, R 7Be CH 2CH 3, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH 2CH 2CH 3, CH 2CH 2CF 3, CH 2CH 2CH 2F or CH 2CH 2CHF 2In another embodiment, R 7Be CH 2CH 3, CH 2CF 3, CH 2CH 2CH 3Or CH 2CH 2CF 3In another embodiment again, R 7Be CH 2CF 3
In another embodiment, R " be H or CH 3In another embodiment, R " be H.
In another embodiment, R 14Be H.In another embodiment again, R 15If exist then be H.In another embodiment, R 15Do not exist.
In another embodiment, the invention provides formula II compound:
Figure A200780003260D00231
X wherein 1ABe N, CH or CF, and R 1ABe
Figure A200780003260D00232
Or
Figure A200780003260D00233
In another embodiment, R 7Be CH 2CH 3, CH 2CF 3, CH 2CH 2CH 3Or CH 2CH 2CF 3In another embodiment again, R 7Be CH 2CF 3
In another embodiment, the invention provides the formula III compound:
Figure A200780003260D00234
X wherein 1ABe N, CH or CF, and R 1ABe
Figure A200780003260D00235
Or
Figure A200780003260D00236
In another embodiment, R 7Be CH 2CH 3, CH 2CF 3, CH 2CH 2CH 3Or CH 2CH 2CF 3In another embodiment again, R 7Be CH 2CF 3
In another embodiment of any formula I, II or III, R 6Be selected from
Figure A200780003260D00237
Figure A200780003260D00241
In another embodiment, R 6Be selected from
Figure A200780003260D00242
Figure A200780003260D00243
Or
Figure A200780003260D00244
In another embodiment again, R 6Be selected from
Or
Figure A200780003260D00246
In another embodiment of any formula I, II or III, ring A is
Figure A200780003260D00251
Figure A200780003260D00252
And R 13' be H or R 13
In another embodiment, ring A is
Figure A200780003260D00253
Or
Figure A200780003260D00254
In another embodiment, ring A is
In one embodiment, each R 13Be independently selected from halogen, R ', NH 2, NHR ', N (R ') 2, SH, SR ', OH, OR ', NO 2, CN, CF 3, COOR ', COOH, COR ', OC (O) R ' or NHC (O) R '; Perhaps any two R on identical substituting group or different substituting group 13Group and each R 13The atom that group connected together, form 3-7 unit saturated, undersaturated or fractional saturation optional by 1-3 R 5The carbocyclic ring or the heterocycle that replace.
In one embodiment of the invention, R 13Do not exist.In another embodiment, ring A is by 1 R 13Replace.In another embodiment, 1 of existence R 13Be OH, CH 3, F, OR ' or NHR '.In another embodiment again, R ' is C 1-2Alkyl or C 2-3Thiazolinyl.In another embodiment, R 13Be OH.
In another embodiment of any formula I, II or III, R 8And R 9Be combined together to form and be selected from following ring:
Figure A200780003260D00261
Wherein, the one or more carbon atoms in described ring are optional and alternative by N, O or S independently.
In another embodiment of any formula I, II or III, R 8And R 9Be
Figure A200780003260D00262
In another embodiment, R 8And R 9Be
In another embodiment again, R 8And R 9Be
Figure A200780003260D00264
Or
Figure A200780003260D00266
In another embodiment again, R 8And R 9Be
Figure A200780003260D00271
Or
Figure A200780003260D00272
In another embodiment, the invention provides formula I, IA, IB, II or III compound, wherein said compound suppresses the lower Ki of one or more kinases that are selected from Aurora-1 (AUR-B), Aurora-2 (AUR-A), Src, CDK2, Flt-3 or c-Kit with more described compound and suppresses jak kinase (that is being more effective).In another embodiment, the invention provides formula I, IA, IB, II or III compound, wherein this compound suppresses the lower K of one or more kinases that are selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 or c-Kit with more described compound iSuppress JAK3.
In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound is to be lower than the K of 0.1 μ M iSuppress JAK3.In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound is to be lower than the K of 0.01 μ M iSuppress JAK3.In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound is to be lower than the K of 0.01 μ M iSuppress JAK3, and with the K than JAK3 iHigh at least 5 times K iSuppress Aurora-2.In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound is to be lower than the K of 0.01 μ M iSuppress JAK3, and with the K than JAK3 iHigh at least 10 times K iSuppress Aurora-2.
In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound in raji cell assay Raji to be lower than the IC of 5 μ M 50Suppress JAK3.In another embodiment, described compound in raji cell assay Raji to be lower than the IC of 1 μ M 50Suppress JAK3.
In another embodiment, described compound suppresses the IC of low at least 5 times of one or more kinases that are selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 or c-Kit with more described compound in raji cell assay Raji 50Suppress JAK3.In another embodiment, the invention provides any formula I, IA, IB, II or III compound, wherein this compound in raji cell assay Raji to be lower than the IC of 5 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 5 times of height.In another embodiment, described compound in raji cell assay Raji to be lower than the IC of 1 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 5 times of height.In another embodiment, described compound in raji cell assay Raji to be lower than the IC of 5 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 10 times of height.In another embodiment, described compound in raji cell assay Raji to be lower than the IC of 1 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 10 times of height.In another embodiment again, the invention provides any formula I, IA, IB, II or III compound, wherein this compound in raji cell assay Raji to be lower than the IC of 1 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 5 times of height, and wherein said compound is to be lower than the K of 0.01 μ M iSuppress JAK3, and with the K than JAK3 iHigh at least 5 times K iSuppress Aurora-2.In another embodiment again, described compound in raji cell assay Raji to be lower than the IC of 1 μ M 50Suppress JAK3, the wherein IC of JAK2 50IC than JAK3 50At least 10 times of height, wherein said compound is to be lower than the K of 0.01 μ M iSuppress JAK3, and with the K than JAK3 iHigh at least 10 times K iSuppress Aurora-2.
In another embodiment, the invention provides the compound of table 1, table 2 or table 3:
Table 1
Figure A200780003260D00291
Figure A200780003260D00301
Figure A200780003260D00311
Figure A200780003260D00321
Figure A200780003260D00331
Figure A200780003260D00341
Figure A200780003260D00351
Figure A200780003260D00361
Figure A200780003260D00371
Figure A200780003260D00401
Figure A200780003260D00421
Figure A200780003260D00431
Table 2
Figure A200780003260D00441
Figure A200780003260D00451
Figure A200780003260D00461
Figure A200780003260D00471
Figure A200780003260D00481
Figure A200780003260D00491
Figure A200780003260D00501
Figure A200780003260D00511
Figure A200780003260D00541
Table 3
Figure A200780003260D00551
Figure A200780003260D00571
Figure A200780003260D00591
Figure A200780003260D00601
Figure A200780003260D00611
Figure A200780003260D00621
Purposes, preparation and administration
Pharmaceutically acceptable composition
In another embodiment, the invention provides and comprise formula I, IA, IB, II or III compound compositions.
In another embodiment, composition comprises in addition and is selected from following therapeutical agent: the medicine of the medicine of the medicine of chemotherapeutic or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressor, neurotrophic factor, treatment cardiovascular diseases, the destructive bone disorders of treatment, the hemopathic medicine of medicine, antiviral agent, treatment of treatment hepatopathy, treatment diabetes or the medicine of treatment immunodeficiency diseases.
According to another embodiment, the invention provides the composition that comprises The compounds of this invention or its pharmaceutically acceptable derivates and pharmaceutically acceptable carrier, auxiliary agent or vehicle.The amount of the compound in the present composition is enough to can measure ground arrestin kinases, particularly JAK family kinase in biological sample or patient.Preferably, prepare the patient that composition of the present invention need to be used to this composition, most preferably, prepare composition of the present invention and be used for the orally give patient.
As used herein, term " patient " expression animal, preferred mammal, and most preferably human.
Therefore, in another aspect of this invention in, pharmaceutically acceptable composition is provided, wherein these compositions comprise arbitrary compound as described herein, and optional pharmaceutically acceptable carrier, auxiliary agent or the vehicle of comprising.In certain embodiments, these compositions are chosen wantonly and are further comprised one or more additional treatment agent.
It is also understood that some compound of the present invention can free form exists is used for the treatment of, or suitably the time, exists with its pharmaceutically acceptable derivates form.According to the present invention, pharmaceutically acceptable derivates comprises, but be not limited to, the salt of pharmaceutically acceptable prodrug, salt, ester, this ester or any other adducts or derivative, they can directly or indirectly provide other described compound of this paper or its metabolite or resistates behind the patient who needs.As used herein, term " its inhibitory activity metabolite or resistates " represents that its metabolite or resistates also are the inhibitor of JAK family kinase.
As used herein, term " pharmacy acceptable salt " is meant in rational medical evaluation scope, be applicable to and contact with human and zootic tissue and do not have those salt of excessive toxicity, pungency, atopic reaction etc.
Pharmacy acceptable salt is well known in the art.For example, people such as S.M.Berge are at J.Pharmaceutical Sciences, and 1977,66, describe pharmacy acceptable salt among the 1-19 in detail, it incorporates this paper by reference into.The pharmacy acceptable salt of The compounds of this invention comprises from suitable inorganic and organic those salt of bronsted lowry acids and bases bronsted lowry deutero-.The example of pharmaceutically acceptable nontoxic acid salt is and mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, sulfuric acid and perchloric acid or the amide that forms with organic acid such as acetic acid, oxalic acid, toxilic acid, tartrate, citric acid, succsinic acid or propanedioic acid, or by using other used method of this area, as the amide of ion-exchange formation.Other pharmacy acceptable salt comprises adipate, alginate, ascorbate salt, aspartate, benzene sulfonate, benzoate, hydrosulfate, borate, butyrates, camphorate, camsilate, Citrate trianion, cyclopentane propionate, digluconate, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, hexanoate, hydriodide, 2-hydroxyl-esilate, Lactobionate, lactic acid salt, lauroleate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulphate, the 3-phenpropionate, phosphoric acid salt, picrate, Pivalate, propionic salt, stearate, succinate, vitriol, tartrate, thiocyanate-, right-tosylate, the undecane hydrochlorate, valerate etc.The salt that derives from suitable alkali comprises an alkali metal salt, alkaline earth salt, ammonium salt and N +(C 1-4Alkyl) 4Salt.The present invention has also expected arbitrary alkaline nitrogen-containing group quaternized of compound disclosed herein.Water-soluble or oil soluble or dispersible product can be by this quaternized acquisitions.Representational basic metal or alkaline earth salt comprise sodium, lithium, potassium, calcium, magnesium etc.Other pharmacy acceptable salt comprises when suiting, the nontoxic ammonium, quaternary ammonium and the amine positively charged ion that use counter ion such as halogenide, oxyhydroxide, carboxylate radical, sulfate radical, phosphate radical, nitrate radical, low alkyl group sulfonate radical and aryl sulfonic acid root to form.
As indicated above, the pharmaceutically acceptable composition of the present invention comprises pharmaceutically acceptable carrier, auxiliary agent or vehicle in addition, as used herein, they comprise any and all solvents, thinner or other liquid excipient, dispersion agent or suspending agent, tensio-active agent, isotonic agent, thickening material or emulsifying agent, sanitas, solid binder, lubricant etc., as long as it is suitable for required particular dosage form.Remington ' s Pharmaceutical Sciences, the 16 edition, E.W.Martin (Mack Publishing Co., Easton, Pa., 1980) various carriers used in the pharmaceutically acceptable composition of preparation and the known technology that is used to prepare them are disclosed.Except with the inconsistent any conventional mounting medium of The compounds of this invention, as produce any undesirable biological action or other interacts with any other component of deleterious mode and pharmaceutically acceptable composition, expect it use within the scope of the present invention.
Some examples that can be used as the material of pharmaceutically acceptable carrier comprise, but be not limited to, ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum albumin, buffer substance such as phosphoric acid salt, glycine, Sorbic Acid or potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, dipotassium hydrogen phosphate, sodium-chlor, zinc salt, colloid silica, Magnesium Trisilicate, polyvinylpyrrolidone, polyacrylic ester, wax, polyethylene-polyoxypropylene block copolymers, lanolin, sugar is as lactose, dextrose plus saccharose; Starch such as W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof such as Xylo-Mucine, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle such as theobroma oil and suppository wax; Oil is as peanut oil, Oleum Gossypii semen; Safflower oil; Sesame oil; Sweet oil; Semen Maydis oil and soya-bean oil; Glycols; As propylene glycol or polyoxyethylene glycol; Ester class such as ethyl oleate and Laurate ethyl; Agar; Buffer reagent such as magnesium hydroxide and aluminium hydroxide; Lalgine; Apirogen water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffer soln and other nontoxic compatible lubricant such as Sodium Lauryl Sulphate BP/USP and Magnesium Stearate, and tinting material, releasing agent, Drug coating, sweeting agent, seasonings and perfume compound, sanitas and antioxidant also can be present in the composition, and this will be according to configuration person's judgement.
As used herein, term " can suppress " sample and the active measurable change of kinase activity, particularly jak kinase between the sample of equal value that comprises jak kinase under the condition that lacks described compound that expression comprises The compounds of this invention and jak kinase with measuring.
Composition of the present invention can per os, parenteral, through suck spraying, partly, per rectum, intranasal, give through cheek, transvaginal or by the storage storehouse of implanting.As used herein, that term " parenteral " comprises is subcutaneous, in the intravenously, intramuscular, intraarticular, synovial membrane chamber, in the breastbone, in the sheath, in the intraocular, liver, in the pathology and intracranial injection or infusion techniques.Preferably, said composition per os, intraperitoneal or intravenously give.The aseptic injection form of the present composition can be moisture or oleaginous suspension.These suspensions can use suitable dispersion agent or wetting agent and suspending agent to make according to technology known in the art.Aseptic injection preparation also can be at nontoxic parenteral acceptable diluent or aseptic injectable solution or the suspension in the solvent, for example solution in 1,3 butylene glycol.Spendable acceptable vehicle and solvent are water, Ringer's solution and isotonic sodium chlorrde solution.In addition, aseptic expressed oil is conventionally used as solvent or suspension medium.
For this reason, can use and comprise synthetic single-or the expressed oil of any gentleness of two-glyceryl ester.Lipid acid can be used for preparing injection as oleic acid and glyceride derivative thereof, because it is natural pharmaceutically acceptable oil, as sweet oil or Viscotrol C, especially with the form of its polyoxyethyleneization.These oil solutions or suspension also can comprise long-chain alcohol thinner or dispersion agent, as carboxymethyl cellulose or be generally used for preparing the similar dispersion agent of the pharmaceutically acceptable formulation that comprises emulsion and suspension.Other normally used tensio-active agent also can be used for the purpose of said preparation, as is generally used for producing Tweens, spans and other emulsifying agent or the bioavailability toughener of pharmaceutically acceptable solid, liquid or other formulation.
The pharmaceutically acceptable composition of the present invention can give by per os in any oral acceptable forms, and oral acceptable forms includes, but not limited to capsule, tablet, aqueous suspension or solution.For the tablet that orally uses, normally used carrier comprises lactose and W-Gum.Usually also add lubricant, as Magnesium Stearate.For the orally give of capsule form, useful thinner comprises lactose and exsiccant W-Gum.When the needs aqueous suspension orally uses, activeconstituents and emulsifying agent and suspensoid combination.If desired, also can add some sweeting agent, seasonings or tinting material.
Perhaps, the suppository form that the pharmaceutically acceptable composition of the present invention can rectal administration gives.This suppository can be by hybrid medicine and suitable non-irritating auxiliary material preparation, and this auxiliary material at room temperature is solid but is liquid under rectal temperature, therefore will melt in rectum to discharge medicine.This class material comprises theobroma oil, beeswax and polyoxyethylene glycol.
But the pharmaceutically acceptable composition of the present invention is topical administration also, especially when the target of treatment comprises can approaching easily zone or organ by topical application, when comprising the disease of eyes, skin or lower intestinal tract.For each these zones or organ, suitable topical formulations prepares easily.
The topical application of lower intestinal tract can realize in rectal suppository (seeing above) or the enema agent that suits.Also can use the topical transdermal patch.
For topical application, pharmaceutically acceptable composition can be made into to comprise the suitable ointment that suspends or be dissolved in the activeconstituents in one or more carriers.The carrier that is used for the topical administration of The compounds of this invention includes, but not limited to mineral oil, whiteruss, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Perhaps, pharmaceutically acceptable composition can be made into to comprise suspendible or be dissolved in the suitable lotion or the emulsifiable paste of activeconstituents in one or more pharmaceutically acceptable carriers.Suitable carrier includes, but not limited to mineral oil, Arlacel-60, Polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.
Use for ophthalmology, pharmaceutically acceptable composition can be made into, for example at isoosmotic, as to regulate pH Sterile Saline or the micronised suspension in other aqueous solution, perhaps preferably be formed in etc. and ooze, to regulate the Sterile Saline of pH or the solution in other aqueous solution, be with or without sanitas such as zephiran chloride alkane ammonium (benzylalkonium chloride).Perhaps, use for ophthalmology, pharmaceutically acceptable composition can be made into ointment, as Vaseline.The pharmaceutically acceptable composition of the present invention also can give by nose gaseous solvents or suction.This based composition is according to technique known preparation in the field of pharmaceutical preparations, and can use phenylcarbinol or other suitable sanitas, the absorption enhancer that is used for improving bioavailability, fluorocarbon and/or other conventional solubilizing agent or dispersion agent to be prepared as solution at salt solution.
Most preferably, the pharmaceutically acceptable composition of the present invention is made the preparation of orally give.
The liquid dosage form that is used for oral administration includes, but not limited to the acceptable emulsion of pharmacy, micro emulsion, solution, suspension, syrup and elixir.Remove the active ingredient beyond the region of objective existence, described liquid dosage form also can comprise the normally used inert diluent in this area as, for example, water or other solvent, solubilizing agent and emulsifying agent such as ethanol, Virahol, ethyl-carbonate, vinyl acetic monomer, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, embryo oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and sorbitan fatty acid esters and composition thereof.Except that inert diluent, described oral compositions also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, seasonings and perfume compound.
Injectable preparation, for example, aseptic aqueous injectable or oleaginous suspension can be used the preparation of suitable dispersion agent or wetting agent and suspension agent according to known technique.The preparation of described sterile injectable can also be nontoxic parenteral acceptable diluent or solvent, for example, and the sterile injectable solution in the 1,3 butylene glycol, suspension or emulsion.Operable acceptable vehicle and solvent are water, Ringer's solution, U.S.P. and isoosmotic sodium chloride solution.In addition, aseptic expressed oil can be used as solvent or suspension medium usually.For this reason, the expressed oil of any gentleness all can use, and comprises synthetic direactive glyceride or two glyceryl ester.In addition, lipid acid such as oleic acid can be used for preparing injectable preparation.
Injectable preparation can pass through, for example, the filter that is detained bacterium filters, or sterilizes by the disinfectant that mixes the aseptic solid composite form, the disinfectant of described aseptic fixing composition form can be dissolved in it or be scattered in sterilized water or other the aseptic injectable medium before use.
In order to prolong the effect of The compounds of this invention, often need slow down compound and absorb from subcutaneous or intramuscularly.This can realize by the liquid suspension that use has relatively poor water miscible crystallization or an amorphous substance.The uptake rate of compound depends on its dissolution rate then, and dissolution rate can be depending on crystalline size and crystallized form successively.Perhaps, the delay of the compound form of parenteral admin absorbs by with compound dissolution or be suspended in the oily vehicle and realize.Injectable depot forms is by at biological degradation polyalcohol, makes as the micro-capsule matrix that forms compound in polylactide-poly-glycollide.According to the ratio of compound and polymkeric substance and the character of used particular polymers, the rate of release of may command compound.The example of other biodegradable polymer comprises poly-(ortho ester) and poly-(acid anhydrides).The bank injectable formulation also can prepare by compound being imbedded in liposome compatible with when injected organism tissue or the micro emulsion.
The preferred suppository of composition that is used for rectum or vagina administration, they can pass through compound of the present invention and suitable nonirritant excipient or carrier, mix and prepare as theobroma oil, polyoxyethylene glycol or suppository wax, they at room temperature are solid, but be liquid under body temperature, therefore can in rectum or vaginal canal, dissolve and release of active compounds.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, pulvis and granule.In this class solid dosage, with active compound and at least a inertia, acceptable vehicle of pharmacy or carrier such as Trisodium Citrate or Lin Suanergai and/or a) weighting agent or filler such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) tackiness agent as, for example, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) wetting agent such as glycerine, d) disintegrating agent such as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash, e) dissolving delayed-action activator such as paraffin, f) absorption enhancer such as quaternary ammonium compound, g) wetting agent as, for example, hexadecanol and glyceryl monostearate, h) absorption agent such as kaolin and wilkinite, and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, Sodium Lauryl Sulphate BP/USP and composition thereof mixes.For capsule, tablet and pill, described formulation also can comprise buffer reagent.
The solids composition of similar type also can be used as soft hard-fill the weighting agent in the gelatine capsule, wherein use this class vehicle such as lactose or lactose and high-molecular weight polyoxyethylene glycol etc.The solid dosage of tablet, drageeing, capsule, pill and granule can be with dressing and housing, other dressing preparation of knowing as enteric coating and medicine formulation art.They can be chosen wantonly and comprise opacifying agent and can also only have, or preferential, at a certain specific part of enteron aisle, randomly, with the composition of delayed mode release of active ingredients.The example of available embedding component comprises polymeric material and wax.The solids composition of similar type also can be used as soft hard-fill the weighting agent in the gelatine capsule, wherein use this class vehicle such as lactose or lactose and high-molecular weight polyoxyethylene glycol etc.
Described active compound can also be the microencapsulation form with above-mentioned one or more vehicle.Other dressing preparation that the solid dosage of tablet, drageeing, capsule, pill and granule can be known with dressing and housing such as enteric coating, controlled release coat and medicine formulation art.In this class solid dosage, described active compound can mix with at least a inert diluent such as sucrose, lactose or starch.This formulation also can comprise, according to standard practices, and other material except that inert diluent, for example film-making lubricant and other compressing tablet used additives are as Magnesium Stearate and Microcrystalline Cellulose.With regard to capsule, tablet and pill, described formulation also can comprise buffer reagent.They also can be chosen wantonly and comprise opacifying agent and can also only have, or preferentially at the specific part of enteron aisle, randomly, with the composition of delayed mode release of active ingredients.The example of available embedding component comprises polymeric material and wax.
The formulation that is used for part or transdermal administration The compounds of this invention comprises ointment, paste, emulsifiable paste, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Described activeconstituents mixes with pharmaceutically acceptable carrier under aseptic condition, and may need any required sanitas or buffer reagent.Ophthalmic preparation, ear drop and eye drops are also comprised within the scope of the present invention by expection.In addition, the present invention has expected the use of transdermal patch, and it has the attendant advantages of compound sustained release to human body.This class formulation can be by with compound dissolution or be scattered in the suitable medium and prepare.Absorption enhancer also can be used for increasing the flux that compound passes skin.Speed can be by providing the rate-controlling film or controlling by compound is dispersed in polymeric matrix or the gel.
Compound of the present invention is preferably made dosage unit form, to be easy to the even of administration and dosage.As used herein, statement " dosage unit form " is meant the unit of the physical sepn of the medicine that is suitable for the patient that treats.Yet, should be appreciated that total consumption every day of The compounds of this invention and composition will reasonably determined within the medical judgment scope by the doctor in charge.Any particular patient or biological concrete effective dose level will depend on multiple factor, comprise the disease of being treated and the severity of disease; The activity of used particular compound; Employed concrete composition; Patient's age, body weight, general health situation, sex and diet; The discharge rate of administration time, route of administration and the particular compound of using; The treatment time length; Unite known similar factor in use or medicine that uses simultaneously and the medical field with used particular compound.
Can will change according to the host of treatment, the special pattern of administration with the amount that carrier substance is united with the The compounds of this invention of generation composition in single formulation.Preferably, said composition being made preparation so that can accept the patient's of these compositions inhibitor dosage is 0.01-100 mg/kg body weight/day.
Depend on the institute particular condition or the disease for the treatment of or preventing, be used for the treatment of usually or prevent other therapeutical agent of this situation also can be present in the composition of the present invention.As used herein, be used for the treatment of usually or prevent other therapeutical agent of specified disease or obstacle to be called as " be suitable for treated disease or obstacle ".
For example, chemotherapeutic or other antiproliferative can with compound coupling of the present invention, with treatment proliferative disease and cancer.The example of known chemotherapeutic includes, but not limited to Gleevec TM, Zorubicin, dexamethasone, vincristine(VCR), endoxan, Fluracil, Hycamtin, taxol, Interferon, rabbit and platinum derivatives.
Also can include, but are not limited to other example of the medicine of inhibitor Combined Preparation of the present invention: the therapeutical agent that is used for Alzheimer as
Figure A200780003260D00701
With
Figure A200780003260D00702
Be used for parkinsonian therapeutical agent such as L-DOPA/ carbidopa, Entacapone, Ropinirole, pramipexole, bromocriptine, pergolide, Trihexyphenidyl (trihexephendyl) and amantadine; (for example, be used for the treatment of the medicament of multiple sclerosis (MS) such as beta-interferon
Figure A200780003260D00703
With
Figure A200780003260D00704
Figure A200780003260D00705
And mitoxantrone; Be used for treatment of asthma agent such as salbutamol and
Figure A200780003260D00706
Be used for the treatment of schizoid medicament such as Zyprexa, Wei Sitong, Seroquel and haloperidol; Anti-inflammatory agent such as reflunomide, TNF blocker, IL-1 RA, azathioprine, endoxan and sulfasalazine; Immunomodulatory and immunosuppressor such as S-Neoral, tacrolimus, rapamycin, mycophenolate mofetil (mycophenolate mofetil), Interferon, rabbit, reflunomide, endoxan, azathioprine and sulfasalazine; Neurotrophic factor such as acetylcholinesterase depressant, MAO inhibitor, Interferon, rabbit, anticonvulsive agent, ion channel blocking agent, Riluzole and antiparkinsonian medicament; The medicament such as beta blocker, ACE inhibitor, diuretic(s), nitric ether, calcium channel blocker and the Statins that are used for the treatment of cardiovascular diseases; The medicament such as reflunomide, Colestyramine, Interferon, rabbit and the antiviral agent that are used for the treatment of hepatopathy; Be used for the treatment of hemopathic medicament such as reflunomide, anti--leukemia medicament and somatomedin; And the medicament such as the gamma globulin that are used for the treatment of immunodeficiency diseases.
The consumption that is present in other therapeutical agent in the present composition can not surpass the consumption that gives usually in comprising the composition of this therapeutical agent as unique promoting agent.Preferably, the consumption of other therapeutical agent in the present disclosed composition comprises the about 50%-100% of this medicament as consumption in the composition of unique therapeutic activity agent for being present in usually.
The application of compound and composition
In one embodiment, the invention provides the active method of jak kinase among a kind of patient of inhibition, it comprises and gives described patient compound of the present invention or composition.
In another embodiment, the present invention comprises the situation or the disease of the mediation of JAK-among a kind of patient of treatment or alleviates the method for its severity.As used herein, term " disease of JAK-mediation " is meant any disease or other harmful situation that known JAK family kinase, especially JAK2 or JAK3 work.In another embodiment, the present invention comprises a kind of method of disease of the JAK3-of treatment mediation.This class situation comprises, but be not limited to, immune response such as allergy or type i allergic reaction, asthma, autoimmune disease such as transplant rejection, graft versus host disease (GVH disease), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative disease is as familial amyotrophic lateral sclerosis (FALS) and entity and hematologic malignancies such as leukemia and lymphoma.
In another embodiment, the invention provides the method that a kind of treatment is selected from following situation or alleviates its severity: proliferative disease, heart disease, neurodegenerative disease, autoimmune disorder, situation, inflammatory diseases, Immunological diseases or the immune-mediated disease relevant with organ transplantation, this method comprise and give described patient compound of the present invention or composition.
In another embodiment, this method comprises and gives the additional step that described patient is selected from following additional therapeutic agent: chemotherapeutic or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressor, neurotrophic factor, be used for the treatment of cardiovascular diseases medicament, be used for the treatment of the medicament of diabetes or be used for the treatment of the medicament of immunodeficiency diseases, wherein said additional therapeutic agent is suitable for the disease of being treated, and described additional therapeutic agent gives as single formulation with described composition or give respectively with described composition as a multi-form part.
In one embodiment, described disease or obstacle are allergy or the anaphylaxis of I type, asthma, diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, the dementia that AI DS-is relevant, amyotrophic lateral sclerosis (ALS, Lou Gehrig ' s disease), multiple sclerosis (MS), schizophrenia, myocardial hypertrophy, perfusion/ischemic again, apoplexy, bald, transplant rejection, graft versus host disease (GVH disease), rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and entity and hematologic malignancies such as leukemia and lymphoma.In another embodiment, described disease or obstacle are asthma.In another embodiment, described disease or obstacle are transplant rejections.In another embodiment, described disease or obstacle are rheumatoid arthritiss.
In another embodiment, compound of the present invention or composition can be used for treating myeloproliferative disorder.In one embodiment, this myeloproliferative disorder is polycyth(a)emia, essential thrombocythemia or chronic spontaneous myelofibrosis.In another embodiment, this myeloproliferative disorder is the life of marrow alienation, chronic myelocytic leukemia (CML), chronic myelomonocytic leukemia, chronic acidophil leukecythemia, hypereosinophilic syndrome, systemic mast cell disease, atypical CML or the teenager's myelomonocytic leukemia with myelofibrosis.
In another embodiment, the invention provides the purposes that formula I, IA, IB, II or III compound are used for the treatment of the disease of JAK-mediation.In another embodiment, the invention provides the purposes that described compound is used for the treatment of arbitrary above-mentioned disease.In another embodiment, the invention provides the purposes that formula I, IA, IB, II or III compound are used to prepare the medicament of the disease that is used for the treatment of the JAK-mediation.In another embodiment, the invention provides the purposes that described compound is used to prepare the medicament that is used for the treatment of above-mentioned arbitrary disease.
In another embodiment, the invention provides the active method of jak kinase in a kind of inhibition biological sample, it comprises makes described biological sample contact with The compounds of this invention or composition.
As used herein, term " biological sample " expression vitro samples, and comprise, be not limited to cell culture or its extract; Tissue or organ samples or its extract; Derive from mammiferous biopsy material or its extract; Blood, saliva, urine, ight soil, seminal fluid, tears or other body fluid or its extract.
The active inhibition of kinase activity in the biological sample, especially jak kinase can be used for various purpose well known by persons skilled in the art.The example of these purposes includes, but not limited to blood transfusion, organ transplantation, biological sample storage and biological assay.
In certain embodiments of the invention, " significant quantity " of compound or pharmaceutically acceptable composition is meant one or more above-mentioned conditions of effective treatment or alleviates the amount of its severity.This compound and composition, the method according to this invention, any dosage and any route of administration administration that can use effective treatment situation or disease or alleviate its severity.Needed accurate consumption will be according to being changed by curer's difference, and this depends on by curer's species, age and general situation, the severity of infection, specific medicine, its administering mode etc.
In alternative embodiment, method of the present invention comprises the additional step that separately gives described other therapeutical agent of patient.When separately giving these other therapeutical agent, they can be before giving the present composition, in turn or afterwards give the patient.
The compounds of this invention or its pharmaceutical composition also can be used for applying implantable medicine equipment, as prosthese, artificial valve, blood vessel graft, support and conduit.For example, intravascular stent has been used to overcome restenosis (restenosis of damage back vessel wall).Yet the patient of use support or other implantable apparatus has the risk of grumeleuse formation or platelet activation.These unwanted effects can prevent or relax by apply described apparatus in advance with the pharmaceutically acceptable composition that comprises The compounds of this invention.
The preparation of the generality of the implantable apparatus of suitable coating and coating is at United States Patent (USP) 6,099, is described in 562,5,886,026 and 5,304,121.Coating is biocompatible polymeric material such as aquogel polymer, poly-methyl sily oxide, polycaprolactone, polyoxyethylene glycol, poly(lactic acid), ethylene vinyl acetate and composition thereof normally.Described coating can be chosen wantonly by the suitable outer coatings of fluorosilicone, polysaccharide, polyoxyethylene glycol, phosphatide or its combination and further cover, thereby gives the composition controlled release characteristics.Implantable apparatus with the The compounds of this invention coating is another embodiment of the invention.This compound also can be coated on implantable medicine equipment such as the pearl, perhaps prepares jointly with polymkeric substance or other molecule, so that " drug depot " to be provided, thereby allows the medicine ratio to give pharmaceutical aqueous solution to discharge the longer time.
The methodology that compound synthesizes and characterizes
The compounds of this invention usually can be by the method preparation that is used for similar compound well known by persons skilled in the art, or those methods preparations by describing among the embodiment hereinafter.Referring to, the embodiment that describes among the WO 2005/095400 for example, its full content is incorporated this paper by reference into.
All reference that provide among the embodiment are all incorporated this paper by reference into.As used herein, all with at the same time those are consistent for employed in the scientific literature for all abbreviations, symbol and agreement.Referring to, for example Janet S.Dodd compiles, The ACS Style Guide:AManual forAuthors and Editors, and second edition, Washington: American Chemical Society, 1997, its full content is incorporated this paper by reference into.
Embodiment
Embodiment
Embodiment 1: the preparation of The compounds of this invention
General synthetic schemes
Figure A200780003260D00751
Step 1
To the Boc-Xie Ansuan (1 in 100 milliliters of DCM that stirs; R 1Be Me; 3.8 gram, 0.02 mole), add trifluoro ethamine HCl salt (2.92 grams, 0.022 mole) in the solution of EDC (4.63 gram, 0.024 mole), HOBt (4.0 grams, 0.026 mole), DIEA (10.5 milliliters, 0.06 mole).Reaction mixture was stirred 16 hours.Reaction mixture is concentrated into dried, and is dissolved in again among the EtOAc, with 0.5N HCl, NaHCO 3Saturated aqueous solution and salt solution continuous washing.With organic layer drying (Na 2SO 4) and concentrate in a vacuum, obtain 5.4 grams and be 2 (98%) of white solid.
Step 2
Compound 2 (5.32 gram, 0.0197 mole) is with the 1:1 mixture of DCM/TFA deprotection 45 minutes at room temperature.Be concentrated into the dried intermediate amine that obtains, it is directly used in next step.With 5-fluoro-2, (3, R is F to the 4-dichloro pyrimidine; 3.28 gram, 0.0197 mole), the stirring 16 hours under room temperature in Virahol of the mixture of the tfa salt of crude product amine (5.25 grams, 0.0197 mole) and DIEA (10.27 milliliters, 0.059 mole).Reaction mixture is concentrated in a vacuum, and be dissolved in again among the EtOAc, with 0.5N HCl, NaHCO 3Saturated aqueous solution and salt solution continuous washing.With organic layer drying (Na 2SO 4), and concentrate in a vacuum, obtaining crude product oily matter, it carries out stratographic analysis (50% EtOAc/50% hexane) and obtains desired compounds 4.
Step 3
With 5 among 1 milliliter of DME (30 milligrams, 0.075 mmole; According to WO 2005/095400 preparation), 4 (23 milligrams, 0.075 mmole), Pd (Ph 3P) 4(9 milligrams, 0.0078 mmole) and yellow soda ash 2M (115 microlitres, 0.23 mmole) mixture was in 150 ℃ of microwave heatings 10 minutes.Reaction mixture is filtered as eluent with 30% EtOAc-70% hexane by the short pad of silica gel, obtain the intermediate crude product behind the concentrate drying, it is directly used in next step.
The crude product intermediate is dissolved in 1 milliliter of dry ethanol, and adds the sodium methylate-methanol solution of 200 microlitres 25%.Reaction mixture stirred 1 hour in 60 ℃, and with 6N HCl (154 microlitre) quencher.Mixture is dry under nitrogen gas stream, and through reversed-phase HPLC (10-60 MeCN/ water w/0.5% TFA) purifying, the formula 6a material that obtains expecting.
Formula 6b and 6c compound similarly method use suitable initial reagent preparation.For example; formula 6b compound usually can be by using 2-(2; 2; 2-trifluoroethyl formamyl) tetramethyleneimine-1-carboxylic acid tert-butyl ester alternative compounds 1 prepares; and formula 6c compound usually can be by using 2-(2; 2,2-trifluoroethyl formamyl) propane-2-aminocarbamic acid tert-butyl ester alternative compounds 1 prepares.
Embodiment 2: analytical results
Following table 4,5 and 6 has been described the exemplary of some compound of the present invention 1H-NMR data (NMR) and the liquid chromatography mass data of reporting with quality+proton (M+H) of measuring through electrospray, and retention time (RT), wherein the compound number in the table 4,5 and 6 corresponds respectively to the compound of describing in the table 1,2 and 3 (blank cell is represented to test):
Table 4
Compound # M+H RT NMR
1 442.90 2.20 DMSO-d6:12.4(br?s，1H)；8.7(dd，1H)；8.65(s， IH)；8.25(m，2H)；8.2(m，1H)；4.8(d，1H)； 4.0-3.8(m，4H)；2.3(m，1H)；2.05-1.9(m，3H)
2 442.90 2.20 DMSO-d6:12.4(br?s，1H)；8.7(dd，1H)；8.65(s， 1H)；8.25(m，2H)；8.2(m，1H)；4.8(d，IH)； 4.0-3.8(m，4H)；2.3(m，1H)；2.05-1.9(m，3H)
3 430.90 2.50 (CD3OD)1.7(s，6H)，3.8(m，2H)，8.15(s，1H)， 8.2(d，1H)，8.25(m，1H)，8.5(t，1H)，8.85(d， 1H)
4 463.00 1.90 (CD3OD)1.9(s，6H)，3.8(m，2H)，7.75(t，1H)，
Compound # M+H RT NMR
7.9(d，1H)，8.05(t，1H)，8.35(d，1H)，8.55 (d+t，2H)，8.7(s，1H)，8.85(d，1H)
5 399.00 1.70 DMSO-d6:8.92(m，1H)；8.60(m，2H)；8.32(s， 1H)；8.18(m，1H)；6.65(m，1H)；6.72(m，1H)； 4.80(m，1H)；4.00(m，2H)；1.429d，3H)
6 417.00 2.40 DMSO-d6:8.70(dd，1H)；8.65*s，1H)；8.28(m， 2H)；8.20(m，1H)；7.90(m，1H)；4.62(m，1H)； 3.88(m，2H)；1.41(d，3H)
7 449.00 2.10 DMSO-d6:8.86(m，1H)；8.76(m，1H)；8.55(m，1H)； 8.40(m，1H)；7.96(m，1H)；7.85(m，1H)；7.70 (m，1H)；5.00(m，1H)；3.98(m，2H)；1.58(d，3H)
8 459.30 1.70 DMSO-d6:12.3(br?s，1H)；8.7(s，1H)；8.6(t， 1H)；8.3(m，2H)；8.2(m，1H)；4.75(m，1H)；4.4 (m，1H)；4.05-3.7(m，5H)；1.9(m，1H)
9 457.30 2.20 DMSO-d6:12.3(br?s，1H)；8.8(m，1H)；8.7(s， 1H)；8.3(m，2H)；8.2(m，1H)；4.3(m，1H)； 4.05-3.8(m，4H)；2.25(m，1H)；2.1(m，1H)；1.7 (m，1H)；1.15(m，3H)
10 459.30 1.80 DMSO-d6:12.35(br?s，1H)；8.8(m，1H)；8.65(s， 1H)；8.25(m，2H)；8.15(m，1H)；4.6(m，1H)；4.3 (m，1H)；4.05(m，1H)；3.9-3.8(m，3H)；1.95(m， 2H)
11 455.30 2.10 DMSO-d6:12.35(br?s，1H)；8.95(m，1H)；8.7(s， 1H)；8.3(m，2H)；8.2(m，1H)；4.9(m，1H)； 4.1-3.9(m，4H)；1.8-1.6(m，2H)；0.75(m，1H)； 0.4(m，1H)
12 459.30 1.70 DMSO-d6:12.3(br?s，1H)；8.7(s，1H)；8.6(t， 1H)；8.25(m，2H)；8.15(m，1H)；4.75(m，1H)； 4.4(m，1H)；4.05-3.65(m，5H)；1.9(m，1H)
13 459.30 1.70 DMSO-d6:12.3(br?s，1H)；8.8(m，1H)；8.7(s， 1H)；8.3(m，2H)；8.2(m，1H)；4.8(m，1H)；4.45 (m，1H)；4.05-3.65(m，4H)；2.25(m，1H)；1.9(m， 1H)
14 425.00 1.70 DMSO-d6:12.9(br?s，1H)；8.9(m，1H)；8.6(m， 2H)；8.4(s，1H)；8.35(m，1H)；6.7(m，1H)；4.9 (m，1H)；4.1-3.9(m，2H)；3.8(m，1H)；3.65(m， 1H)；2.4(m，1H)；2.15-1.95(m，3H)
15 461.30 2.10
Compound # M+H RT NMR
16 425.00 1.70 DMSO-d6:12.9(br?s，1H)；8.85(m，1H)；8.6(m， 2H)；8.35(s，1H)；8.3(m，1H)；6.7(m，1H)；4.9 (m，1H)；4.1-3.9(m，2H)；3.75(m，1H)；3.6(m， 1H)；2.4(m，1H)；2.15-1.95(m，3H)
17 461.30 2.20
18 427.20 1.90 DMSO?d6:13.0ppm(bs，1H)，9.0(t，1H)，8.7(s， 1H)，8.6(s，1H)，8.4(s，1H)，8.2(d，1H)，6.8 (bs，1H)，4.8(t，1H)，4.1(m，1H)，3.8(m，2H)， 2.3(m，1H)，1.05(d，3H)，1.0(d，3H)
19 441.20 2.00 DMSO?d6:13.0ppm(bs，1H)，9.0(t，1H)，8.7(s， 2H)，8.4(s，1H)，8.1(d，1H)，6.6(d，1H)，4.8 (t，1H)，3.8-4.2(m，4H)，1.7(bs，2H)，1.0(d， 3H)，0.9(d，3H)
20 445.20 2.90 DMSO?d6:12.4ppm(bs，1H)，8.8(t，1H)，8.7(s， 1H)，8.3(s，1H)，8.2(d，2H)，7.6(d，1H)，4.5 (t，1H)，3.9-4.1(m，2H)，2.2(m，1H)，1.0(d， 3H)，0.9(d，3H)
21 459.20 3.00 DMSO?d6:12.4ppm(bs，1H)，8.8(t，1H)，8.7(s， 1H)，8.3(m，3H)，7.8(d，1H)，4.7(t，1H)，3.9 (m，2H)，1.9(m，1H)，1.8(m，1H)，1.6(m，1H)， 1.0(d，3H)，0.9(d，3H)
22 473.20 3.40 DMSO?d6:8.7ppm(t，1H)，8.6(s，1H)，8.4(s， 1H)，8.35(s，1H)，8.3(s，1H)，7.9(d，1H)，4.7 (t，1H)，4.0(m，2H)，3.9(s，3H)，1.9(m，1H)， 1.8(m，1H)，1.7(m，1H)，1.0(d，3H)，0.9(d， 3H)
23 431.10 2.50 DMSO?d6:12.4(bs，1H)，8.8(t，1H)，8.7(s，1H)， 8.3(s，1H)，8.25(dd，2H)，7.7(bs，1H)，4.5(q， 1H)，3.8-4.0(m，2H)，1.9(q，2H)，1.0(t，3H)
24 413.10 1.80 DMSO?d6:12.9ppm(bs，1H)，9.0(t，2H)，8.65(s， 1H)，8.6(s，1H)，8.4(s，1H)，8.1(d，1H)，6.7 (bs，1H)，4.7(m，1H)，3.8-4.2(m，2H)，1.9(m， 2H)，1.0(t，3H)
25 439.20 2.00 1H?NMR(CD3OD，500MHz):1.53-2.05(m，6H)， 2.45-2.53(m，1H)，3.46-3.59(m，1H)，3.83-4.32 (m，3H)，7.06(s，br.，1H)，8.18(d，1H)，8.38 (d，1H)，8.42(s，1H)，8.83(s，br.，1H)
26 457.10 3.20 1H?NMR(CD3OD，500MHz):1.57-2.03(m，6H)，
Compound # M+H RT NMR
2.37-2.44 (m, 1H), 3.50-3.57 (m, 1H), 3.90-4.09 (m, 2H), 4.49-4.57 (m, 1H), 5.38 (s, br., 1H), 8.26 (s, 1H), 8.28 (d, 1H), 8.31 (d, 1H), 8.60 (d, 1H)
27 429.30 2.30 (CD3OD) 1.3 (m, 2H), 1.8 (m, 2H), 3.9 (m, 2H), 8.25 (m, 3H), 8.6 (t, 1H), 8.8 (d, 1H)
28 439.20 1.90 DMSO d6:13.0ppm (bs, 1H), 9.0 (s, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 6.7 (s, 1H), 4.9 (d, 1H), 3.9-4.1 (m, 3H), 1.9 (q, 1H), 1.6 (q, 1H), 0.9 (bs, 1H), 0.5 (m, 2H), 0.2 (m, 2H)
29 457.10 2.80 DMSO d6:12.4ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s, 1H), 8.3 (s, 1H), 8.25 (m, 2H), 7.8 (bs, 1H), 4.7 (q, 1H), 3.8-4.0 (m, 3H), 1.9 (m, 1H), 1.6 (m, 1H), 0.9 (m, 1H), 0.4 (m, 2H), 0.2 (m, 2H)
30 459.10 1.90 DMSO d6:12.9ppm (bs, 1H), 9.0 (s, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.4 (s, 1H), 8.2 (d, 1H), 6.7 (s, 1H), 4.9 (s, 1H), 3.9-4.1 (m, 2H), 2.5-2.7 (m, 2H), 2.1 (m, 3H), 2.0 (s, 3H)
31 477.10 2.70 DMS0 d6:12.4ppm (bs, 1H), 8.8 (t, 1H), 8.7 (s, 1H), 8.3 (s, 2H), 8.25 (s, 1H), 7.9 (s, 1H), 4.8 (q, 1H), 3.8-4.0 (m, 2H), 2.5-2.7 (m, 2H), 2.2 (m, 2H), 2.1 (s, 3H)
32 458.10 1.90 (d4-methyl alcohol) 8.71 (s, 1H), 8.24 (d, 1H), 8.20 (s, 1H), 8.15 (s, 1H), 5.11 (br s, 1H), 4.32 (d, 1H), 4.01-3.55 (m, 4H), 3.17 (dd, 1H), 3.11-2.95 (m, 2H)
33 440.10 1.40 (d4-methyl alcohol) 8.72 (d, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.21 (d, 1H), 6.65 (d, 1H), 5.25 (br s, 1H), 4.12-3.87 (m, 3H), 3.57 (d, 1H), 3.44 (dd, 1H), 3.14-2.82 (m, 3H)
34 457.00 3.00 DMSO-d6:12.4 (s, 1H); 8.65 (s, 1H); 8.35-8.25 (m, 3H); 8.1 (s, 1H); 3.95-3.8 (m, 2H); 3.7 (m, 2H); 2.05 (m, 4H); 1.65 (s, 3H).
35 483.10 2.80
36 469.10 2.50 DMSO?d6?12.5(bs，1H)；9.0(m，1H)；8.7(m，3H)； 8.3(m，1H)；4.8(bs，1H)；4.0-3.5(m，4)；2.3 (m，1H)；2.0(m，3H)
Compound # M+H RT NMR
37 411.10 2.10 1H?NMR(CD3OD，500MHz):2.42-2.52(m，1H)， 2.80-2.93(m，1H)，3.89-4.14(m，2H)，4.27-4.37 (m，2H)，5.09-5.16(m，1H)，7.34(d，1H)，8.18 (d，1H)，8.30(s，1H)，8.50(s，1H)，8.66(s，1H)
38 459.10 2.90 1H?NMR(CD3OD，500MHz):3.46-3.69(m，2H)， 3.88-4.04(m，3H)，4.13-4.52(m，3H)，4.83-4.90 (m，1H)，6.47(d，1H)，7.44(d，1H)，8.00(d，1H)， 8.14(d，1H)，8.27-8.35(m，2H)，8.68(s，1H)
39 458.10 1.80 (d4-methyl alcohol) 8.74 (d, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 8.23 (d, 1H), 5.62 (br s, 1H), 4.62 (d, 1H), 4.04-3.95 (m, 3H), 3.66 (ddd, 1H), 3.46 (dd, 1H), 3.41-3.34 (m, 2H)
40 440.10 1.40 (d4-methyl alcohol) 8.72 (d, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.21 (d, 1H), 6.65 (d, 1H), 5.26 (br s, 1H), 4.10-2.84 (m, 8H)
41 525.10 2.70 (d4-methyl alcohol) 8.72 ﹠ 8.70 (2d, 1H), 8.31 ﹠ 8.27 (2d, 1H), 8.21 (d, 1H), 8.18 ﹠ 8.14 (2s, 1H), 7.35,7.24 (2d, 1H), 5.36 (br s, 1H), 4.51-3.52 (m, 10 H)
42 508.10 1.80 (d4-methyl alcohol) 8.73 ﹠ 8.70 (2d, 1H), 8.36 ﹠ 8.33 (2d, 1H), 8.25 (s, 1H), 8.22 (d, 1H), 6.73,6.61 (2d, 1H), 5.50,5.22 (2br s, 1H), 4.51-3.51 (m, 10 H)
43 427.10 1.90 DMSO?d6:13.0ppm(bs，1H)，9.0(s，1H)，8.6(d， 2H)，8.4(s，1H)，8.2(d，1H)，6.7(s，1H)，4.8 (s，1H)，3.8-4.2(m，3H)，1.9(m，2H)，1.4-1.5 (m，2H)，0.9(t，3H)
44 445.10 2.70 DMSOd6:12.4ppm(s，1H)，8.8(t，1H)，8.7(s， 1H)，8.3(m，3H)，7.8(bs，1H)，4.6(q，1H)， 3.8-4.0(m，2H)，1.8(m，2H)，1.3-1.5(m，2H)， 0.9(t，3H)
45 425.10 2.20 DMSO-d6:12.45(s，1H)；8.65(s，1H)；8.5(m， 1H)；8.3(m，2H)；8.2(m，1H)；5.9(t，1H)；4.8 (d，1H)；4.0(m，1H)；3.85(m，1H)；3.6-3.4(m， 2H)；2.25(m，1H)；2.0(m，3H)
46 443.10 2.50 DMSO?1.9(m，2H)，2.3(q，2H)，2.75(bq，2H)，3.8 (m，2H)，8(d，1H)，8.15(overlap?bt，bs，2H)， 8.25(s，1H)，8.3(d，1H)，8.7(s，1H)，12.3(bs，
Compound # M+H RT NMR
1H)
47 407.10 1.60 DMSO-d6:13.0 (br s, 1H); 8.7-8.6 (m, 3H); 8.4 (m, 1H); 8.3 (m, 1H); 6.75 (d, 0.7H); 6.3 (d, 0.3H); 5.9 (t, 1H); 4.9 (d, 0.7H); 4.65 (0.3H); 4.05-3.6 (m, 2H); 2.35 (m, 1H); 2.05 (m, 3H).
48 413.10 1.70 (CD3OD) 1.75 (s, 6H), 3.85 (m, 2H), 6.75 (d, 1H), 8.05 (d, 1H), 8.3 (d, 1H), 8.5 (d, 1H), 8.65 (bt, 1H), 8.8 (s, 1H)
49 389.10 2.00 DMSO-d6:12.4 (br s, 1H); 8.65 (s, 1H); 8.3 (m, 2H); 8.25 (m, 1H); 8.05 (m, 1H); 4.7 (d, 1H); 3.95 (m, 1H); 3.8 (m, 1H); 3.5 (m, 1H); 3.1 (m, 1H); 2.25 (m, 1H); 2.0 (m, 3H); 0.95 (m, 3H)
50 457.10 2.70 H NMR (500MHz, methyl alcohol-d4) 8.76 (d, J=2.3Hz, 1H), 8.48 (t, J=6.2Hz, 1H), 8.31-8.29 (m, 3H), 3.82 (m, 2H), 3.31 (qn, methyl alcohol-d4), 2.55-2.53 (m, 2H), 2.27-2.24 (m, 2H), 1.88 (m, 4H)
51 471.10 3.07
52 371.20 1.50 DMSO-d6:13.0 (s, 1H); 8.75-8.6 (m, 2H); 8.4 (m, 1H); 8.3 (m, 1H); 8.2 (m, 1H); 6.75 (d, and 0.7H) 6.35 (d, 0.3H); 4.85 (d, 0.7H); 4.55 (d, 0.3H); 3.8-3.6 (m, 2H); 3.2-3.0 (m, 2H); 2.35 (m, 1H); 2.05 (m, 3H); 1.05 (dd, 0.7H); 0.95 (dd, 2.3H)
53 439.20 1.80 DMSO-d6:12.85 (br s, 1H); 8.7 (s, 1H); 8.5 (s, 1H); 8.4-8.35 (m, 2h); 8.3 (d, 1H); 6.7 (m, 1h); 3.95-3.7 (m, 4H); 2.15 (m, 4H); 1.7 (s, 3H)
54 456.80 2.95 DMSO-d6:12.25 (br s, 1H); 8.7 (s, 1H); 8.3 (m, 3H); 8.0 (m, 1H); 4.1-3.7 (m, 4H); 2.05 (m, 4H); 1.6 (s, 3H)
55 439.20 1.80 DMSO-d6:12.85 (br s, 1H); 8.7 (s, 1H); 8.5 (s, 1H); 8.4-8.35 (m, 2h); 8.3 (d, 1H); 6.7 (m, 1h); 3.95-3.7 (m, 4H); 2.15 (m, 4H); 1.7 (s, 3H)
56 469.10 2.00 DMSO-d6:9.30 (m, 1H); 8.70 (s, 1H); 8.35 (m, 1H); 8.28 (m, 2H); 4.75 (m, 1H); 3.40 (m, 2H); 2.25 (m, 2H); 2.00 (m, 4H)
57 497.10 2.70 DMSO-d6:8.80 (m, 2H); 8.55 (s, 1h); 8.28 (m, 2H); 4.80 (m, 1H); 4.24 (m, 2H); 3.80 (m, 4H); 2.20 (m, 1H); 1.90 (m, 23H); 1.20 (t, 2H)
58 441.10 2.00 H NMR (500MHz, DMSO-d6) 12.9 (bs, 1H), 9.00 (s,
Compound # M+H RT NMR
1H)，8.66(s，1H)，8.63(s，1H)，8.41(d，J＝2.0 Hz，1H)，8.16(d，J＝6.2Hz，1H)，6.80(s，1H)， 4.81(s，1H)，4.11-4.06(m，1H)，3.87(m，2H)， 2.00(s，1H)，1.66(s，1H)，1.27-1.21(m，1H)， 0.98(d，J＝6.4Hz，3H)，0.92(t，J＝7.2Hz， 3H)
59 459.10 3.10 H?NMR(500MHz，DMSO-d6)12.40(s，1H)，8.80(t， J＝6.3Hz，1H)，8.71(d，J＝2.4Hz，1H)，8.34 (d，J＝2.8Hz，1H)，8.29(s，1H)，8.27(d，1H)， 7.58(d，J＝6.2Hz，1H)，4.57(t，J＝8.0Hz， 1H)，4.04-3.98(m，1H)，3.89-3.83(m，1H)， 2.05-1.99(m，1H)，1.65-1.60(m，1H)，1.33 -1.23(m，1H)，0.96(d，3H)，0.88(t，3H)
60 441.10 2.00 H?NMR(500MHz，DMSO-d6)13.0(bs，1H)，8.98(s， 1H)，8.66(s，1H)，8.62(s，1H)，8.41(d，J＝1.9 Hz，1H)，8.17(d，J＝6.3Hz，1H)，6.84(s，1H)， 4.90(s，1H)，4.08-4.07(m，1H)，3.88(m，2H)， 2.11-2.08(m，1H)，1.50(t，J＝6.9Hz，1H)， 1.27(m，1H)，1.00(d，J＝6.9Hz，3H)，0.92(q， J＝7.5Hz，3H)
61 459.10 3.10 H?NMR(500MHz，DMSO-d6)12.38(s，1H)，8.76(t， J＝6.3Hz，1H)，8.70(d，J＝2.4Hz，1H)，8.28 (m，J＝4.2Hz，3H)，8.28(s，1H)，7.36(d，J＝ 5.7Hz，1H)，4.72(t，1H)，4.02-3.85(m，2H)， 2.05(q，J＝6.8Hz，1H)，1.54-1.49(m，1H)， 1.27-1.21(m，1H)，0.99(d，J＝6.8Hz，3H)， 0.92(t，J＝7.4Hz，3H)
62 441.10 2.00 H?NMR(500MHz，DMSO-d6)13.01(s，1H)，9.05(s， 1H)，8.78(s，1H)，8.64(s，1H)，8.42(d，J＝2.0 Hz，1H)，8.16(d，J＝6.4Hz，1H)，6.91(s，1H)， 4.89(d，J＝8.0Hz，1H)，4.15-4.07(m，1H)， 3.82-3.85(m，1H)，1.08(s，9H)
63 459.10 3.30 H?NMR(500MHz，DMSO-d6)12.41(s，1H)，8.85(t， J＝6.3Hz，1H)，8.74(d，J＝2.4Hz，1H)，8.31 (d，1H)，8.29(s，2H)，6.86(d，J＝7.8Hz，1H)， 4.77(d，J＝8.8Hz，1H)，4.09-4.02(m，1H)， 3.88-3.82(m，1H)，1.08(s，9H)
64 429.10 2.39 1H?NMR(CD3OD，500MHz):2.45-2.52(m，1H)，
Compound # M+H RT NMR
2.91-3.00(m，1H)，3.89-4.14(m，2H)，4.50-4.61 (m，2H)，5.25-5.30(m，1H)，8.23-8.30(m，3H)， 8.63(s，1H)
65 373.40 1.90 DMSO-d6:12.9(br?s，1H)；8.7(s，1H)；8.6(s， 1H)；8.4(s，1H)；8.3(s，1H)；8.15(m，1H)；6.8 (s，1H)；4.6(s，1H)；3.1(m，1H)；2.7(m，1H)； 2.25(m，1H)；1.1-0.95(m，9H)
66 425.10 2.20 H NMR (500MHz, and methyl alcohol-d4) 8.73 (d, J=2.0Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 8.35 (d, J=2.1Hz, 1H), 8.10 (d, J=7.2Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 3.85 (m, 2H), 3.01-2.97 (m, 2H), 2.44-2.39 (m, 2H), 2.16 (m, 2H)
67 409.20 1.80 DMSO-d6:13.0(br?s，1H)；8.75(m，1H)；8.65(s， 1H)；8.6(s，1H)；8.4(s，1h)；8.15(d，1H)；6.8 (m，1h)；6.05(t，1H)；4.75(m，1H)；3.75-3.5(m， 2H)；2.25(m，1H)；1.1-0.95(m，6H)
68 456.60 3.83 1H?NMR(CD3OD，500MHz):1.68-2.00(m，6H)， 2.26-2.33(m，1H)，3.49-3.58(m，1H)，3.84-4.02 (m，2H)，4.45-4.53(m，1H)，5.36-5.42(m，1H)， 6.71(d，1H)，8.11-8.39(m，4H)，8.86-8.92(m， 1H)
69 497.80 1.79 1H?NMR(CD3OD，500MHz):3.38-4.35(m，10H)，4.67 (d，1H)，5.19-5.54(m，1H)，6.80-7.07(m，1H)， 8.23-8.80(m，4H)
70 525.80 2.08 1H?NMR(CD3OD，500MHz):1.29(d，6H)，3.43-4.30 (m，7H)，4.68(d，1H)，4.86-4.94(m，1H)，5.44 (s，br.，1H)，7.01(s，br.，1H)，8.23-8.58(m， 4H)
71 523.80 2.05 1H?NMR(CD3OD，500MHz):3.40-4.30(m，7H)， 4.53-4.74(m，3H)，5.19-5.54(m，3H)，5.92-6.01 (m，1H)，6.98(s，br.，1H)，8.24-8.57(m，4H)
72 459.50 2.99 10.5(s，1H)，8.74(d，1H)，8.39(s，1H)，8.35 (d，1H)，8.28(d，1H)，7.20(m，1H)，6.73(s，1H)， 4.5-4.8(s，6H)，3.98(m，1H)，3.68(m，1H)，2.32 (m，1H)，1.70(s，3H)，1.08(dd，6H)(CD3CN)
73 441.20 1.80
74 429.10 1.60 H?NMR(500MHz，DMSO-d6)12.95(bs，1H)，8.78(s， 1H)，8.65(s，1H)，8.59(s，1H)，8.39(d，J＝1.8
Compound # M+H RT NMR
Hz，1H)，8.17(d，J＝4.8Hz，1H)，6.90(s，1H)， 5.30(s，1H)，4.74(s，1H)，4.21(s，1H)，4.04 -3.80(m，2H)，1.21(d，J＝5.7Hz，3H)
75 423.00 1.80 H?NMR(500MHz，DMSO-d6)12.95(bs，1H)，9.07(s， 1H)，8.63(s，1H)，8.60(s，1H)，8.40(d，J＝2.1 Hz，1H)，8.20(s，1H)，6.75(s，1H)，4.99(s，1H)， 4.05-3.83(m，2H)，2.98(t，J＝2.4Hz，1H)， 2.80(d，J＝7.3Hz，2H)
76 429.10 1.60 H?NMR(500MHz，DMSO-d6)12.96(s，1H)，8.79(s， 1H)，8.65(s，1H)，8.61(s，1H)，8.40(d，J＝2.1 Hz，1H)，8.20-8.17(m，1H)，6.91(s，1H)，5.25 (bs，1H)，4.75(s，1H)，4.21(s，1H)，4.04-3.88 (m，2H)，1.22(d，J＝6.2Hz，3H)
77 482.40 1.69 1H?NMR(CD3OD，500MHz):2.08(s，3H)，3.18-4.97 (m，9H)，6.87-7.08(m，1H)，8.24-8.59(m，4H)
78 518.40 1.83 1H?NMR(CD3OD，500MHz):2.93(s，3H)，3.18-4.97 (m，9H)，7.00-7.10(m，1H)，8.26-8.56(m，4H)
79 526.50 2.00 1H?NMR(CD3OD，500MHz):0.98(t，3H)，1.67-1.74 (m，2H)，3.18-4.90(m，11H)，6.86-7.00(m，1H)， 8.24-8.59(m，4H)
80 540.50 2.12 1H?NMR(CD3OD，500MHz):0.97(d，6H)，1.91-2.01 (m，1H)，3.18-4.90(m，11H)，6.86-7.00(m，1H)， 8.24-8.59(m，4H)
81 482.50 1.61 1H?NMR(CD3OD，500MHz):2.08(s，3H)，3.18-4.97 (m，9H)，6.87-7.08(m，1H)，8.24-8.59(m，4H)
82 518.40 1.82 1H?NMR(CD3OD，500MHz):2.93(s，3H)，3.18-4.97 (m，9H)，7.00-7.10(m，1H)，8.26-8.56(m，4H)
83 441.20 1.50 DMSO-d6:12.85(br?s，1H)；9.05(s，0.3H)；8.9 (s，0.7H)；8.7(m，0.3H)；8.65-8.5(m，1.7H)； 8.4-8.25(m，2H)；6.75(m，0.7H)；6.2(m， 0.3H)；4.9(m，0.7H)；4.7(m，0.3H)；4.5(m，1H)； 4.05-3.5(m，5H)；2.05(m，1H)
84 473.10 2.20 DMSO-d6:12.35(br?s，1H)；8.7(s，1H)；8.35-8.1 (m，4H)；6.4(m，1H)；4.7(dd，1H)；4.0(m，2H)； 3.8(m，2H)；3.15(m，1H)；2.25(m，1H)；2.0(m， 3H)
85 459.10 2.00 DMSO-d6:12.3(br?s，1H)；8.8(s，1H)；8.7(m， 1H)；8.3(m，2H)；8.15(m，1H)；4.85(m，1H)；4.45
Compound # M+H RT NMR
(m，1H)；4.05-3.7(m，5H)；1.9(m，1H)
86 413.20 2.30 H?NMR(500MHz，DMSO)12.63(s，1H)，8.87-8.86 (bs，1H)，8.61(m，2H)，8.35-8.31(m，2H)，7.25 (d，J＝4.8Hz，1H)，5.39(q，J＝7.1Hz，1H)， 3.95-3.81(m，2H)，3.18(s，3H)，1.43(d，J ＝6.9Hz，3H)
87 431.20 2.70 H?NMR(500MHz，DMSO)12.38(s，1H)，8.70-8.65 (m，2H)，8.32(d，J＝6.9Hz，1H)，8.29(dd，J ＝2.4，2.8Hz，2H)，5.16(q，J＝7.0Hz，1H)， 3.95-3.86(m，2H)，3.17(d，J＝4.2Hz，3H)， 1.46(d，J＝7.0Hz，3H)
88 400.10 2.30 DMSO-d6:12.6(m，1H)；8.60(m，1H)；8.50(m， 1H)；8.30(m，1H)；8.25(m，1H)；4.50(m，1H)； 3.80(m，2H)；1，42(m，3H)
89 441.20 2.10 H?NMR(500MHz，DMSO)12.41(s，1H)，8.78(t，J ＝6.3Hz，1H)，8.71(d，J＝2.4Hz，1H)，8.36(d， 1H)，8.33(d，1H)，8.30(d，J＝2.4Hz，1H)，4.86 (d，J＝10.4Hz，1H)，3.98-3.88(m，2H)，3.20 (d，J＝4.9Hz，3H)，2.44-2.40(m，1H)，1.04 (d，J＝6.5Hz，3H)，0.90(d，J＝6.7Hz，3H)
90 459.10 3.40 H?NMR(500MHz，DMSO)12.98(s，1H)，8.87(bs， 1H)，8.70(s，2H)，8.42(d，1H)，8.38(d，1H)， 5.4(bs，1H)，3.97-3.89(m，2H)，3.14(bs，3H)， 2.51-2.42(m，1H)，1.03(bs，3H)，0.86(d，J ＝6.7Hz，3H)
91 459.40 2.95 10.95(s，1H)，8.68(s，1H)，8.51(s，1H)，8.36 (s，1H)，8.28(d，1H)，7.25(m，2H)，4.1-4.5(s， 8H)，3.95(m，1H)，3.69(m，1H)，2.39(m，1H)， 1.72(s，3H)，1.09(dd，6H)(CD3CN)
92 445.40 2.70 10.69(s，1H)，8.70(d，1H)，8.48(s，1H)，8.41 (d，1H)，8.28(d，1H)，7.34(s，1H)，7.23(m，1H)， 3.75-4.2(m，26H)，2.20(m，2H)，1.72(s，3H)， 0.93(t，3H)(CD3CN)
93 487.30 2.10 DMSO-d6:12.3(br?s，1H)；8.85(s，1H)；8.65(s， 1H)；8.3(m，2H)；8.15(s，1H)；4.75(dd，1H)； 4.25(m，1H)；4.05-3.8(m，4H)；3.6-3.45(m，3H)； 2.0(m，1H)；1.1(dd，3H)
94 499.40 2.20
Compound # M+H RT NMR
95 469.40 1.90 DMSO-d6:12.3(br?s，1H)；9.1-8.3(m，5H)；6.75 (m，0.7H)；6.2(m，0.3H)；4.85(m，0.7H)；4.6(m， 0.3H)；4.3(m，1H)；4.1-3.5(m，7H)；2.1(m，1H)； 1.1(dd，3H)
96 481.40 2.00
97 426.10 2.51 DMSO-d6:12.6(m，1H)；8.82(m，0.5H)；8.75(s， 0.5H)；8.62(m，1H)；8.58(s，0.5H)；8.48(m， 1H)；8.38(m，0.5H)；8.35(m，0.5H)；8.22(m， 0.5H)；4.65-4.55(m，1H)；3.80-3.60(m，4H)； 2.25(m，1H)；1.90(m，3H)
98 414.10 2.52 DMSO-d6:12.6(m，1H)；8.95(s，0.5H)；8.70(m， 0.5H)；8.50(m，0.5H)；8.40(0.5H)；8.20(m， 2.0H)；8.10-7.90(m，1H)
99 427.10 1.80 H?NMR(500MHz，DMSO-d6)13.07(s，1H)，9.17(s， 1H)，8.69-8.66(m，3H)，8.61(m，1H)，8.39(d， J＝2.2Hz，1H)，8.20(d，J＝7.1Hz，1H)，6.78 (d，J＝6.9Hz，1H)，3.83-3.78(m，2H)，2.14 -2.07(m，1H)，2.01-1.94(m，1H)，1.61(s，3H)， 0.88(t，J＝7.5Hz，3H)
100 445.10 2.70 H?NMR(500MHz，DMSO-d6)12.36(s，1H)，8.68(d， J＝2.4Hz，1H)，8.41(t，J＝6.4Hz，1H)，8.30 -8.27(m，2H)，8.11(s，1H)，7.53(s，1H)，3.85 -3.72(m，2H)，2.19-2.15(m，1H)，1.99-1.95 (m，1H)，1.55(s，3H)，0.81(t，J＝7.5Hz，3H)
101 473.21 2.55 DMSO-d6:12.3(br?s，1H)；8.8(s，1H)；8.7(s， 1H)；8.3(m，2H)；8.15(m，1H)；8.75(m，1H)；4.15 (m，1H)；4.1-3.75(m，4H)；3.45(m，4H)；2.0(m， 1H)
102 487.23 2.70 DMSO-d6:12.3(br?s，1H)；8.8(s，1H)；8.7(s， 1H)；8.3(m，2H)；8.15(m，1H)；4.75(m，1H)；4.2 (m，1H)；4.05-4.75(m，4H)；3.5(m，3H)；2.0(m， 1H)；1.1(dd，3H)
103 455.10 1.70
104 500.10 1.90
105 499.10 2.90 DMSO-d6:12.35(br?s，1H)；8.85(s，1H)；8.65(s， 1H)；8.3(m，2H)；8.15(m，1H)；5.9(m，1H)；5.3 (d，1H)；5.15(d，1H)；4.8(m，1H)；4.3(m，1H)； 4.05(m，2H)；4.0-3.8(m，5H)；2.0(m，1H)
Compound # M+H RT NMR
106 455.10 1.70
107 427.40 1.80 10.07(s，1H)，8.83(d，1H)，8.26(d，1H)，8.22 (d，1H)，8.13(d，1H)，7.20(m，1H)，6.38(d，1H)， 6.00(s，1H)，3.88(m，1H)，3.77(m，1H)，1.95 (m，2H)，1.57(s，3H)，0.91(t，3H)(CD3CN)
108 359.40 1.65
109 395.40 1.77
110 441.40 1.91 10.01(s，1H)，8.71(d，1H)，8.23(d，1H)，8.17 (d，1H)，8.12(d，1H)，7.16(m，1H)，6.40(d，1H)， 5.86(s，1H)，3.97(m，1H)，3.61(m，1H)，1.53 (s，3H)，1.02(dd，6H)(CD3CN)
111 414.10 2.50 DMSO-d6:12.65(m，1H)；8.95(s，0.5H)；，8.72(m， 0.5H)；8.70(m，0.5H)；8.50(m，1H)；8.48(m， 0.5H)；8.40(m，0.5H)；8.30(m，1H)；8.28(m， 0.5H)；8.03(m，0.5H)；4.45(m，1H)；3.80(m， 2H)；1.75(m，2H)；1.00(m，3H)
112 440.10 2.70 DMSO-d6:12.68(m，1H)；8.98(s，0.5H)；8.68(s， 0.5H)；8.58(s，0.5H)；8.48(s，0.5H)；8.43(s， 0.5H)；8.35-8.15(m，3.5H)；3.75(m，2H)；2.15 (m，2H)；2.02(m，2H)；1.65(m，4H)
113 426.10 2.60 DMSO-d6:12.55(m，1H)；8.95(m，0.5H)；8.68(m， 0.5H)；8.62(m，0.5H)；8.56(m，0.5H)；8.52(m， 0.5H)；8.45(m，0.5H)；8.40(m，0.5H)；8.35(m， 1H)；8.22(0.5H)；8.16(m，1H)；3.80(m，2H)； 2.70(m，1H)；2.40(m，1H)；2.25(m，2H)；1.88 (m，2H)
114 512.10 1.80 DMSO-d6:12.5(bs，1H)；8.95(bs，1H)；8.50(m， 2H)；8.32(m，2H)；6.80(m，1H)；4.50(m，1H)； 4.00-3.40(m，10H)；1.15(t，3H)
115 540.10 2.10
116 496.10 1.70 DMSO-d6:12.6(m，1H)；8.95(m，1H)；8.50(m， 2H)；8.32(m，2H)；6.80(m，1H)；4.50(m，1H)； 4.00-3.40(m，10):1.15(t，3H)
117 508.10 1.70
118 522.20 1.90
119 459.30 1.70 DMSO-d6:12.35(br?s，1H)；8.8(m，1H)；8.65(s， 1H)；8.3(m，2H)；8.15(m，1H)；4.8(m，1H)；4.4 (m，1H)；4.05-3.7(m，4H)；2.3(m，1H)；1.95(m，
Compound # M+H RT NMR
1H)
120 441.40 1.70 DMSO-d6:12.9(br?s，1H)；9.05(m，0.3H)；8.9(m， 0.7H)；8.7-8.5(m，2H)；8.4-8.25(m，2H)；6.75 (m，0.7H)；6.2(m，0.3H)；4.95(m，0.7H)；4.7(m， 0.3H)；4.5(m，1H)；4.05-3.5(m，4H)；2.4(m， 1H)；2.05(m，1H)
121 425.00 2.03 10.1(s，1H)，8.89(s，1H)，8.29(m，3H)，7.27 (s，1H)，6.51(d，1H)，3.88(m，2H)，3.30(s，6H)， 1.86(m，1H)，1.57(m，1H)，1.43(m，1H)，1.19 (m，1H)(CD3CN)
122 461.30 2.40
123 443.30 1.90
124 487.40 2.20
125 479.40 2.30
126 443.30 1.90
127 439.17 1.84 H?NMR(500MHz，MeOD)8.79(d，J＝2.3Hz，1H)， 8.51(t，J＝6.4Hz，1H)，8.48(s，1H)，8.35(d， J＝2.3Hz，1H)，8.06(d，J＝7.2Hz，1H)，6.73 (d，J＝7.2Hz，1H)，3.87-3.81(m，2H)，2.56 -2.52(m，2H)，2.25-2.20(m，2H)，1.93-1.86 (m，4H)，0.00(TMS)
128 441.40 2.20 H?NMR(500MHz，DMSO)8.66(s，1H)，8.62(s，1H)， 8.58(s，1H)，8.38(d，J＝2.0Hz，1H)，8.18(d， J＝7.0Hz，1H)，6.81(s，1H)，4.09-3.78(m， 2H)，2.18-2.16(m，2H)，2.10(m，2H)，0.77(t， J＝7.4Hz，6H)，0.00(TMS)
129 459.40 2.40
130 461.30 2.40
131 377.30 1.67
132 441.09 1.65 H?NMR(500MHz，MeOD)8.70(d，J＝2.2Hz，1H)， 8.48(s，1H)，8.36(d，J＝2.3Hz，H)，8.12(d， J＝7.2Hz，1H)，7.59(d，J＝8.2Hz，2H?*0.7?equiv p-TsOH)，7.37(d，J＝8.0Hz，2H*0.7?equiv p-TsOH)，6.76(d，J＝7.2Hz，1H)，4.41(d，J ＝9.6Hz，1H)，4.22(d，J＝9.5Hz，1H)，4.07- 4.04(m，2H)，3.88-3.83(m，2H)，2.88-2.82 (m，1H)，2.52-2.43(m，1H)，2.43(s，3H*0.7
Compound # M+H RT NMR
equiv?p-TsOH)，0.00(TMS)
133 443.30 2.86
134 441.16 1.50
135 455.10 1.80 DMSO-d6:12.8(br?s，1H)；9.05-8.85(m，1H)； 8.8-8.4(m，2H)；8.35(m，2H)；6.75(m，0.8H)； 6.2(m，0.2H)；4.85(m，0.8H)；4.6(m，0.2H)；4.2 (m，1H)；4.0(m，1H)；3.9-3.6(m，3H)；3.3(s， 3H)；2.2(m，1H)
136 455.10 1.80 DMSO-d6:12.9(br?s，1H)；8.75-8.25(m，5H)；6.75 (m，0.8H)；8.45(m，0.2H)；4.95(m，0.8H)；4.75 (m，0.2H)；4.2(m，1H)；4.1-3.7(m，4H)；3.2(s， 3H)；2.3(m，1H)
137 473.10 2.00 DMSO-d6:12.35(br?s，1H)；8.65(m，1H)；8.45 (dd，1H)；8.25(m，2H)；8.15(m，1H)；4.8(d，1H)； 4.1(m，1H)；4.0(m，1H)；3.9(m，1H)；3.85(m， 2H)；3.2(s，3H)；2.2(m，1H)
138 397.00 1.74 (500MHz，CD3OD)8.57(t，J＝6.2Hz，1H)，8.50 (s，1H)，8.48(d，J＝2.6Hz，1H)，8.3(d，J＝1.2 Hz，1H)，8.05(d，J＝7.2Hz，1H)，6.7(d，J＝7.2 Hz，1H)，3.86-3.8(m，2H)，1.74(s，6H)，0(TMS)
139 445.10 3.30 H?NMR(500MHz，DMSO)12.24(s，1H)，8.69(s，1H)， 8.32(d，J＝6.9Hz，1H)，8.24(m，2H)，8.15(s， 1H)，3.68-3.63(m，2H)，3.20(s，1H)，1.51(s， 1H)
140 427.10 1.80 H?NMR(500MHz，DMSO)12.7(bs，1H)，8.82(s，1H)， 8.34-8.30(m，2H)，8.16(s，1H)，8.07(d，J＝ 6.2Hz，1H)，6.63(d，J＝6.2Hz，1H)，3.77-3.70 (m，2H)，3.06(s，3H)，1.56(s，6H)
141 431.10 2.50 DMSO-d6:12.2(m，1H)；8.60(m，1H)；8.22(s， 1H)；8.18(s，1H)；8.10(s，1H)；7.70(m，1H)； 5.16(m，1H)；4.18(m，2H)；3.3(s，2.5H)；2.9(s， 0.5H)；1.35(m，3H)
142 413.10 1.80 DMSO-d6:12.5(m，1H)；8.70(m，1H)；8.30(m， 2H)；8.18(m，2H)；6.42(m，1H)；5.25(m，1H)； 4.20(m，2H)；3.30(s，2.5H)；2.90(s，0.5H)； 1.32(m，3H)
143 413.10 1.84
144 377.10 1.70
Compound # M+H RT NMR
145 395.10 1.74
146 428.10 2.00
147 411.10 2.00
148 497.10 2.40
149 554.00 2.20
150 498.00 1.80 DMSO-d6:12.7(m，1H)；8.92(m，1H)；8.60(m， 1H)；8.42(m，1H)；8.32(m，1H)；8.28(m，1H)； 6.80(m，1H)；5.20(m，1H)；4.30-3.60(m，8H)； 3.55(m，3H)
151 512.00 1.90 DMSO-d6:12.5(m，1H)；8.90(m，1H)；8.55(m， 1H)；8.42(m，1H)；8.32(m，1H)；8.30(m，1H)； 6.70(m，1H)；5.20(m，1H)；4.35-3.55(m，10H)； 1.15(t，3H)
152 526.10 2.00
153 526.00 2.00
154 540.10 2.10
155 540.10 2.10
156 532.80 3.10 DMSO-d6:12.35(br?s，1H)；8.9(m，1H)；8.7(s， 1H)；8.4-8.1(m，3H)；4.85(dd，1H)；4.35-4.1(m， 2H)；4.0-3.7(m，2H)；3.3(m，4H)；2.85(m，1H)； 2.4(m，1H)
157 546.90 3.20 DMSO-d6:12.35(br?s，1H)；8.9(m，1H)；8.7(s， 1H)；8.35-8.15(m，3H)；4.9(dd，1H)；4.1-3.75 (m，4H)；3.1-2.9(m，5H)；2.15(m，1H)；1.95(m， 2H)
158 493.90 1.70
159 522.00 1.90
160 524.00 1.90
161 538.00 2.10
162 511.00 1.70 DMSO-d6:12.8(m，1H)；8.90(m，1H)；8.55z9m， 2H)；8.35(，2H)；6.80(m，1H)；5.25(，1H)； 4.20-3.60(m，8H)；2.62(s，6H)
163 525.00 1.80
164 560.00 2.20
165 508.00 1.80
166 443.00 1.60 DMSO-d6:12.8(br?s，1H)；8.95-8.65(m，1H)； 8.65-8.45(m，2H)；8.4-8.25(m，2H)；6.75(m， 0.7H)；6.25(m，0.3H)；5.5(d，1H)；5.05(m，
Compound # M+H RT NMR
0.7H); 4.85 (m, 0.3H); 4.2-3.7 (m, 4H); 2.8-2.55 (m, 1H); 2.5-2.35 (m, 1H)
167 460.90 1.80 DMSO-d6:12.75 (br s, 1H); 9.0 (m, 1H); 8.65-8.3 (m, 4H); 6.7 (m, 1H); 5.15 (m, 1H); 4.2 (m, 2H); 4.0 (m, 1H); 3.85 (m, 1H); 3.1 (m, 1H); 2.6 (m, 1H)
168 443.00 1.60 DMSO-d6:12.8 (br s, 1H); 9.2-8.9 (m, 1H); 8.7-8.45 (m, 2H); 8.4-8.3 (m, 2H); 6.75 (m, 0.7H); 6.25 (m, 0.3H); 5.55 (d, 1H); 5.0 (m, 0.7H); 4.8 (m, 0.3H); 4.2-3.7 (m, 4H); 2.9-2.7 (m, 1H); 2.3-2.1 (m, 1H)
169 403.10 2.20 DMSO-d6:12.45 (s, 1H); 8.7 (s, 1H); 8.3 (m, 2H); 8.25 (m, 1H); 8.0 (dd, 1H); 4.7 (m, 1H); 3.95 (m, 1H); 3.8 (m, 1H); 3.05 (m, 1H); 2.95 (m, 1H); 2.25 (m, 1H); 2.0 (m, 3H); 1.4 (m, 2H); 0.75 (m, 3H).
170 385.10 1.70 DMSO-d6:12.9(br?s，1H)；8.7-8.6(m，2H)；8.4 (m，1H)；8.3(m，1H)；8.15(m，1H)；6.7(d，0.7H)； 6.3(d，0.3H)；4.85(d，0.7H)；4.5(0.3H)； 4.05-3.6(m，2H)；3.2-3.05(m，1H)；2.9(m，1H)； 2.35(m，1H)；2.05(m，3H)；1.5-1.3(m，2H)；0.8 (m，1H)；0.7(m，2H)。
171 387.40 2.00 DMSO-d6:12.95(br?s，1H)；8.7(s，1H)；8.6(s， 1H)；8.4(s，1H)；8.3(s，1H)；8.15(m，1H)；6.8 (s，1H)；4.65(s，1H)；3.2(m，1H)；3.0(m，1H)； 2.25(m，1H)；1.45(m，2H)；1.1-0.95(m，6H)； 0.85(m，3H)。
172 457.10 2.40 DMSO-d6:12.35(br?s，1H)；8.7(s，1H)；8.3-8.25 (m，3H)；8.2(m，1H)；4.65(d，1H)；4.0(m，1H)； 3.8(m，1H)；3.5-3.3(m，2H)；2.4-2.2(m，3H)； 2.0(m，3H)。
173 439.20 1.70 DMSO-d6:12.9(br?s，1H)；8.7-8.65(m，2H)； 8.45-8.25(m，3H)；6.75(d，0.8H)；6.3(d，0.2H)； 4.85(d，0.8H)；4.55(d，0.2H)；4.05-3.55(m， 4H)；2.4-2.25(m，3H)；2.1-2.0(m，3H)。
174 441.40 2.00
175 373.40 1.74
176 427.30 1.87
177 401.10 2.00 DMSO-d6:12.45(s，1H)；8.7(s，1H)；8.3(m，2H)；
Compound # M+H RT NMR
8.25 (s, 1H); 8.15 (s, 1H); 4.6 (d, 1H); 3.9 (m, 1H); 3.8 (m, 1H); 2.6 (m, 1H); 2.25 (m, 1H); 1.95 (m, 3H); 0.6 (m, 2H); 0.4 (m, 1H); 0.35 (m, 1H).
178 383.10 1.60 DMSO-d6:13.0(br?s，1H)；8.65(m，1H)；8.6(s， 1H)；8.4(m，1H)；8.35-8.2(m，2H)；6.75(d， 0.7H)；6.3(d，0.3H)；4.8(d，0.7H)；4.5(0.3H)； 4.05-3.6(m，2H)；2.7-2.55(m，1H)；2.35(m，1H)； 2.05(m，3H)；0.7-0.2(m，4H)。
179 385.40 1.90 DMSO-d6:12.95(br?s，1H)；8.7(s，1H)；8.6(s， 1H)；8.4(s，1H)；8.35(s，1H)；8.15(m，1H)；6.8 (s，1H)；4.6(s，1H)；2.7(m，1H)；2.25(m，1H)； 1.05-0.95(m，6H)；0.65(m，2H)；0.45(m，2H)。
180 371.40 1.65
Table 5
Compound # M+H RT NMR
181 473.1 1.9
182 415.1 1.8 (500MHz，DMSO)12.22(s，1H)，8.42(dd，J＝2.8， 9.9Hz，1H)，8.37(t，J＝6.4Hz，1H)，8.26- 8.25(m，2H)，8.10(d，J＝2.5Hz，1H)，3.78- 3.71(m，2H)，1.57(s，6H)，0.00(TMS)
183 361.1 1.6 (500MHz，DMSO)12.27(s，1H)，8.47(dd，J＝2.8， 9.8Hz，1H)，8.25(d，J＝3.0Hz，2H)，8.19(d， J＝2.2Hz，1H)，7.75(t，J＝5.6Hz，1H)，7.56 (bs，1H)，3.02-2.99(m，2H)，1.56(s，6H)，0.77 (t，J＝7.1Hz，3H)，0.00(TMS)
184 379.1 1.6 (500MHz，DMSO)12.3(s，1H)，8.45(dd，J＝2.8， 9.8Hz，1H)，8.25(m，2H)，8.19(bs，1H)，8.05 (t，1H)，7.7(bs，1H)，4.2(dt，2H，under?water)， 3.2(dq，2H)，1.6(s，6H)，0.00(TMS)
185 397.1 1.7 (500MHz，DMSO)12.28(s，1H)，8.44(dd，J＝2.8， 9.9Hz，1H)，8.27(d，J＝4.4Hz，2H)，8.19(t， J＝5.9Hz，1H)，8.15(d，J＝2.5Hz，1H)，7.69 (bs，1H)，5.7(tt，J＝48Hz，J＝4.3Hz，1H)， 3.39-3.31(m，2H)，1.57(s，6H)，0.00(TMS)
186 375.1 1.7
Compound # M+H RT NMR
187 361.1 2.04
188 379.1 2.21
189 343.1 2.04
190 357.1 2.3
191 457 2.9 (DMSO-d6) 12.35 (s, 1H); 8.7 (d, 1H); 8.4-8.25 (m, 3H); 8.1 (s, 1H); 4.1 (m, 1H); 3.95 (m, 1H); 3.85 (m, 1H); 3.7 (m, 1H); 2.05 (m, 4H); 1.65 (s, 3H).
192 439 1.7 (DMSO-d6)12.9(s，1H)；8.75-8.65(m，1.1H)； 8.55(m，0.9H)；8.45-8.15(m，3H)；6.7(m， 0.9H)；6.1(m，0.1H)；4.15(m，0.1H)；3.95(m， 0.9H)；3.8(m，3H)；2.2-2.05(m，4H)；1.75-1.6 (m，3H)。
193 455.1 1.8 (500MHz，DMSO)12.95(s，1H)，8.71(s，1H)，8.59 (bd，2H)，8.36(d，J＝2.2Hz，1H)，8.23(d，J ＝6.9Hz，1H)，6.82(s，1H)，3.82-3.77(m，4H)， 3.66(t，J＝10.5Hz，4H)，2.27-2.20(m，2H)， 2.20-2.08(m，2H)，0.00(TMS)
194 439.1 1.7 (500MHz，DMSO)12.89(s，1H)，8.61(m，2H)，8.46 (d，J＝9.6Hz，1H)，8.36(s，1H)，8.22(d，J ＝6.9Hz，1H)，6.82(bd，1H)，3.81-3.79(m， 4H)，3.67-3.63(m，2H)，2.23(t，J＝10.2Hz， 2H)，2.12(m，2H)，0.00(TMS)
195 409.1 1.8
196 427.08 1.7
197 528.9 2 (DMSO-d6)12.5(br?s，1H)；8.9(m，1H)；8.65(m， 1H)；8.4-8.3(m，3H)；6.75(m，0.5H)；6.5(m， 0.5H)；4.9(m，1H)；4.1-3.7(m，4H)；3.1-2.9(m， 5H)；2.2(m，1H)；1.95(m，2H)。
198 409.1 1.9 (500MHz，MeOD)8.91(d，J＝2.2Hz，1H)，8.72 (s，1H)，8.55(d，J＝8.3Hz，1H)，8.38(d，J ＝2.2Hz，1H)，8.03(t，J＝7.6Hz，2H)，7.88 (d，J＝8.3Hz，1H)，7.74(t，J＝7.8Hz，1H)， 3.21-3.15(m，2H)，1.87(s，6H)，0.89(t，J ＝7.2Hz，3H)。
Compound # M+H RT NMR
199 447.1 1.79 (500MHz, MeOD) 8.73 (s, 1H), 8.63 (d, J=9.5 Hz, 1H), 8.57 (m, 2H), 8.33 (s, 1H), 8.03 (m, 1H), 7.89 (d, J=8.4Hz, 1H), 7.74 (t, J=7.7 Hz, 1H), 3.82 (m, 2H), 2.66 (s, 1.3H), 1.88 (s, 6H).(peak at 2.66 places is not differentiated)
200 397.1 1.65 (500MHz, DMSO-d6) 12.90 (s, 1H), 9.05 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 8.16 (d, J=6.4Hz, 1H), 6.73 (s, 1H), 4.75 (s, 1H), 4.08-4.01 (m, 2H), 3.87 (d, J=6.5Hz, 1H), 1.93-1.83 (m, 2H), 1.00 (t, J=7.4Hz, 3H), 0.00 (TMS)
201 445 1.7 (DMSO-d6) 12.75 (br s, 1H); 9.0 (dd, 1H); 8.55 (s, 1H); 8.45-8.25 (m, 3H); 6.7 (m, 1H); 5.2 (m, 1H); 4.2 (m, 2H); 4.05-3.7 (m, 2H); 3.1 (m, 1H); 2.6 (m, 1H).
202 441 2.7 (DMSO-d6)12.25(br?s，1H)；8.4(d，1H)；8.35 (dd，1H)；8.3(d，1H)；8.25(s，1H)；8.1(s，1H)； 4.1(m，1H)；3.95(m，1H)；3.8(m，1H)；3.7(m， 1H)；2.1-2.0(m，4H)；1.65(s，3H)。
203 423 1.7 (DMSO-d6)12.8(br?s，1H)；8.5-8.2(m，5H)；6.7 (m，1H)；4.0-3.7(m，4H)；2.2-2.0(m，4H)；1.7 (s，3H)。
204 427 1.5 (DMSO-d6)12.85(br?s，1H)；9.2-9.0(m，1H)； 8.7-8.6(m，1H)；8.4(m，3H)；6.85(m，0.8H)； 6.25(m，0.2H)；5.55(d，1H)；5.05(dd，0.8H)； 4.8(m，0.2H)；4.2-3.6(m，4H)；2.8(m，1H)； 2.3-2.15(m，1H)。
205 423.1 2
206 441.1 2
207 459.1 2.1 (500MHz，DMSO)13.17(s，1H)，8.87(s，1H)，8.80 -8.60(m，2H)，8.40-8.30(m，2H)，8.05-7.94 (m，1H)，7.89(d，J＝8.3Hz，1H)，7.70(m，1H)， 5.70(tt，J＝15.1，3.9Hz，1H)，3.40-3.30(m， 2H)，2.38-2.31(m，1H)，2.07(m，1H)，1.70(s， 3H)，0.89(t，J＝7.5Hz，3H)。
Compound # M+H RT NMR
208 477.1 2.2 (500MHz, and DMSO) 8.85 (s, 1H), 8.67-8.55 (m, 3H), 8.39 (s, 1H), 7.99 (m, 1H), 7.89 (d, J=8.1Hz, 1H), 7.69 (m, 1H), and 3.86-3.71 (m, 2H), 2.40-2.34 (m, 1H), and 2.10-2.06 (m, 1H), 1.70 (s, 3H), 0.89 (t, J=7.5Hz, 3H).
209 359.1 1.6 (500MHz，MeOD)8.48(dd，J＝2.8，9.3Hz，1H)， 8.43(s，1H)，8.35-8.33(m，1H)，8.28-8.27 (m，1H)，3.21(q，J＝7.2Hz，2H)，1.77-1.75 (m，2H)，1.29(m，2H)，0.97(t，J＝7.2Hz，3H)。
210 395.1 1.7 (500MHz，DMSO)12.35(s，1H)，8.57(s，1H)，8.39 (d，J＝6.1Hz，2H)，8.31(d，J＝3.9Hz，1H)， 8.27-8.25(m，2H)，5.95-5.71(m，1H)，3.45 -3.37(m，2H)，1.53(br，2H)，1.16(br，2H)。
211 413 1.8 (500MHz，MeOD)8.46-8.43(m，2H)，8.37(t， J＝4.8Hz，1H)，8.27-8.26(m，1H)，3.90-3.83 (m，2H)，1.82(m，2H)，1.38(m，2H)。Multiplet (0.47H), 8.71, be accredited as not the exchangeable protons of exchange fully, be reduced to 0.38H behind its 1h.
212 373.1 1.72 (500MHz，DMSO-d6)13.04(s，1H)，9.16(d，J＝ 3.2Hz，1H)，8.82(s，1H)，8.66(d，J＝3.0Hz， 1H)，8.39(d，J＝2.0Hz，1H)，8.15(d，J＝7.0 Hz，1H)，7.64(d，J＝7.2Hz，1H)，6.68(d，J ＝7.1Hz，1H)，3.88-3.84(m，1H)，1.60(s，6H)， 0.84(d，J＝6.2Hz，6H)，0.00(TMS)
213 405.1 1.6 (500MHz，MeOD)8.83(d，J＝2.3Hz，1H)，8.58 (s，1H)，8.35(d，J＝2.3Hz，1H)，8.18(m，1H)， 4.21(t，J＝4.8Hz，1H)，4.11(t，J＝4.8Hz， 1H)，3.37-3.32(m，2H)，2.58(s，3H)，2.27(s， 3H)，1.79(s，6H)。
214 423 1.71 (500MHz，MeOD)8.79(d，J＝2.3Hz，1H)，8.58 (s，1H)，8.36(d，J＝2.3Hz，1H)，8.29(m，1H)， 5.67-5.43(m，1H)，3.48-3.38(m，2H)，2.58 (s，3H)，2.27(s，3H)，1.79(s，6H)。
215 441 1.8 (500MHz，MeOD)8.77(d，J＝2.3Hz，1H)，8.56 (s，1H)，8.44-8.34(m，1H)，8.34(d，J＝2.2 Hz，1H)，3.86-3.79(m，2H)，2.58(s，3H)，2.28 (s，3H)，1.79(s，6H)。
Compound # M+H RT NMR
216 471 2.9 (500MHz, and DMSO) 12.32 (s, 1H), 8.69 (m, 2H), 8.28-8.13 (m, 3H), 4.9-4.75 (m, 1H), and 4.7-4.5 (m, 1H), 3.95-3.75 (m, 3H), and 2.15-1.95 (m, 1H), 1.87 (m, 2H), 1.6 (s, 1H), 1.44-1.41 (m, 1H), and 1.1-0.85 (m, 3H)
217 439 1.8 (500MHz, and MeOD) 8.77 (s, 1H), 8.22-8.19 (m, 3H), 6.40 (s, 1H), 4.69 (s, 1H), 4.32 (bs, 1H), 4.01-3.91 (m, 2H), and 2.43-2.38 (m, 1H), 2.27-2.16 (m, 2H), and 1.86-1.82 (m, 1H), 1.45 (d, J=6.0Hz, 3H)
218 457 2.7 (500MHz, MeOD) 8.78-8.77 (m, 1H), 8.20 (d, J=2.1Hz, 1H), and 8.15-8.10 (m, 2H), 4.90 (d, J=9.4Hz, 1H), 3.94-3.82 (m, 2H), 2.58-2.40 (m, 1H), 2.24-2.21 (m, 1H), 2.0-2.1 (m, 1H), 1.82 (m, 1H), 1.50 (d, 1H), 1.4-1.23 (m, 3H)
219 452.9 2 (500MHz, and MeOD) 8.76 (s, 1H), 8.21-8.17 (m, 3H), 6.40 (d, J=5.9Hz, 1H), 4.90 (d, J=9.1 Hz, 1H), 4.04-3.88 (m, 2H), 3.63 (s, 1H), 2.53-2.39 (m, 1H), 2.22-2.11 (m, 3H), 2.01-1.92 (m, 1H), and 1.60-1.45 (m, 1H), 1.08 (t, J=7.2 Hz, 2H), 1.01 (t, J=7.1Hz, 1H)
220 469.1 1.84 (500MHz, DMSO) 13.52-13.35 (br, 1H), 13.12-12.96 (br, 1H), and 9.07-8.61 (br, 1H), 8.93 (s, 1H), 8.37 (s, 1H), 8.07-7.54 (m, 2H), and 7.40-7.27 (br, 1H), 3.02-2.97 (m, 2H), 1.71 (s, 6H), 0.72 (t, J=7.1Hz, 3H).
221 487.1 1.85 (500MHz，MeOD)8.93(d，J＝2.3Hz，1H)，8.61 (s，1H)，8.37(d，J＝2.2Hz，1H)，8.21(m，1H)， 7.98(s，1H)，7.31(s，1H)，4.20(t，J＝4.8Hz， 1H)，4.11(t，J＝4.9Hz，1H)，4.07(s，3H)，4.06 (s，3H)，3.36-3.35(m，2H)，1.87(s，6H)。
222 505.1 1.9 (500MHz，MeOD)8.89(d，J＝2.3Hz，1H)，8.61 (s，1H)，8.37(d，J＝2.3Hz，1H)，8.33(m，1H)， 7.99(s，1H)，7.32(s，1H)，5.67-5.43(m，1H)， 4.07(s，3H)，4.06(s，3H)，3.35-3.33(m，2H)， 1.87(s，6H)。
Compound # M+H RT NMR
223 483 1.9 (500MHz, and MeOD) 8.91 (d, J=2.3Hz, 1H), 8.62 (s, 1H), 8.37 (d, J=2.3Hz, 1H), 7.98 (s, 1H), 7.31 (s, 1H), 4.07 (s, 3H), 4.07 (s, 3H), 3.12-3.08 (m, 2H), 1.86 (s, 6H), 1.33-1.25 (m, 2H), 0.62 (t, J=7.5Hz, 3H).
224 329.05 1.4 (500MHz, and MeOD) 8.49 (d, J=3.2Hz, 1H), 8.45-8.40 (m, 1H), 8.33 (d, J=1.5Hz, 1H), 8.03 (d, J=7.1Hz, 1H), 6.69 (d, J=6.9Hz, 1H), and 4.77-4.75 (m, 1H), 3.3 (m and meoh signal overlaps, 2H), 1.61 (d, 7.1Hz, 3H), 1.10 (t, J=7.2Hz, 3H), 0.00 (TMS)
225 346.93 1.4
226 365 1.4 (500MHz, and MeOD) 8.49 (s, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.33-8.32 (m, 1H), 8.04 (d, J=6.9 Hz, 1H), 6.70 (d, J=6.6Hz, 1H), 5.84 (t, J=55.8Hz, 1H), and 3.74-3.44 (2m, 2H), 1.63 (d, J=7.2Hz, 3H), 0.00 (TMS)
227 383 1.6
228 391.1 2.3 (500MHz, DMSO) 12.96 (s, 1H), 8.65 (s, 1H), 8.42-8.38 (m, 2H), 8.25 (s, 1H), 8.20 (d, J=7.0 Hz, 1H), 6.68 (d, J=6.8Hz, 1H), 5.76 (t, J=56.1Hz, 1H), 3.43-3.37 (m, 2H), 2.81-2.78 (m, 2H), 2.30 (dd, J=8.6,18.9Hz, 2H), 2.01 (qn, J=8.1Hz, 2H), 0.00 (TMS)
229 409.1 2.4 (500MHz, DMSO) 12.91 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.41 (d, J=8.8Hz, 1H), 8.36 (s, 1H), 8.20 (d, J=6.7Hz, 1H), 6.66 (d, J=6.6Hz, 1H), 3.82-3.79 (m, 2H), 2.84 (m, 2H), 2.32-2.28 (m, 2H), and 2.02-1.95 (m, 2H), 0.00 (TMS)
230 369.2 1.6 (500MHz, DMSO) 12.92 (s, 1H), 8.63 (s, 1H), 8.47 (d, J=8.5Hz, 1H), 8.37 (s, 1H), 8.18 (d, J=6.8Hz, 1H), 7.84 (s, 1H), 6.65 (d, J=6.5 Hz, 1H), 2.97 (m, 2H), 2.79 (m, 2H), 2.26 (m, 2H), 2.00 (m, 2H), 1.23 (dd, J=6.9,14.1Hz, 2H), 0.54 (t, J=7.1Hz, 3H), 0.00 (TMS)
Compound # M+H RT NMR
231 373.1 1.76 (500MHz，DMSO-d6)13.02(s，1H)，8.99(s，1H)， 8.76(s，1H)，8.63(s，1H)，8.39(d，J＝2.3Hz， 1H)，8.16(d，J＝6.7Hz，1H)，7.92(s，1H)，6.75 (d，J＝4.9Hz，1H)，3.07-3.05(m，2H)，2.10 -1.93(m，2H)，1.58(s，3H)，0.86(t，J＝7.5 Hz，3H)，0.81(s，3H)，0.00(TMS)
232 391.1 1.77 (500MHz，DMSO-d6)13.66-13.49(m，1H)，12.96 -12.93(m，1H)，8.76(s，1H)，8.57(d，J＝10.2 Hz，1H)，8.37(s，1H)，8.16-8.13(m，2H)，6.68 (d，J＝9.6Hz，1H)，4.21(d，J＝51.9Hz，2H)， 3.28(q，J＝5.4Hz，2H)，2.10-1.94(m，2H)， 1.57(s，3H)，0.87(t，J＝7.5Hz，3H)，0.00(TMS)
233 409.1 1.87 (500MHz，DMSO-d6)13.02(s，1H)，9.05(s，1H)， 8.70(s，1H)，8.62(s，1H)，8.39(d，J＝2.2Hz， 1H)，8.35(s，1H)，8.18(d，J＝7.0Hz，1H)，6.75 (d，J＝5.6Hz，1H)，5.86-5.64(m，1H)，3.43 -3.37(m，2H)，2.12-1.93(m，2H)，1.59(s， 3H)，0.88(t，J＝7.5Hz，3H)，0.00(TMS)
234 387.1 1.87 (500MHz，DMSO-d6)13.56(s，1H)，12.89(s，1H)， 8.89(s，1H)，8.57(s，1H)，8.36(s，1H)，8.16 (d，J＝6.8Hz，1H)，6.63(s，1H)，3.24(s，3H)， 2.94(s，2H)，2.20-1.87(m，2H)，1.57(s，3H)， 0.87(t，J＝7.4Hz，3H)，0.75(s，3H)，0.00(TMS)
235 523.1 1.9
236 355.2 1.8
237 373.1 1.8
238 398 2.6 (DMSO-d6)12.56(m，1H)；8.80(m，0.5H)；8.55 (s，0.5H)；8.50(s，0.5H)；8.45(m，1.0H)； 8.40-8.30(m，1.5H)；8.28(m，1.5H)；8.10(m， 0.5H)；3.80(m，2H)；1.42(m，6H)
239 410.9 1.7 (500MHz, DMSO) (warm) 12.26 in 100 ℃ (s, 1H), 8.84 (d, J=2.2Hz, 1H), 8.43 (bs, 1H), 8.38 (s, 1H), 8.29 (d, J=2.4Hz, 1H), 8.23 (d, J=6.3Hz, 1H), 8.13 (bt, 1H), 6.46 (d, J=6.3 Hz, 1H), and 3.93-3.83 (m, 2H), 1.62-1.60 (m, 2H), and 1.23-1.17 (m, 2H), 0.0 (TMS)
Compound # M+H RT NMR
240 395 1.6 (500MHz, CD3OD, RT) 8.8 (m, 0.6H), 8.65 (bt, 1H), 8.5 (s, 1H), 8.45 (bd, 1H), 8.25 (m, 1.3H), 8.1 (d, 0.8H), 6.7 (d, 1H), 3.9 (m, 2H), 1.8 (bm, 2H), 1.35 (bm, 2H), 0 (TMS)
241 371.1 1.76
242 393.1 1.77
243 411.1 1.86
244 341.1 1.5 (rt contains conformer for 500MHz, MeOD) 8.77 (dd, J=2.8,9.2Hz, 0.29H), 8.54-8.49 (m, 1.66H), 8.31 (d, J=1.5Hz, 1H), 8.26-8.24 (m, 0.3H), 8.10 (dd, J=4.3,7.2Hz, 0.82H), 6.70 (d, J=7.3Hz, 0.29H), 6.66 (dd, J=4.3,7.2Hz, 0.71H), 3.27-3.18 (m, 2H), 1.77-1.72 (m, 2H), and 1.28-1.24 (m, 2H), 1.09 (t, J=7.1Hz, 0.98H), 0.96 (t, J=7.1Hz, 2.2H).
245 359.1 1.6 (rt contains conformer for 500MHz, MeOD) 8.82-8.72 (m, 0.26H), 8.50 (m, 1.67H), 8.43-8.31 (m, 1.84H), 8.25 (br, 0.26H), 8.10 (d, J=6.4Hz, 0.72H), 6.70-6.65 (m, 1H), 4.48-4.25 (m, 2H), 3.49-3.37 (m, 2H), 1.80 (m, 2H), 1.27 (br, 2H).
246 377.1 1.65 (rt contains conformer for 500MHz, MeOD) 8.77 (dd, J=2.8,9.1Hz, 0.28H), 8.57-8.45 (m, 2.29H), 8.32 (d, J=1.5Hz, 1H), 8.27-8.26 (m, 0.29H), 8.11 (dd, J=4.0,7.1Hz, 0.74H), 6.72 (d, J=7.3Hz, 0.29H), 6.68 (d, J=7.1Hz, 0.73H), 5.89-5.60 (m, 1H), 3.59-3.47 (m, 2H), 1.80-1.76 (m, 2H), 1.34-1.30 (m, 2H).
247 355.1 1.6 (rt contains conformer for 500MHz, MeOD) 8.77 (dd, J=2.8,9.3Hz, 0.28H), 8.56-8.50 (m, 1.68H), 8.31 (d, J=1.5Hz, 1H), 8.26 (dd, J=4.4,7.2 Hz, 0.28H), 8.10 (dd, J=4.4,7.2Hz, 0.75H), 6.72-6.70 (m, 0.29H), 6.67 (m, 0.72H), 3.18-3.12 (m, 2H), 1.77-1.72 (m, 2H), 1.50 (m, 0.6H), 1.38 (m, 1.57H), 1.29-1.24 (m, 2H), 0.87 (t, J=7.4Hz, 0.92H), 0.67 (t, J=7.3Hz, 2.2H).
Compound # M+H RT NMR
248 460.9 2.7 (DMSO-d6) 12.4 (s, 1H); 8.9 (m, 1H); 8.65 (s, 1H); 8.35 (d, 1H); 8.3 (s, 1H); 8.2 (m, 1H); 5.5 (d, 1H); 4.9 (dd, 1H); 4.3-3.8 (m, 4H); 2.7 (m, 1H); 2.2-2.0 (m, 1H).
249 478.9 2.9 (DMSO-d6)12.4(s，1H)；8.9(m，1H)；8.65(s， 1H)；8.4(d，1H)；8.3(m，1H)；8.2(m，1H)；5.05 (m，1H)；4.3(m，2H)；3.9(m，2H)；3.0(m，1H)； 2.5(m，1H)。
250 373 1.59 (500MHz，MeOD)8.81(d，J＝2.1Hz，1H)，8.45 (s，1H)，8.36(d，J＝2.1Hz，1H)，7.99(s，1H)， 3.98(s，1H)，3.19(q，J＝7.2Hz，2H)，2.31(s， 3H)，1.79(s，6H)，0.90(t，J＝7.2Hz，3H)。
251 391 1.61 (500MHz，DMSO)13.07-12.73(br，1H)，8.83(d， J＝2.0Hz，1H)，8.55(s，1H)，8.36(d，J＝1.8 Hz，1H)，8.12(s，1H)，8.09(br，1H)，4.18(t， J＝5.1Hz，1H)，4.08(t，J＝5.1Hz，1H)，3.27 (q，J＝5.3Hz，1H)，3.22(q，J＝5.3Hz，1H)， 2.24(s，3H)，1.65(s，6H)。
252 409.1 1.69 (500MHz，MeOD)8.79(d，J＝2.1Hz，1H)，8.44 (s，1H)，8.37(d，J＝2.0Hz，1H)，8.32(br，1H)， 8.01(s，1H)，5.58(m，1H)，3.48-3.42(m，2H)， 2.31(s，3H)，1.79(s，6H)。
253 427.1 1.77 (500MHz，MeOD)8.78(s，1H)，8.46(br，1H)，8.42 (s，1H)，8.35(s，1H)，8.01(s，1H)，3.85-3.82 (m，2H)，2.32(s，3H)，1.79(s，6H)。Not definite peak at d 1.94 places.
254 387 1.66 (500MHz，MeOD)8.81(d，J＝2.0Hz，1H)，8.45 (s，1H)，8.36(d，J＝2.0Hz，1H)，8.00(s，1H)， 3.98(s，1H)，3.12-3.09(m，2H)，2.31(s，3H)， 1.79(s，6H)，1.33(m，2H)，0.67(t，J＝7.4Hz， 3H)。
255 344 2 (500MHz，MeOD)8.79(br，0.27H)，8.59(d，J＝ 8.9Hz，0.69H)，8.53(s，1H)，8.47(s，1H)，8.24 (s，1H)，3.17(m，2H)，1.66(s，6H)，1.08(br， 0.93H)，0.91(m，2.14H)。
256 385 1.9
257 403 1.8
Compound # M+H RT NMR
258 421 2
259 399.1 2
260 428 2.7 (500MHz, MeOD) 9.07 (s, 0.33H), 8.78 (s, 0.56H), 8.57-8.31 (m, 3.58H), 3.88 (m, 2H), 2.18 (m, 1H), 2.05-2.03 (m, 1H), 1.66 (m, 3H), 0.96 (t, J=7.4Hz, 3H).
261 412 2.5 (500MHz，MeOD)8.80(m，0.35H)，8.56-8.47(m， 3.2H)，8.40(m，0.36H)，8.26(m，1H)，3.85(m， 2H)，2.18(m，1H)，2.04(m，1H)，1.66(m，3H)， 0.96(t，J＝7.5Hz，3H)。
262 360 2.1
263 445 2.4 (DMSO-d6)12.3(br?s，1H)；8.9(m，1H)；8.4(d， 1H)；8.35(d，1H)；8.25(s，1H)；8.2(s，1H)； 5.5(d，1H)；4.9(dd，1H)；4.3-3.75(m，4H)；2.7 (m，1H)；2.2-2.0(m，1H)。
264 463 2.8 (DMSO-d6)12.3(br?s，1H)；8.9(dd，1H)；8.4-8.3 (m，2H)；8.25-8.2(m，2H)；5.05(d，1H)；4.35 (m，2H)；3.9(m，2H)；3.0(m，1H)；2.5(m，1H)。
265 432.2 2.6 (CD3CN)10.40(s，1H)，8.80(s，1H)，8.29(m， 3H)，6.97(m，1H)，5.22(m，1H)，4.79(m，1H)， 4.43(dt，2H)，3.49(dt，2H)，2.54(m，1H)，2.43 (m，1H)，2.39(m，1H)，2.22(m，1H)
266 450.2 2.7 (CD3CN)10.48(s，1H)，8.79(s，1H)，8.30(m， 3H)，7.01(t，1H)，5.90(tt，1H)，5.24(m，1H)， 5.83(m，1H)，3.60(m，2H)，2.53(m，1H)，2.42 (m，1H)，2.36(m，1H)，2.21(m，1H)
267 468.2 2.86 (CD3CN)10.38(s，1H)，8.79(s，1H)，8.29(m， 3H)，7.21(t，1H)，5.21(m，1H)，4.83(m，1H)， 3.99(m，1H)，3.86(m，1H)，2.51(m，1H)，2.45 (m，1H)，2.35(m，1H)，2.20(m，1H)
268 450.1 1.88
269 450.1 1.93
270 374.1 2.3 (500MHz，MeOD)9.05(s，0.32H)，8.84(s， 0.65H)，8.53(s，1H)，8.43(s，1H)，8.29(s，1H)， 3.27-3.17(m，2H)，2.18-2.10(m，1H)，2.07 -2.00(m，1H)，1.64(m，3H)，1.08(m，1H)，0.95 (t，J＝7.4Hz，5H)。
Compound # M+H RT NMR
271 358 2.1 (500MHz, and MeOD) 8.78 (br, 0.33H), 8.58 (d, J=8.6Hz, 0.81H), 8.53 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 3.26-3.16 (m, 2H), 2.17-2.13 (m, 1H), 2.01 (m, 1H), 1.71-1.57 (m, 3H), 0.95 (t, J=7.5Hz, 6H).
272 450 2.4 (500MHz, MeOD) 8.87 (s, 1H), 8.56 (bt, 1H), 8.53 (s, 1H), 8.43 (d, J=6.9Hz, 1H), 8.35 (d, J=2.2Hz, 1H), 6.91 (d, J=6.7Hz, 1H), 5.09 (proximate d, 1H), 4.86 (proximate d, 1H), 4.02-3.96 (m, 1H), 3.87-3.81 (m, 1H), 2.03 (m, 1H), 1.88-1.80 (m, 2H), 1.48-1.43 (m, 1H), 0.00 (TMS)
273 464.1 2.5 (500MHz, and MeOD) 8.86 (d, J=2.1Hz, 1H), 8.44 (t, 1H), 8.40 (s, 1H), 8.37 (d, J=6.6Hz, 1H), 8.31 (d, J=2.2Hz, 1H), 6.52 (bs, 1H), 4.85 (s, 2H), 3.93 (m, 2H), 2.86 (m, 2H), 2.72 (m, 2H), 2.25 (m, 1H), 2.06 (m, 1H), 0.00 (TMS)
274 428 2.4 (DMSO-d6) (the about 1.3:1 of optically-active mixture): 12.6 (m, 1H); 9.0 (dd, 0.6H); 8.8 (dd, 0.4H); 8.65-8.3 (m, 4H); 5.6-5.35 (m, 1H); 4.8 (t, 0.6H); 4.7 (t, 0.4H); 4.35 (m, 0.4H); 4.2 (m, 0.6H) 4.1-3.7 (m, 3H); 2.75-2.6 (m, 1H); 2.25-2.05 (m, 1H).
275 428 2.3 (DMSO-d6) (the about 1.3:1 of optically-active mixture): 12.6 (m, 1H); 8.7-8.25m, 5H); 5.5-5.3 (m, 1H); 4.9 (d, 0.6H); 4.75 (d, 0.4H); 4.1-3.7 (m, 4H); 2.75-2.6 (m, 1H); 2.4-2.3 (m, 1H).
276 444 2.5 (DMSO-d6) (the about 1.3:1 of optically-active mixture): 12.7 (m, 1H); 9.0-8.3 (m, 5H); 5.6-5.4 (m, 1H); 4.8 (t, 0.6H); 4.7 (t, 0.4H); 4.4-3.75 (m, 4H); 2.8-2.6 (m, 1H); 2.25-2.05 (m, 1H).
277 473 2.3 (DMSO-d6)12.35(m，1H)；8.75-8.6(m，2H)； 8.35-8.15(m，3H)；4.75(m，1H)；4.0-3.7(m， 4H)；2.3(m，1H)；2.0(m，1H)；1.35(s，3H)。
278 487 2.5 (DMSO-d6)12.35(m，1H)；8.75-8.6(m，2H)； 8.35-8.15(m，3H)；4.75(m，1H)；4.0-3.7(m， 4H)；2.3(m，1H)；2.0(m，1H)；1.6(m，2H)；1.0 (m，3H)。
279 468.1 1.59
Compound # M+H RT NMR
280 455 1.5 (DMSO-d6) 13.05-12.9 (m, 1H); 8.8-8.25 (m, 5H); 6.75 (m, 0.7H); 6.35 (m, 0.3H); 4.95 (m, 0.7H); 4.75 (m, 0.3H); 4.05-3.6 (m, 4H); 2.4-2.1 (m, 2H); 1.4 (m, 3H).
281 469 1.6 (DMSO-d6)13.0-12.9(m，1H)；8.8-8.25(m，5H)； 6.7(m，0.7H)；6.3(m，0.3H)；5.05-4.8(m，1H)； 4.1-3.6(m，4H)；2.4-2.05(m，2H)；1.75-1.6(m， 2H)；1.05-0.9(m，3H)。
282 392.9 2.7 (500MHz，MeOD)8.80(d，J＝2.3Hz，1H)，8.35 (s，1H)，8.33(s，1H)，8.28(d，J＝2.3Hz，1H)， 3.19(q，J＝7.2Hz，2H)，1.74(s，6H)，0.93(t， J＝7.2Hz，3H)。
283 410.9 2.7 (500MHz，MeOD)8.81(d，J＝2.3Hz，1H)，8.35 (s，1H)，8.33(s，1H)，8.28(d，J＝2.2Hz，1H)， 8.19-8.17(m，0.33H)，4.23(dt，J＝47.4，5.1 Hz，2H)，3.42(dt，J＝25.5，5.1Hz，2H)，1.75 (s，6H)。
284 439.9 1.9 (500MHz，MeOD)8.72(s，1H)，8.57-8.53(m， 2H)，8.45(s，1H)，8.26(s，1H)，3.85-3.78(m， 2H)，1.75(s，6H)。
285 428 2.8 (500MHz，MeOD)9.07(d，J＝1.9Hz，0.53H)，8.81 -8.78(m，0.84H)，8.55(d，J＝10.5Hz，1H)， 8.45(d，J＝15.6Hz，1H)，8.30(s，1H)，4.56 -4.52(m，1H)，4.06-4.00(m，1H)，3.89-3.84 (m，1H)，2.34-2.24(m，1H)，1.12-1.06(m， 6H)。
286 428.9 2.9 (500MHz，MeOD)8.79(d，J＝2.3Hz，1H)，8.36 (s，1H)，8.33-8.28(m，2.8H)，5.64(tt，J＝ 56.5，4.2Hz，1H)，3.51-3.43(m，2H)，1.74(s， 6H)。
287 446.9 3 (500MHz，MeOD)8.78(d，J＝2.3Hz，1H)，8.45 (t，J＝6.1Hz，1H)，8.34(s，1H)，8.25(d，J ＝3.3Hz，2H)，3.86-3.44(m，2H)，1.73(s，6H)。
288 437.96 2.9 (500MHz，MeOD)9.24(m，0.5H)，8.87-8.73(m， 0.27H)，8.62-8.29(m，2.7H)，7.76-7.37(m， 0.46H)，3.86-3.76(m，2H)，1.80-1.50(m， 6H)。
Compound # M+H RT NMR
289 403.5 2.9 (DMSO-d6) 12.3 (br s, 1H); 8.7 (s, 1H); 8.3-8.2 (m, 2H); 8.1 (s, 1H); 7.65 (m, 1H); 4.1-3.85 (m, 2H); 3.15-2.9 (m, 2H); 2.1-1.9 (m, 4H); 1.6 (s, 3H); 0.8 (m, 3H).
290 421.5 2.9 (DMSO-d6)12.3(br?s，1H)；8.7(s，1H)；8.25(m， 2H)；8.1(s，1H)；7.95(m，1H)；4.35-4.05(m， 3H)；3.95(m，1H)；3.35-3.2(m，2H)；2.1-1.9(m， 4H)；1.6(s，3H)。
291 439.5 3 (DMSO-d6)12.3(br?s，1H)；8.7(s，1H)；8.3(m， 2H)；8.15-8.05(m，2H)；5.8(dd，1H)；4.1(m， 1H)；3.9(m，1H)；3.4(m，2H)；2.1-1.9(m，4H)； 1.6(s，3H)。
292 417.1 2.7 (DMSO-d6)12.3(s，1H)；8.7(s，1H)；8.25(m， 2H)；8.1(s，1H)；7.7(dd，1H)；4.1(m，1H)；3.9 (m，1H)；3.1-2.8(m，2H)；2.1-1.9(m，4H)；1.6 (s，3H)；1.35-1.15(m，2H)；0.6(m，3H)。
293 455.1 2.09
294 483.1 2.42
295 453 2.02
296 410.3 1.75
297 407.1 2.3 (DMSO-d6):12.45(br?s，1H)；8.7(s，1H)； 8.4-8.2(m，4H)；5.5(d，1H)；4.75(t，1H)； 4.25-3.9(m，2H)；3.2-3.0(m，2H)；2.6-2.0(m， 2H)；1.0(m，3H)。
298 421.2 2.5 (DMSO-d6)12.4(br?s，1H)；8.7(s，1H)；8.4-8.2 (m，4H)；5.5(d，1H)；4.75(t，1H)；4.25-3.9(m， 2H)；3.8(m，1H)；3.0(m，1H)；2.3-2.0(m，2H)； 1.45-1.2(m，2H)；0.75(m，3H)。
299 425.1 2.3 (DMSO-d6)12.4(br?s，1H)；8.7(s，1H)；8.6(m， 1H)；8.35-8.2(m，3H)；5.5(d，1H)；4.8(t，1H)； 4.45(m，1H)；4.3-3.9(m，3H)；3.3(m，1H)；2.7 (m，1H)；2.3-2.0(m，2H)。
300 443.1 2.5 (DMSO-d6)12.4(br?s，1H)；8.8-8.6(m，2H)； 8.4-8.2(m，3H)；5.9(dd，1H)；5.5(d，1H)；4.85 (t，1H)；4.3-3.9(m，2H)；2.75-2.0(m，4H)。
301 441.1 2.6
302 465.2 1.9
Compound # M+H RT NMR
303 411.2 1.8
304 447.2 1.8
305 425.2 1.9
-306 437.2 1.8
307 455.2 2
308 437.2 1.9
309 457.1 1.8 (DMSO-d6) 12.3 (br s, 1H); 8.75 (s, 1H); 8.35-8.2 (m, 3H); 8.1 (s, 1H); 6.45 (m, 1H); 5.55 (m, 1H); 4.2-3.7 (m, 4H); 2.4-2.2 (m, 2H); 1.7 (s, 3H).
Table 6
Compound # M+H RT NMR
310 409.00 1.80 DMSO-d6:12.25 (br s, 1H); 8.8 (m, 1H); 8.7 (m, 1H); 8.35-8.3 (m, 2H); 8.2 (m, 1H); 7.2 (m, 1H); 4.85 (d, 1H); 4.0 (m, 1H); 3.95-3.8 (m, 3H); 2.35 (m, 1H); 2.1-1.85 (m, 3H).
311 409.00 1.80 DMSO-d6:12.25(br?s，1H)；8.8(m，1H)；8.7(m， 1H)；8.35-8.3(m，2H)；8.2(m，1H)；7.2(m，1H)； 4.85(d，1H)；4.0(m，1H)；3.95-3.8(m，3H)；2.35 (m，1H)；2.1-1.85(m，3H)。
312 444.90 2.20 500MHz?DMSO-d6@60C:12.8(br?m，1H)， 8.85(m，1H)，8.8(m，1H)，8.65(s，1H)，8.3(d，1H)， 8.25(1H)，7.75(br?m，1H)，7.3(d，1H)， 4.85(m，1H)，3.9(m，2H)，3.0(d?m，2H)，2.2(s，3H)
313 495.00 2.30
314 438.00 2.00 500MHz?MeOD-d4:8.68(m，1H)，8.5(s，1H)， 8.35(s，1H)，8.1(d.1H)，6.71(d，1H)，4.04(m，1H)， 3.99m，1H)，2.7(t，2H)，2.4(m，1H)，2.24(m，1H)
315 456.00 2.80 500MHz?MeOD-d4:8.66(s，1H)，8.4(s，1H)， 8.35(d，1H)，8.3(d.1H)，5.45(m，1H，parially?ex)， 5.04(m，1H)，4.01m，1H)，3.93(m，1H)，2.73(t，2H)， 2.5(m，1H)，2.32(m，1H)
316 488.00 2.10 500MHz?MeOD-d4:8.77(s，1H)，8.71(s，1H)， 8.5(d，1H)，8.35(s.1H)，8.02(t，1H)，7.88(d，1H)， 7.71(t，1H)，5.25(m，1H)，4.02(m，1H)，
Compound # M+H RT NMR
3.90 (m, 1H) 2.73 (t, 2H), 2.6 (m, 1H), 2.5 (m, 1H)
317 482.00 2.70 DMSO d5 12.8 (bs, 1H); 8.7 (bs, 1H); 8.5 (m, 2H); 8.4 (s, 1H); 7.7 (s, 1H); 6.9 (s, 1H); 4.8 (m, 1H); 3.8 (m, 2H); 3.6 (m, 3H); 29 (m, 2H); 2.0 (m, 2H); 1.2 (m, 2H)
318 496.10 2.90 DMSO d5 12.6 (bs, 1H); 8.8 (bs, 1H); 8.7 (m, 2H); 8.4 (s, 1H); 7.7 (s, 1H); 6.9 (s, 1H); 4.8 (m, 1H); 3.8 (m, 2H); 3.6 (m, 2H); 3.5 (m, 5H); 2.0 (m, 2H); 1.2 (t, 3H)
319 510.10 3.10 DMSO d5 12.6 (bs, 1H); 8.9 (bs, 1H); 8.6 (m, 2H); 8.4 (s, 1H); 7.8 (s, 1H); 4.7 (m, 1H); 3.9 (m, 2H); 3.7 (m, 2H); 3.3 (m, 2H); 2.0 (m, 2H); 1.5 (m, 2H); 0.9 (t, 3H)
320 508.10 3.00 DMSO d5 12.6 (bs, 1H); 8.8 (bs, 1H); 8.6 (m, 2H); 8.4 (s, 1H); 7.7 (s, 1H); 4.7 (m, 1H); 4.0 (m, 2H); 3.8 (m, 2H); 2.9 (s, 1H); 2.0 (m, 2H); 1.9 (m, 3H); 0.8 (t, 2H); 0.6 (m, 1H)
321 424.20 1.50 (d4-methyl alcohol) 8.86 (d, 1H), 8.40 (d, 1H), 8.29 (d, 1H), 8.25 (s, 1H), 7.30 (dd, 1H), 5.65 (br s, 1H), 4.62 (d, 1H), 4.03-3.35 (m, 7H)
322 403.10 2.10 DMSO-d6:12.5 (s, 1H); 8.7 (s, 1H); 8.3 (m, 3H); 7.9 (d, 1H); 4.65 (d, 1H); 3.95 (m, 1H); 3.85 (m, 2H); 2.25 (m, 1H); 2.0 (m, 3H); 1.05 (m, 3H).
323 395.10 1.70 (500MHz，DMSO-d6)d12.31(s，1H)，8.79(s，1H)， 8.65(d，J＝7.8Hz，1H)，8.61(t，J＝6.3Hz， 1H)，8.38(d，J＝4.1Hz，1H)，8.29(dd，J＝4.7， 1.5Hz，1H)，8.24(s，1H)，7.15(dd，J＝7.9，4.7 Hz，1H)，，3.81(m，2H)，1.57(t，2H)，1.19(t， 2H)
324 385.20 1.70 DMSO-d6:13.0(br?s，1H)；8.7-8.6(m，2H)；8.4 (m，1H)；8.3(m，1H)；8.15(d，0.3H)；8.0(d， 0.7H)；6.75(d，0.7H)；6.3(d，0.3H)；4.85(d， 0.7H)；4.5(0.3H)；4.0-3.85(m，1H)；3.8-3.6(m， 2H)；2.35(m，1H)；2.05(m，3H)；1.1(dd，2H)； 0.95(dd，4H)。
325 399.10 2.10 DMSO-d6:12.4(br?s，1H)；8.65(s，1H)；8.55(m， 1H)；8.3(m，2H)；8.25(s，1H)；4.7(d，1H)；3.95 (m，1H)；3.85(m，2H)；3.8(m，1H)；3.0(s，1H)；
Compound # M+H RT NMR
2.25 (m, 1H); 2.0 (m, 3H).
326 452.39 3.60 CD3OD/CDCl3:1.68(6H，s)，2.14(2H，m)，3.38 (2H，m)，7.98(1H，t)，8.22(1H，s)，8.28(1H， s)，8.54(1H，s)，8.83(1H，s)
327 438.41 3.56 CD3OD/CDCl3:1.70(6H，s)，3.81(2H，m)，7.59 (1H，m)，8.22(1H，s)，8.26(1H，s)，8.45(1H， t)，8.58(1H，s)，8.81(1H，s)
328 404.34 3.23 DMSO-d6/CD3OD/CDCl3:1.58(6H，s)，3.12(1H，s)， 3.75(2H，m)，7.21(1H，m)，8.19(1H，s)，8.28 (1H，m)，8.45(1H，t)，8.69(1H，s)，8.71(1H， d)
329 470.35 3.24 MeOD:1.75(6H，s)，2.16(2H，m)，3.35(2H，m)， 8.34(2H，s)，8.48(1H，s)，8.75(1H，s)，8.85 (1H，s)
330 381.20 1.50 DMSO-d6:12.8(s，1H)；8.7-8.5(m，3H)；8.4-8.25 (m，2H)；6.7(m，0.7H)6.3(m，0.3H)；4.8(m， 0.7H)；4.6(m，0.3H)；4.0-3.6(m，4H)；2.95(m， 1H)；2.35(m，1H)；2.05(m，3H)。
331 383.20 1.70 DMSO-d6:12.9(br?s，1H)；8.8(s，1H)；8.7(s， 1H)；8.6(s，1H)；8.4(s，1H)；8.15(m，1H)；6.8 (s，1H)；4.7(s，1H)；4.05-3.85(m，2H)；3.1(s， 1H)；2.25(m，1H)；1.1-0.95(m，6H)。
332 387.40 2.00 DMSO-d6:12.95(br?s，1H)；8.7(s，1H)；8.6(s， 1H)；8.4(s，1H)；8.15(m，2H)；6.8(s，1H)；4.6 (s，1H)；3.9(m，1H)；2.25(m，1H)；1.1-0.95(m， 12H)。
333 400.20 2.00 DMSO-d6:12.35(br?s，1H)；8.77(dd，1H)；8.65 (s，1H)；8.3(m，2H)；8.2(s，1H)；4.7(d，1H)； 4.1(m，2H)；3.95(m，1H)；3.8(m，1H)；2.25(m， 1H)；2.0(m，3H)。
334 382.20 1.50 DMSO-d6:12.9(br?s，1H)；8.95(dd，1H)；8.75(m， 0.4H)；8.6(m，1.6H)；8.4-8.3(m，2H)；6.75(d， 0.8H)；6.35(d，0.2H)；4.9(d，0.8H)；4.65(d， 0.2H)；4.2-4.0(m，2H)；3.8(m，1H)；3.6(m，1H)； 2.35(m，1H)；2.1-2.0(m，3H)。
335 387.40 2.00
336 403.40 1.90
337 385.40 1.80
Compound # M+H RT NMR
338 511.20 2.50 DMSO-d6:8.60(m，2H)；8.30(s，1H)；8.23(bs， 1H)；5.50(m，2H)；4.38(m，2H)；4.10(m，2H)； 3.38(m，4H)；2.50(m，1H)；1.90-2.00(m，3H)； 1.32(t，3H)
339 421.30 2.00
340 455.20 2.10
341 439.20 1.90 DMSO-d6:13.0(bs，1H)；8.55(m，1H)；8.45(m， 1H)；8.35(m，1H)；6.72(m，1H)；5.60(m，1H)； 4.20-3.70(m，5H)；3.30(s，3H)；2.00(m，3H)
342 457.10 2.40 DMSO-d6:8.30(m，1H)；8.30(m，3H)；7.70(m， 1H)；5.40(m，1H)；4.20-3.70(m，5H)；3.30(s， 3H)；2.00(m，3H)
343 379.20 2.04 (500MHz，DMSO)12.83(s，1H)，9.30(s，1H)，8.61 (t，J＝7.6Hz，2H)，8.37(d，J＝4.5Hz，1H)， 8.17(d，J＝7.1Hz，1H)，7.27(dd，J＝4.7，7.7 Hz，1H)，6.69(d，J＝6.9Hz，1H)，3.79-3.76 (m，2H)，1.63(s，6H)
344 366.10 1.87 DMSO-d6:12.5(m，1H)；8.95(m，0.5H)；8.78(m， 0.5H)；8.65(m，0.5H)；8.52(m，0.5H)；8.48(s， 1H)；8.32-8.25(m，2H)；8.30(m，1.5H)；8.12(m， 1H)；7.20(m，1H)；4.54(m，1H)；3.80(m，2H)； 1.32(m，3H)
345 411.20 1.90 (500MHz，DMSO-d6)12.20(s，1H)，8.67(dd，J＝ 1.4，7.9Hz，1H)，8.43(t，J＝6.2Hz，1H)，8.32 -8.28(m，2H)，8.10(s，1H)，7.5(bs，1H)，7.20 (dd，J＝4.7，7.9Hz，2H)，3.81-3.73(m，2H)， 2.20-2.16(m，1H)，1.99-1.95(m，1H)，1.56 (s，3H)，0.82(t，J＝7.5Hz，3H)
346 393.20 1.60 (DMSO-d6，300MHz)11.95(bs，1H)，8.7(d，1H)， 8.25(m，2H)，8.12(d，1H)，8.02(d，1H)，7.28 (s，1H)，7.13(dd，1H)，6.38(bd，1H)，3.75(m， 2H)，2.06(m，1H)，1.83(m，1H)，1.46(s，3H)， 0.8(t，3H)；
347 425.27 2.25 (500MHz，MeOD)8.87(d，J＝8.1Hz，1H)，8.60 (t，1H)，8.36(d，1H)，8.27-8.26(m，2H)，7.39 (dd，J＝5.0，8.0Hz，1H)，3.86(m，2H)，2.29 (t，J＝7.5Hz，4H)，0.87(t，J＝7.5Hz，6H)
348 407.20 1.67 (500MHz，DMSO-d6)d?12.81(s，1H)，8.92(s，1H)，
Compound # M+H RT NMR
8.68-8.57 (m, 3H), 8.38 (d, J=3.3Hz, 1H), 8.17 (d, 1H), 7.30-7.27 (m, 1H), 6.82 (d, 1H), 3.82-3.74 (m, 2H), 2.26-2.12 (m, 2H), 2.12-2.05 (m, 2H), 0.82-0.78 (m, 6H)
349 373.40 1.74
350 407.40 1.72 CD3CN:9.89 (s, 1H), 8.79 (d, 1H), 8.27 (m, 1H), 8.19 (d, 1H), 8.10 (d, 1H), 7.18 (m, 2H), 6.49 (d, 1H), 5.80 (s, 1H), 3.97 (m, 1H), 3.59 (m, 1H), 1.53 (s, 3H), 1.02 (dd, 6H)
351 425.40 1.40 DMSO-d6:12.2 (br s, 1H); 8.85 (m, 1H); 8.7 (d, 1H); 8.3 (m, 2H); 8.15 (m, 1H); 7.2 (m, 1H); 4.9 (dd, 1H); 4.45 (m, 1H); 4.05-3.7 (m, 4H); 2.3 (m, 1H); 1.95 (m, 1H).
352 407.40 1.40 DMSO-d6:12.8(br?s，1H)；9.1(m，1H)；8.7-8.6 (m，2H)；8.45-8.3(m，2H)；7.4(m，0.3H)；7.3(m， 0.7H)；6.85(d，0.7H)；6.35(d，0.3H)；5.1(dd， 0.7H)；4.8(dd，0.3H)；4.5(m，1H)；4.2-3.6(m， 4H)；2.4(m，1H)；2.1(m，1H)。
353 401.40 1.95
354 387.40 1.87
355 369.30 1.69
356 409.40 2.25
357 423.30 1.90
358 405.40 1.80
359 399.10 1.80 DMSO-d6:12.7(br?s，1H)；8.8(s，1H)；8.7-8.2 (s，3H)；6.5(m，0.8H)；6.2(m，0.2H)；4.2(m， 0.3H)；4.0(m，0.7H)；3.8-3.6(m，2H)；3.4(m， 1H)；3.2-3.05(m，1H)；2.7(m，2H)；2.2(m，3H)； 2.05(m，1H)；1.7(s，2.7H)；1.6(s，0.3H)；1.0 (m，0.3H)；0.7(m，2.7H)。
360 379.20 1.60 DMSO-d6:11.92(m，1H)；8.72(bs，1H)；8.22(m， 1H)；8.05(m，2H)；7.42(m，1H)；7.18(m，1H)； 6.32(bs，1H)；5.22(m，1H)；4.20(m，2H)；3.32 (s，3H)；1.35(m，3H)
361 397.10 1.90 DMSO-d6:11.9(m，1H)；8.55(m，1H)；8.25(m， 1H)；8.18(m，1H)；7.98(m，1H)；7.65(m，1H)； 7.15(m，1H)；5.15(m，1H)；4.18(m，2H)；3.30 (s，2.5H)；2.90(s，0.5H)；1.35(m，3H)
Compound # M+H RT NMR
362 357.10 1.51
363 343.10 1.40
364 361.10 1.41
365 391.10 1.85
366 393.10 1.60 (500MHz, DMSO) 12.83 (s, 1H), 9.2 (bs, 1H), 9.07 (s, 1H), 8.68 (d, J=7.8Hz, 1H), 8.61 (s, 1H), 8.42 (d, J=4.6Hz, 1H), 8.15 (d, J=7.1Hz, 1H), 7.35 (dd, J=4.8,7.8Hz, 1H), 6.86 (d, J=7.2Hz, 1H), 4.86 (t, J=6.3Hz, 1H), 4.12-4.04 (m, 1H), 3.90-3.85 (m, 1H), 2.31 (t, J=6.6Hz, 1H), 1.02 (d, 6H)
367 410.91 2.10 (500MHz, DMSO) 12.36 (s, 1H), 8.86 (t, J=6.3 Hz, 1H), 8.72 (dd, J=1.4,7.9Hz, 1H), 8.35-8.31 (m, 3H), 7.86 (s, 1H), 7.26 (dd, J=4.7,7.9Hz, 1H), 4.60 (t, J=7.6Hz, 1H), 4.04-3.96 (m, 1H), and 3.90-3.83 (m, 1H), 2.28 (td, J=13.8,6.9Hz, 1H), 1.02 (t, 6H)
368 474.00 1.60
369 490.00 1.80
370 504.10 1.90
371 477.00 1.50
372 491.00 1.60
373 409.00 1.40 DMSO-d6:12.9 (m, 1H); 8.95-8.85 (m, 1H); 8.8-8.65 (m, 2H); 8.55-8.3 (m, 2H); 7.4 (m, 0.3H); 7.3 (m, 0.7H); 6.85 (d, 0.7H); 6.5 (d, 0.3H); 5.55 (d, 1H); 5.2 (d, 0.7H); 5.0 (d, 0.3H); 4.3-3.8 (m, 4H); 2.8-2.6 (m, 1H); 2.5-2.4 (m, 1H).
374 427.00 1.60 DMSO-d6:12.8(br?s，1H)；9.1(m，1H)；8.7-8.35 (m，4H)；7.3(m，1H)；6.8(m，0.7H)；6.5(m， 0.3H)；5.3(m，0.7H)；5.1(m，0.3H)；4.3(m，2H)； 3.9(m，2H)；3.15(m，1H)；2.65(m，1H)。
375 409.00 1.40 DMSO-d6:12.9(m，1H)；9.25-9.1(m，1H)； 8.75-8.6(m，2H)；8.45-8.35(m，2H)；7.4(m， 0.3H)；7.3(m，0.7H)；6.9(d，0.7H)；6.3(d， 0.3H)；5.6(d，1H)；5.1(dd，0.7H)；4.9(dd， 0.3H)；4.5(m，0.3H)；4.2(m，0.7H)；4.3-3.6(m， 3H)；2.8(m，1H)；2.3-2.1(m，1H)。
Compound # M+H RT NMR
376 343.10 1.37
377 361.10 1.48
378 325.10 1.37
379 339.10 1.49
380 397.10 1.60
381 379.10 1.99
382 429.35 1.70 (500MHz, and MeOD) 8.83 (d, J=8Hz, 2H), 8.68 (s, 1H), 8.59-8.57 (m, 2H), 8.42-8.41 (m, 1H), 8.07-8.03 (m, 1H), 7.90 (dd, J=4.4,8.2Hz, 1H), 7.77-7.73 (m, 1H), 7.41 (m, 1H), 3.83-3.76 (m, 2H), 1.88 (s, 6H).
383 423.00 2.10 DMSO-d6:12.3(s，1H)；8.7(d，1H)；8.45-8.25(m， 3H)；8.15(s，1H)；7.25(m，1H)；4.15(m，1H)； 4.0(m，1H)；3.85(m，1H)；3.7(m，1H)；2.05(m， 4H)；1.75(s，3H)。
384 405.10 1.50 DMSO-d6:12.8(s，1H)；8.8-8.2(m，5H)；7.4(m， 0.2H)；7.25(m，0.8H)；6.8(d，0.8H)；6.15(d， 0.2H)；4.2(m，0.2H)；3.95(m，0.8H)；3.8(m， 3H)；2.2-2.0(m，4H)；1.8-1.6(m，3H)。
385 488.00 1.70
386 380.00 1.90 DMSO-d6:12.4 (bs, 1H); 8.92 (m, 0.5H); 8.62 (m, 0.5H); 8.50 (s, 0.5H); 8.42 (s, 0.5H); 8.40-8.20 (m, 4H); 7.20 (m, 0.5H); 7.15 (m, 0.5H); 3.72 (m, 2H); 1.45 (m, 6H)
387 421.10 1.50 (500MHz, and DMSO) 12.81 (s, 1H), 8.65-8.56 (m, 3H), 8.36 (d, J=4.4Hz, 1H), 8.22 (d, J=6.9 Hz, 1H), 7.26 (dd, J=4.7,7.9Hz, 1H), 6.85 (d, J=6.4Hz, 1H), 3.80 (bm, 4H), and 3.66-3.62 (m, 2H), 2.26-2.22 (m, 2H), 2.15 (m, 2H), 0.00 (TMS)
388 453.30 1.68 (500MHz, and MeOD) 8.88 (dd, J=1.5,8.1Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=3.1Hz, 1H), 8.32-8.26 (m, 1H), 7.99 (s, 1H), 7.40 (dd, J=4.7,8.0Hz, 1H), 7.31 (s, 1H), 4.19 (t, J=4.8Hz, 1H), 4.11-4.09 (m, 1H), 4.07 (s, 3H), 4.07 (s, 3H), 3.35-3.32 (m, 2H), 1.87 (s, 6H), 1.38-1.29 (m, 2H, impurity).
389 489.00 1.78 (500MHz，MeOD)8.82(dd，J＝1.4，8.1Hz，1H)，
Compound # M+H RT NMR
8.58 (s, 1H), 8.52 (m, 1H), 8.40 (d, J=3.2Hz, 1H), 8.00 (s, 1H), 7.39 (dd, J=4.7,8.0Hz, 1H), 7.32 (s, 1H), 4.08 (s, 3H), 4.07 (s, 3H), 3.80-3.77 (m, 2H), 1.87 (s, 6H).
390 471.10 1.70 (500MHz，MeOD)8.85(dd，J＝1.4，8.1Hz，1H)， 8.60(s，1H)，8.42-8.40(m，1H)，8.37-8.30 (m，1H)，8.00(s，1H)，7.40(dd，J＝4.7，8.0Hz， 1H)，7.32(s，1H)，5.64-5.41(m，1H)，4.08(s， 3H)，4.07(s，3H)，3.44(m，2H)，1.87(s，6H)。
391 449.20 1.70 (500MHz，MeOD)8.88-8.87(m，1H)，8.59(s，1H)， 8.40(d，J＝3.3Hz，1H)，8.03-8.02(m，1H)， 7.99(s，1H)，7.40(dd，J＝4.7，8.1Hz，1H)，7.31 (s，1H)，4.07(s，3H)，4.07(s，3H)，3.07(m，2H)， 1.86(s，6H)，1.29(m，2H)，0.61(t，J＝7.5Hz， 3H)。
392 339.10 1.45
393 353.10 1.56
394 357.10 1.47
395 375.10 1.56
396 427.00 1.90 DMSO-d6:12.25(s，1H)；8.95(m，1H)；8.7(d， 1H)；8.35(d，1H)；8.3(m，1H)；8.2(m，1H)；7.25 (dd，1H)；5.5(d，1H)；4.95(dd，1H)；4.3-3.75 (m，4H)；2.7(m，1H)；2.2-2.0(m，1H)。
397 445.00 2.30 DMSO-d6:12.15(s，1H)；8.9(m，1H)；8.65(d， 1H)；8.35(d，1H)；8.3(m，1H)；8.15(m，1H)；7.2 (m，1H)；5.1(m，1H)；4.3(m，2H)；3.9(m，2H)； 3.0(m，1H)；2.5(m，1H)。
398 394.00 2.10 (500MHz，MeOD)9.14(m，0.25H)，8.95(d，J＝6.7 Hz，0.66H)，8.59-8.41(m，3.64H)，7.45(m，1H)， 3.84(m，2H)，2.21-2.18(m，1H)，2.05-2.02 (m，1H)，1.67(m，3H)，0.97(t，J＝7.3Hz，3H)。
399 325.90 1.60
400 340.00 1.80 (500MHz，MeOD)9.07(br，0.24H)，8.54(s，1H)， 8.46(s，1H)，8.36(d，J＝4.3Hz，1H)，7.39- 7.36(m，1H)，3.25-3.15(m，2H)，2.19-2.00 (m，2H)，1.65(m，3H)，0.97-0.90(m，6H)。
401 410.10 2.10 DMSO-d6 (the about 1.3:1 of optically-active mixture): 12.45 (m, 1H); 9.05-8.3 (m, 5H); 7.3-7.2 (m, 1H); 5.6-5.4 (m,
Compound # M+H RT NMR
1H); 4.8 (t, 0.6H); 4.7 (t, 0.4H); 4.45 3.75 (m, 4H); 2.8-2.6 (m, 1H); 2.25-2.1 (m, 1H).
402 410.10 2.00 DMSO-d6 (the about 1.3:1 of optically-active mixture): 12.45 (m, 1H); 8.8-8.3m, 5H); 7.3-7.15 (m, 1H); 5.5-5.35 (m, 1H); 4.9 (d, 0.6H); 4.75 (d, 0.4H); 4.15-3.8 (m, 4H); 2.75-2.6 (m, 1H); 2.4-2.3 (m, 1H).
403 392.10 2.00
404 409.10 1.50
405 409.00 1.50
Embodiment 3:JAK3 suppresses assay method
Assay method SCREENED COMPOUND shown in using hereinafter suppresses the ability of JAK3.Comprising 100mMHEPES (pH7.4), 1mM DTT, 10mM MgCl 2, 25mM NaCl and 0.01% BSA kinase buffer liquid in react.Concentration of substrate in the assay method is 5 μ M ATP (200uCi/ μ mole ATP) and 1 μ M poly-(Glu) 4Tyr.React with 1nM JAK3 at 25 ℃.
In each hole of 96 hole polycarbonate plates, add 1.5 microlitre candidate JAK3 inhibitor and contain 2 μ M poly-(Glu) 4The 50 microlitre kinase buffer liquid of Tyr and 10 μ M ATP.Then it is mixed, and add the 50 microlitre kinase buffer liquid that contain 2nM JAK3 enzyme, so that the reaction beginning.Room temperature (25 ℃) stops reaction with 50 microlitres, 20% trichoroacetic acid(TCA)s (TCA) that also contain 0.4mM ATP after following 20 minutes.Then, use TomTek Cell Harvester that the entire contents in each hole is transferred in the 96 hole glass fibre filter flat boards.After the washing, add 60 microlitre scintillation solutions, and use Perkin Elmer TopCount to detect 33P mixes.
Embodiment 4:JAK2 suppresses assay method
This assay method is as above described in the embodiment 3, different JAK-2 enzyme, poly-(Glu) of being to use 4The final concentration of Tyr is 15 μ M, and the final concentration of ATP is 12 μ M.
All compounds of describing in the table of discovery 1,2 and 3 all suppress JAK3 with the Ki that is lower than 0.1 μ M beyond removing compound 22,35,56,68,177,223,310,317,318,319,320,321,322,326,336,337,338,339,340,351,356,367,369,370,388 and 390.All compounds in the table 1,2 and 3 all suppress JAK3 with the Ki that is lower than 2.0 μ M except that compound 68 and 319.All compounds in the table of discovery 1,2 and 3 all suppress JAK2 with the Ki that is lower than 0.5 μ M except that compound 9,22,35,56,57,68,310,317,38,319,320,321,336,338,339,340,348,351,356,367 and 372.All compounds in the table 1,2 and 3 all suppress JAK2 with the Ki that is lower than 5.0 μ M except that compound 68,318 and 319.
Embodiment 5:JAK3 cell suppresses assay method
In the insulation can of humidification, HT-2 clone A5E cell (ATCC Cat.#CRL-1841) is grown and maintain cell culture medium (RPMI1640 at 37 ℃, replenished the 2mM L-glutaminate, be adjusted to Con A comprise 1.5 grams per liter sodium bicarbonates, 4.5 grams per liter glucose, 10mM HEPES, 1.0mM Sodium.alpha.-ketopropionate, 0.05mM2-mercaptoethanol, 10% foetal calf serum and 10% the rat T-STIM factor [Fisher Scientific Cat # CB40115] by volume).Testing the same day, washing HT-2 cell is with every milliliter 5 x 10 6The density of cell in the fresh cell culture medium that does not contain T-STIM, is cultivated its resuspending 4 hours under the condition of no T-STIM.After 4 hours, in each hole of 96 orifice plates, add 50 microlitres (0.25 x 10 6Cell) resuspending cell.The compound of preparation serial dilution adds it among RPMI then in DMSO.The diluted compounds of 100 microlitres is added in each hole, and plate was cultivated 1 hour in 37 ℃.Reorganization mouse interleukin II (rmIL-2) (the R ﹠amp that adds 50 microlitres, 40 nanograms/milliliter; D systems Inc.Cat # 402-ML), and with plate cultivated 15 minutes in 37 ℃.
Then with plate under 1000rpm centrifugal 5 minutes, the sucking-off supernatant, every hole adds 3.7% formaldehyde of 50 microlitres in phosphate buffered saline (PBS) (PBS).Plate was being cultivated 5 minutes under room temperature on the oscillator plate.With plate recentrifuge 5 minutes under 1000rpm.The sucking-off supernatant adds 90% methyl alcohol of 50 microlitres in each hole, and plate was cultivated on ice 30 minutes.The sucking-off supernatant is used the PBS wash plate.PhosphoSTAT-5 (Y694) PE with every hole 25 microlitres adding 1:10 dilution in plate puts together antibody (PS-5PE antibody; Becton-Dickinson Cat.#61256), and with plate under room temperature, cultivating 45 minutes on the oscillator plate.Add 100 microlitre PBS, and plate is centrifugal.The sucking-off supernatant, and with the cell resuspending in 100 microlitre PBS.Then, plate is gone up reading at 96 hole FACS readers (Guava PCA-96).
Found that The compounds of this invention suppresses JAK3 in this assay method.
Embodiment 6:JAK2 cell suppresses assay method
In the insulation can of humidification, TF-1 cell (ATCC Cat.#CRL-2003) is grown and maintain cell culture medium (RPMI 1640 at 37 ℃, replenished the 2mM L-glutaminate, be adjusted to and comprise 1.5 grams per liter sodium bicarbonates, 4.5 grams per liter glucose, 10mM HEPES, 1.0mM Sodium.alpha.-ketopropionate, 10% foetal calf serum and macrophage colony stimulating factor of recombinant human granulocyte [rhGMCSF, R﹠amp; D Systems Inc.Cat.# 215-GM]) in.Testing the same day, washing TF-1 cell is with every milliliter 5 x 10 6The density of cell in the fresh cell culture medium that does not contain rhGMCSF, is cultivated its resuspending 4 hours under the condition of no rhGMCSF.After 4 hours, add 50 microlitres (0.25 x 10 to each Kong Zhongjun of 96 orifice plates 6Cell) resuspending cell.The compound of preparation serial dilution adds it among RPMI then in DMSO.The diluted compounds of 100 microlitres is added in each hole, and plate was cultivated 1 hour in 37 ℃.The rhGMCSF that adds 50 microlitres, 10 nanograms/milliliter, and plate cultivated 15 minutes in 37 ℃.Then, according to the disposable plates that describes in detail among the embodiment 5 above, be used for facs analysis.Found that The compounds of this invention suppresses JAK2 in this raji cell assay Raji.
Though we have described many embodiment of the present invention, be apparent that the basic embodiment that can change us, so that other embodiment of utilizing The compounds of this invention and method to be provided.Therefore, will be understood that scope of the present invention will be by additional claim but not determine by the specific embodiments that embodiment above represents.

Claims (50)

1. the compound of formula (I) or its pharmacy acceptable salt,
Figure A200780003260C00021
Wherein:
R 3Be H, Cl or F;
X 1Be N or CR 4
R 2Be H, F, R ', OH, OR ', COR ', COOH, COOR ', CONH 2, CONHR ', CON (R ') 2Or CN;
R 4Be H, F, R ', OH, OR ', COR ', COOH, COOR ', CONH 2, CONHR ', CON (R ') 2Or CN;
Perhaps R 2And R 4Be combined together to form optional by 1-4 R 10The 5-7 unit's aryl rings or the heteroaryl ring that replace;
R ' is optional by 1-4 R 5The C that replaces 1-3Aliphatic group;
Each R 5Be independently selected from halogen, CF 3, OCH 3, OH, SH, NO 2, NH 2, SCH 3, NCH 3, CN or unsubstituted C 1-2Aliphatic group, perhaps two R 5Form cyclopropyl rings or C=O jointly with its carbon that is connected;
Each R 10Be independently selected from halogen, OCH 3, OH, NO 2, NH 2, SH, SCH 3, NCH 3, CN or unsubstituted C 1-2Aliphatic group;
R 1Be
Figure A200780003260C00022
Or
R " be H, or optional by 1-3 R 11Replace-C 1-2Aliphatic group;
Each R 11Be independently selected from halogen, OCH 3, OH, SH, NO 2, NH 2, SCH 3, NCH 3, CN, CON (R 15) 2Or unsubstituted C 1-2Aliphatic group, perhaps two R 11Group forms cyclopropyl rings or C=O jointly with its carbon that is connected;
R 6Be optional by 1-5 R 12The C that replaces 1-4Aliphatic group;
Each R 12Be independently selected from halogen, OCH 3, OH, NO 2, NH 2, SH, SCH 3, NCH 3, CN or unsubstituted C 1-2Aliphatic group, perhaps two R 12Group forms cyclopropyl rings jointly with its carbon that is connected;
Ring A is the saturated azo-cycle that contains of 4-8 unit, and this ring comprises two other heteroatomss that are selected from N, O or S at the most, and optional by 1-4 R 13Replace;
Each R 13Be independently selected from halogen, R ', NH 2, NHR ', N (R ') 2, SH, SR ', OH, OR ', NO 2, CN, CF 3, COOR ', COOH, COR ', OC (O) R ' or NHC (O) R '; Perhaps any two R on identical substituting group or different substituting group 13Group and each R 13The atom that group connected forms 3-7 unit carbocyclic ring or heterocycle saturated, undersaturated or fractional saturation jointly, and this carbocyclic ring or heterocycle are optional by 1-3 R 5Replace;
R 8Be optional by 1-5 R 12The C that replaces 1-4Aliphatic group;
R 9Be C 1-2Alkyl; Perhaps
R 8And R 9Be combined together to form optional by 1-5 R 12The 3-7 unit's carbocyclic ring saturated rings or the heterocycle saturated rings that replace;
R 14Be H or unsubstituted C 1-2Alkyl;
R 15Be H or unsubstituted C 1-2Alkyl; And
R 7Be optional quilt 6 C that F replaces at the most 2-3Aliphatic series or alicyclic group.
2. according to the compound of claim 1, wherein this compound has formula I-A:
Figure A200780003260C00031
3. according to claim 1 or 2 each compounds, wherein R 3Be H or Cl.
4. according to the compound of claim 3, R wherein 3Be Cl.
5. according to the compound of claim 3, R wherein 3Be H.
6. the compound any, wherein R according to claim 1-5 2Be H, F, R ', OH or OR '.
7. according to the compound of claim 6, R wherein 2Be H or F.
8. the compound any according to claim 1-5, wherein this compound is a formula I-A compound, and R 4Be H, F, R ', OH or OR ', perhaps R 2And R 4Be combined together to form 6-unit aryl rings.
9. compound according to Claim 8, wherein R 4Be H or F.
10. according to the compound of claim 9, if R wherein 4Be F, R then 2Be H, and if R 2Be F, R then 4Be H.
11. according to the compound of claim 9, wherein R 2And R 4All be H.
12. according to claim 10 or 11 each compounds, wherein R 3Be Cl.
13. according to claim 10 or 11 each compounds, wherein R 3Be H.
14. the compound any, wherein R according to claim 1-13 7Be CH 2CH 3, CH 2CF 3, CH 2CHF 2, CH 2CH 2F, CH 2CH 2CH 3, CH 2CH 2CF 3, CH 2CH 2CH 2F or CH 2CH 2CHF 2
15. according to the compound of claim 14, wherein R 7Be CH 2CH 3, CH 2CF 3, CH 2CH 2CH 3Or CH 2CH 2CF 3
16. according to the compound of claim 15, wherein R 7Be CH 2CF 3
17. the compound any, wherein R according to claim 1-16 " be H or CH 3
18. according to the compound of claim 17, wherein R " be H.
19. the compound any, wherein R according to claim 1-18 14Be H.
20. the compound any, wherein R according to claim 1-19 15Be H.
21. according to the compound of claim 1, wherein this compound is formula II or III compound:
Figure A200780003260C00051
X wherein 1ABe N, CH or CF, and R 1ABe
Figure A200780003260C00052
Or
Figure A200780003260C00053
22. according to the compound of claim 21, wherein R 7Be CH 2CH 3, CH 2CF 3, CH 2CH 2CH 3Or CH 2CH 2CF 3
23. according to the compound of claim 22, wherein R 7Be CH 2CF 3
24. the compound any, wherein R according to claim 1-23 6Be selected from
Figure A200780003260C00061
25. according to the compound of claim 24, wherein R 6Be selected from
Figure A200780003260C00071
26. according to the compound of claim 25, wherein R 6Be selected from
Figure A200780003260C00072
Or
Figure A200780003260C00073
27. the compound any according to claim 1-23 wherein encircles A and is
Figure A200780003260C00074
And R 13' be H or R 13
28., wherein encircle A and be according to the compound of claim 27
Figure A200780003260C00075
Or
Figure A200780003260C00076
29., wherein encircle A and be according to the compound of claim 28
30. according to the compound of claim 29, wherein R 13Do not exist.
31., wherein encircle A by 1 R according to the compound of claim 29 13Replace.
32. according to the compound of claim 31, wherein R 13Be OH, CH 3, F, OR ' or NHR '.
33. according to the compound of claim 32, wherein R ' is C 1-2Alkyl or C 2-3Thiazolinyl.
34. according to the compound of claim 32, wherein R 13Be OH.
35. the compound any, wherein R according to claim 1-23 8And R 9Be combined together to form and be selected from following ring:
Figure A200780003260C00082
Figure A200780003260C00083
One or more carbon atoms in the wherein said ring are optional and alternative by N, O or S independently.
36. the compound any, wherein R according to claim 1-23 8And R 9Be
Figure A200780003260C00091
Figure A200780003260C00092
Or
37. according to the compound of claim 36, wherein R 8And R 9Be
Figure A200780003260C00094
Figure A200780003260C00095
Or
Figure A200780003260C00096
38. according to the compound of claim 37, wherein R 8And R 9Be
Or
Figure A200780003260C00098
39. the compound any, wherein X according to claim 21-38 1ABe CH or CF.
40. be selected from the compound of table 1, table 2 or table 3.
41. a pharmaceutical composition, it comprises compound and pharmaceutically acceptable carrier, auxiliary agent or the vehicle any one according to claim 1-40.
42. according to the described composition of claim 41, it comprises in addition and is selected from following therapeutical agent: chemotherapeutic or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressor, neurotrophic factor, the medicament that is used for the treatment of cardiovascular diseases, the medicament that is used for the treatment of destructive bone disorders, the medicament that is used for the treatment of hepatopathy, antiviral agent, be used for the treatment of hemopathic medicament, be used for the treatment of the medicament of diabetes or be used for the treatment of the medicament of immunodeficiency diseases.
43. one kind is suppressed the active method of jak kinase in the biological sample, it comprises makes described biological sample and contacts according to any one compound of claim 1-40 or according to claim 41 or 42 each compositions.
44. one kind is suppressed the active method of jak kinase among the patient, it comprises and will give described patient according to any one compound of claim 1-40 or according to claim 41 or 42 each compositions.
45. method for the treatment of disease of patient or obstacle or alleviating its severity, described disease or obstacle are selected from proliferative disease, heart disease, neurodegenerative disease, autoimmune disorder, situation, inflammatory diseases or the immune-mediated disease relevant with organ transplantation, and this method comprises according to any one compound of claim 1-40 or comprise the step that described compound compositions gives described patient.
46. the method for claim 45, it comprises the other step that other therapeutical agent is given described patient, described other therapeutical agent is selected from chemotherapeutic or antiproliferative, anti-inflammatory agent, immunomodulator or immunosuppressor, neurotrophic factor, be used for the treatment of the medicament of cardiovascular diseases, be used for the treatment of the medicament of diabetes or be used for the treatment of the medicament of immunodeficiency diseases, and wherein said other therapeutical agent is suitable for the disease of being treated.
47. method according to claim 45, the dementia that wherein said disease or obstacle are allergy or the anaphylaxis of I type, asthma, diabetes, Alzheimer, Huntington Chorea, Parkinson's disease, AIDS-is relevant, amyotrophic lateral sclerosis (ALS, Lou Gehrig ' s disease), multiple sclerosis (MS), schizophrenia, myocardial hypertrophy, perfusion/ischemic, apoplexy, bald, transplant rejection, graft versus host disease (GVH disease), rheumatoid arthritis, solid malignant, hematologic malignancies, leukemia, lymphoma and myeloproliferative disorder again.
48. according to the method for claim 47, wherein said disease or obstacle are asthma.
49. according to the method for claim 47, wherein said disease or obstacle are transplant rejections.
50. according to the method for claim 47, wherein said disease or obstacle are rheumatoid arthritiss.
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CN104940202A (en) * 2009-06-17 2015-09-30 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
CN104940202B (en) * 2009-06-17 2018-10-16 沃泰克斯药物股份有限公司 Inhibitors of influenza viruses replication
CN103502247A (en) * 2011-02-01 2014-01-08 默克专利股份公司 7-azaindole derivatives
CN103502247B (en) * 2011-02-01 2016-02-24 默克专利股份公司 7-7-azaindole derivatives
CN103702998A (en) * 2011-07-05 2014-04-02 沃泰克斯药物股份有限公司 Processes and intermediates for producing azaindoles
CN103833753B (en) * 2012-11-22 2017-02-01 广东东阳光药业有限公司 Alkynyl compound and its use method and purpose
WO2018019222A1 (en) * 2016-07-26 2018-02-01 张文燕 Heterocyclic compound as jak inhibitor, and salts and therapeutic use thereof
CN109790158A (en) * 2016-07-26 2019-05-21 天津隆博基因药物科技有限公司 As JAK inhibitor heterocyclic compound, the salt and its therapeutical uses of the compound
US11279699B2 (en) 2016-07-26 2022-03-22 Suzhou Longbiotech Pharmaceuticals Co., Ltd. Compound as selective JAK inhibitor, and salt and therapeutic use thereof
CN109790158B (en) * 2016-07-26 2022-06-24 苏州隆博泰药业有限公司 Heterocyclic compounds as JAK inhibitors, salts of the compounds and therapeutic use thereof
US11414413B2 (en) 2016-07-26 2022-08-16 Suzhou Longbiotech Pharmaceuticals Co., Ltd. Heterocyclic compound as JAK inhibitor, and salts and therapeutic use thereof
EA039344B1 (en) * 2017-01-19 2022-01-17 Сучжоу Лонгбайотек Фармасьютикалз Ко., Лтд. Heterocyclic compound as jak inhibitor and salts and therapeutic use thereof

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