HK1125632A - Azaindoles useful as inhibitors of janus kinases - Google Patents

Description

Azaindoles useful as inhibitors of janus kinases

Technical Field

The present invention relates to compounds useful as inhibitors of Janus (Janus) kinases (JAKs). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Background

Janus kinases (JAKs) are a family of tyrosine kinases consisting of JAK1, JAK2, JAK3 and TYK 2. JAKs play a key role in cytokine signaling. Downstream substrates of JAK family kinases include signal transduction and transcriptional activation (STAT) proteins. JAK/STAT signaling is implicated in the mediation of many aberrant immune responses such as allergy, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematologic malignancies such as leukemias and lymphomas. JAK2 is also implicated in myeloproliferative disorders including polycythemia, essential thrombocythemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome and systemic mastocytosis.

Therefore, there is a great need to develop compounds suitable as inhibitors of protein kinases. In particular, it would be desirable to develop compounds suitable as JAK family kinase inhibitors.

Disclosure of Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of protein kinases, particularly JAK family kinases. These compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein X¹、R¹、R²And R³As defined herein.

These compounds and pharmaceutically acceptable salts thereof are useful for treating or lessening the severity of a variety of diseases in a patient, including proliferative diseases, cardiac diseases, neurodegenerative diseases, autoimmune diseases, conditions associated with organ transplantation, inflammatory diseases, or immune-mediated diseases.

The compounds and compositions provided by the invention are also useful in the study of JAK kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of novel kinase inhibitors.

Definitions and general terms

The following definitions as used herein shall apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the periodic Table of the elements, CAS edition, and Handbook of chemistry and Physics, 75 th edition, 1994. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry", 5 th edition, Smith, M.B. and March, J. eds, John Wiley & Sons, New York:2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, which are generally exemplified above, or exemplified by specific classes, subclasses, and species of the invention. It should be understood that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. Generally, the term "substituted", whether preceded by the term "optionally" or not, refers to the substitution of one or more hydrogen groups in a known structure with a group having a specified substituent. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in any known structure can be substituted with more than one substituent selected from the indicated groups, the substituents at each position may be the same or different.

As used herein, when the term "optionally substituted" precedes a list, the term refers to all of the following substitutable groups in that list. If the substituent group or structure is not substitutedThe substituent group or structure is unsubstituted if determined or defined as "optionally substituted". For example, if X is halogen, optionally substituted C_1-3Alkyl or phenyl; x may be optionally substituted alkyl or optionally substituted phenyl. Likewise, unless otherwise specified, if the term "optionally substituted" follows the list, the term also refers to all substitutable groups preceding the list. For example, if X is halogen, C_1-3Alkyl or phenyl, wherein X is optionally J^XSubstituted, then C_1-3Both alkyl and phenyl groups may optionally be substituted by J^XAnd (4) substitution. Will not include, for example, H, halogen, NO₂、CN、NH₂OH or OCF₃Etc. as they are not substitutable groups, as will be apparent to those of ordinary skill in the art.

The combinations of substituents contemplated by the present invention are preferably those that can form stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that allow their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not substantially change when held at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions.

As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Further examples of aliphatic groups include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, and sec-butyl.

The term "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a hydrocarbon that is fully saturated or contains one or more units of unsaturation, but which is not aromatic, has a single point of attachment to the rest of the molecule, and wherein any individual ring in the bicyclic ring system has 3-7 members. Unless otherwise indicated, the term "alicyclic" refers to a monocyclic C₃-C₈C of hydrocarbons or bicyclic rings₈-C₁₂A hydrocarbon. Suitable alicyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, or cycloalkynyl. Further examples of cycloaliphatic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl.

As used herein, the term "heterocycle", "heterocyclyl" or "heterocyclic" refers to a monocyclic, bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms, and which system is fully saturated or contains one or more units of unsaturation, but which is not aromatic, having a single point of attachment to the remainder of the molecule. In some embodiments, a "heterocycle", "heterocyclyl", or "heterocyclic" group has 3-14 ring members, wherein one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3-7 ring members.

Examples of heterocycles include, but are not limited to, monocyclic 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyriperazinyl, 2-tetrahydropyriperazinyl, 3-tetrahydropyriperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and bicyclic rings of 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiepin, benzodiazacyclo-hexane, and 1, 3-dihydro-imidazol-2-one.

The term "heteroatom" denotes one or more of oxygen, sulfur, nitrogen, phosphorus or silicon, including any oxidized form of nitrogen, sulfur, phosphorus or silicon, quaternized form of any basic nitrogen, or heterocyclic substitutable nitrogen, such as N (e.g. N in 3, 4-dihydro-2H-pyrrolyl), NH (e.g. NH in pyrrolidinyl) or NR⁺(e.g. NR in N-substituted pyrrolidinyl⁺)。

As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic carbocyclic systems having a total of 6 to 14 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and has a single point of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aryl ring". Examples of aryl rings would include phenyl, naphthyl, and anthracene.

The term "heteroaryl", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and has a single point of attachment to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Further examples of heteroaryl rings include monocyclic rings of 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 2, 3-triazolyl, 1, 2, 3-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, pyrazinyl, 1, 3, 5-triazinyl, and bicyclic rings of benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atoms of aryl or heteroaryl groups are selected from R below²And R⁴The substituents listed in the definitions. Other suitable substituents include halogen, -R^o、-OR^o、-SR^o1, 2-methylenedioxy, 1, 2-ethylenedioxy, optionally with R^oSubstituted phenyl (Ph), optionally with R^osubstituted-O (Ph), optionally with R^oSubstituted- (CH)₂)_1-2(Ph), optionally with R^osubstituted-CH ═ CH (Ph), -NO₂、-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^oCO₂R^o、-NR^oNR^oC(O)R^o、-NR^oNR^oC(O)N(R^o)₂、-NR^oNR^oCO₂R^o、-C(O)C(O)R^o、-C(O)CH₂C(O)R^o、-CO₂R^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、-SO₂N(R^o)₂、-S(O)R^o、-NR^oSO₂N(R^o)₂、-NR^oSO₂R^o、-N(OR^o)R^o、-C(＝NH)-N(R^o)₂Or- (CH)₂)_0-2NHC(O)R^o(ii) a Wherein each independently present R^oSelected from hydrogen, optionally substituted C_1-6Aliphatic radical, unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O (Ph) or-CH₂(Ph), or two independently present R on the same substituent or different substituents^oAnd each R^oThe atoms to which groups are attached are joined together to form a 5-8 membered heterocyclic, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R^oIs selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halogeno C_1-4Aliphatic radical, wherein each of the aforementioned R^oC of (A)_1-4The aliphatic groups are all unsubstituted.

In some embodiments, an aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may comprise one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic group or of the nonaromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of the aryl or heteroaryl groupAnd furthermore includes the following substituents ═ O, ═ S, ═ NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl) or ═ NR^*Wherein each R^*Independently selected from hydrogen or optionally substituted C_1-6An aliphatic group. R^*Optional substituents on the aliphatic radical being selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical), wherein each of the aforementioned R^*C of (A)_1-4The aliphatic groups are all unsubstituted.

In some embodiments, the optional substituent on the nitrogen of the non-aromatic heterocyclic ring comprises-R⁺、-N(R⁺)₂、-C(O)R⁺、-CO₂R⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-SO₂R⁺、-SO₂N(R⁺)₂、-C(＝S)N(R⁺)₂、-C(＝NH)-N(R⁺)₂or-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6Aliphatic radical, optionally substituted phenyl, optionally substituted-O (Ph), optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph), optionally substituted-CH ═ CH (Ph), or an unsubstituted 5-6 membered heteroaryl ring or heterocycle having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur; or two independently present R on the same substituent or different substituents⁺And each R⁺The atoms to which groups are attached are joined together to form a 5-8 membered heterocyclic, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R⁺Is selected from NH or an optional substituent on the phenyl ring₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radicalBall)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical), wherein each of the aforementioned R⁺C of (A)_1-4The aliphatic groups are all unsubstituted.

As noted above, in some embodiments, two independently present R ° (or R [ - ])⁺Or any other variable similarly defined herein) may be taken together with the atom to which each variable is attached to form a 5-8 membered heterocyclic, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring. Two independently present R^o(or R)⁺Or any other variable similarly defined herein) and the atoms to which each variable is attached include, but are not limited to, a) two independently occurring R^o(or R)⁺Or any other variable similarly defined herein) are bound to the same atom and taken together with that atom to form a ring, e.g. N (R)^o)₂Wherein two R are present^oTaken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl or morpholin-4-yl group; b) two independently present R^o(or R)⁺OR any other variable similarly defined herein) are bound to different atoms and taken together with those atoms to form a ring, e.g. wherein the phenyl group is bound by the presence of two OR groups^oSubstituted byThe two R present^oTogether with the oxygen atom to which they are bound form a fused 6-membered oxygen-containing ring:it is understood that when two R are independently present^o(or R)⁺Or any other variable similarly defined herein) may form various other rings when taken together with the atoms to which each variable is attached, and the examples detailed above are not considered to be limiting.

In some embodimentsThe alkyl or aliphatic chain may optionally be interrupted by another atom or group. This means that the methylene units of the alkyl or aliphatic chain are optionally replaced by other atoms or groups as described. Examples of such atoms or groups include, but are not limited to, -NR-, -O-, -S-, -CO₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR-、-C(＝N-CN)、-NRCO-、-NRC(O)O-、-SO₂NR-、-NRSO₂-、-NRC(O)NR-、-OC(O)NR-、-NRSO₂NR-, -SO-or-SO₂-, wherein R is as defined herein. Unless otherwise indicated, optional substitutions form chemically stable compounds. Optional discontinuities may occur within the chain and at either end of the chain, i.e., at the point of attachment and/or also at the end. The two optional substitutions may also be contiguous to each other within the chain, so long as they form a chemically stable compound. Unless otherwise indicated, if a substitution or interruption occurs at a terminus, the substituting atom is attached to the terminal H. For example, if-CH₂CH₂CH₃Optionally interrupted by-O-, the resulting compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂OH。

As described herein, the bond drawn from one substituent to the center of one ring within a polycyclic ring system (as shown below) represents the substitution of the substituent at any substitutable position in any one ring within the polycyclic ring system. For example, diagram a represents a possible substitution in any of the positions shown in diagram b.

Drawing a and b

This also applies to multiple ring systems that are fused with an optional ring system (which is shown in dashed lines). For example, in figure c, X is an optional substituent for both ring a and ring B.

FIG. c is a drawing

However, unless otherwise specified, if two rings in a polycyclic ring system each have a different substituent drawn from the center of each ring, each substituent is only indicated as being substituted on the ring to which it is attached. For example, in figure d, Y is only a ring a optional substituent and X is only a ring B optional substituent.

FIG. d

Unless otherwise indicated, a structure described herein is also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomeric) forms of the structure; for example, the R and S configuration of each asymmetric center, double bond isomers of (Z) and (E), and conformational isomers of (Z) and (E). Thus, single stereoisomers as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformers) of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Further, unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having structures of the invention other than, or in addition to, deuterium or tritium in place of, hydrogen¹³C-or¹⁴It is within the scope of the present invention for C-enriched carbon to replace compounds of the present structures other than carbon. Such compounds are useful, for example, as analytical tools or probes in bioassays.

Description of the Compounds of the invention

The present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein

R³Is H, Cl or F;

X¹is N or CR⁴；

R²Is H, F, R ', OH, OR', COR ', COOH, COOR', CONH₂、CONHR’、CON(R’)₂Or CN;

R⁴is H, F, R ', OH, OR', COR ', COOH, COOR', CONH₂、CONHR’、CON(R’)₂Or CN;

or R²And R⁴Taken together to form optionally substituted 1-4R¹⁰A substituted 5-7 membered aryl or heteroaryl ring;

r' is optionally substituted by 1-4R⁵Substituted C_1-3An aliphatic group;

each R⁵Independently selected from halogen, CF₃、OCH₃、OH、SH、NO₂、NH₂、SCH₃、NCH₃CN or unsubstituted C_1-2Aliphatic radical, or two R⁵The group taken together with the carbon to which it is attached forms a cyclopropyl ring or C ═ O;

each R¹⁰Independently selected from halogen, OCH₃、OH、NO₂、NH₂、SH、SCH₃、NCH₃CN or unsaturated C_1-2An aliphatic group;

R¹is thatOr

R' is H or optionally substituted by 1-3R¹¹substituted-C_1-2An aliphatic group;

each R¹¹Independently selected from halogen, OCH₃、OH、SH、NO₂、NH₂、SCH₃、NCH₃、CN、CON(R¹⁵)₂Or unsubstituted C_1-2Aliphatic radical, or two R¹¹The group taken together with the carbon to which it is attached forms a cyclopropyl ring or C ═ O;

R⁶is optionally substituted by 1-5R¹²Substituted C_1-4An aliphatic group;

each R¹²Independently selected from halogen, OCH₃、OH、NO₂、NH₂、SH、SCH₃、NCH₃CN or unsubstituted C_1-2Aliphatic radical, or two R¹²The groups together with the carbon to which they are attached form a cyclopropyl ring;

ring A is a 4-to 8-membered saturated nitrogen-containing ring containing up to two additional heteroatoms selected from N, O or S, optionally substituted with 1-4R¹³Substitution;

each R¹³Independently selected from halogen, R', NH₂、NHR’、N(R’)₂、SH、SR’、OH、OR’、NO₂、CN、CF₃、COOR’、COOH、COR’、OC(O)H、OC(O)R’、CONH₂、CONHR’、CON(R’)₂NHC (O) R ' or NR ' C (O) R ', or any two R on the same or different substituents¹³Radical and each R¹³The atoms to which the groups are attached together form a 3-7 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring optionally substituted with 1-3R⁵Substitution;

R⁸is optionally substituted by 1-5R¹²Substituted C_1-4An aliphatic group;

R⁹is C_1-2An alkyl group; or

R⁸And R⁹Taken together to form an optionally substituted 1-5R¹²A substituted 3-7 membered carbocyclic or heterocyclic saturated ring;

R¹⁴is H or unsubstituted C_1-2An alkyl group;

R¹⁵is H or unsubstituted C_1-2An alkyl group; and

R⁷is C optionally substituted by up to 6F_2-3Aliphatic or cycloaliphatic radicals.

In one embodiment, the compounds of the invention have one of the formulas I-A or I-B:

in one embodiment, R³Is H or Cl. In another embodiment, R³Is Cl. In another embodiment, R³Is H.

In one embodiment, R²Is H, F, R ', OH OR OR'. In another embodiment, R²Is H or F.

In one embodiment, the compound is a compound of formula I-A and R⁴Is H, F, R ', OH OR OR'. In another embodiment, R⁴Is H or F. In another embodiment, R⁴Is F and R²Is H. In another embodiment, R²Is F and R⁴Is H. In another embodiment, R²And R⁴Are all H. In another embodiment, R³Is Cl. In alternative embodiments, R³Is H.

In another embodiment, the compound is a compound of formula I-A and R²And R⁴Taken together to form a 6-membered aryl ring. In another embodiment, R³Is Cl. In alternative embodiments, R³Is H.

In another embodiment, R⁷Is CH₂CH₃、CH₂CF₃、CH₂CHF₂、CH₂CH₂F、CH₂CH₂CH₃、CH₂CH₂CF₃、CH₂CH₂CH₂F or CH₂CH₂CHF₂. In another embodiment, R⁷Is CH₂CH₃、CH₂CF₃、CH₂CH₂CH₃Or CH₂CH₂CF₃. In yet another embodiment, R⁷Is CH₂CF₃。

In another embodiment, R' is H or CH₃. In another embodiment, R "is H.

In another embodiment, R¹⁴Is H. In yet another embodiment, R¹⁵H if present. In another embodiment, R¹⁵Is absent.

In another embodiment, the invention provides a compound of formula II:

wherein X^1AIs N, CH or CF, and R^1AIs that

OrIn another embodiment, R⁷Is CH₂CH₃、CH₂CF₃、CH₂CH₂CH₃Or CH₂CH₂CF₃. In yet another embodiment, R⁷Is CH₂CF₃。

In another embodiment, the invention provides a compound of formula III:

wherein X^1AIs N, CH or CF, and R^1AIs that

OrIn another embodiment, R⁷Is CH₂CH₃、CH₂CF₃、CH₂CH₂CH₃Or CH₂CH₂CF₃. In yet another embodiment, R⁷Is CH₂CF₃。

In another embodiment of any of formulas I, II or III, R⁶Is selected from

In another embodiment, R⁶Is selected from

Or

In yet another embodiment, R⁶Is selected from

Or

In another embodiment of any of formulas I, II or III, ring A is

And R is¹³' is H or R¹³。

In another embodiment, ring A is

Or

In another embodiment, ring A is

In one embodiment, each R is¹³Independently selected from halogen, R', NH₂、NHR’、N(R’)₂、SH、SR’、OH、OR’、NO₂、CN、CF₃COOR ', COOH, COR', OC (O) R 'or NHC (O) R'; or any two R on the same substituent or different substituents¹³Radical and each R¹³Atom to which the group is attachedTo form a 3-7 membered saturated, unsaturated or partially saturated optionally substituted by 1-3R⁵A substituted carbocyclic or heterocyclic ring.

In one embodiment of the invention, R¹³Is absent. In another embodiment, ring A is substituted with 1R¹³And (4) substitution. In another embodiment, there are 1R¹³Is OH, CH₃F, OR 'or NHR'. In yet another embodiment, R' is C_1-2Alkyl or C_2-3An alkenyl group. In another embodiment, R¹³Is OH.

In another embodiment of any of formulas I, II or III, R⁸And R⁹Taken together to form a ring selected from:

wherein one or more carbon atoms in the ring are optionally and independently replaced by N, O or S.

In another embodiment of any of formulas I, II or III, R⁸And R⁹Is that

In another embodiment, R⁸And R⁹Is that

In yet another embodiment, R⁸And R⁹Is that

Or

In yet another embodiment, R⁸And R⁹Is that

Or

In another embodiment, the invention provides A compound of formulA I, IA, IB, II or III wherein said compound inhibits JAK kinases with A lower Ki (i.e., is more effective) than said compound inhibits one or more kinases selected from AurorA-1(AUR-B), AurorA-2(AUR-A), Src, CDK2, Flt-3 or c-Kit. In another embodiment, the invention provides a compound of formula I, IA, IB, II or III wherein the compound has a lower K than said compound inhibits one or more kinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3 or c-Kit_iInhibit JAK 3.

In another embodiment, the present invention provides a compound of any one of formulas I, IA, IB, II or III, wherein the compound has a K of less than 0.1 μ M_iInhibit JAK 3. In another embodiment, the present invention provides a compound of any one of formulas I, IA, IB, II or III, wherein the compound has a K of less than 0.01 μ M_iInhibit JAK 3. In another embodiment, the present invention provides a compound of any one of formulas I, IA, IB, II or III, wherein the compound has a K of less than 0.01 μ M_iInhibiting JAK3 and increasing K compared with JAK3_iAt least 5 times higher K_iInhibit Aurora-2. In another embodiment, the present invention provides a compound of any one of formulas I, IA, IB, II or III, wherein the compound has a K of less than 0.01 μ M_iInhibiting JAK3 and increasing K compared with JAK3_iAt least 10 times higher K_iInhibit Aurora-2.

In another embodiment, the invention provides a compound of any one of formulas I, IA, IB, II or III wherein the compound has an IC in a cellular assay of less than 5 μ M₅₀Inhibit JAK 3. In another embodiment, the compound has an IC of less than 1 μ M in a cellular assay₅₀Inhibit JAK 3.

In another embodiment, the compound has an IC in a cellular assay that is at least 5-fold lower than the compound inhibits one or more kinases selected from JAK2, Aurora-1, Aurora-2, Src, CDK2, Flt-3, or c-Kit₅₀Inhibit JAK 3. In another embodiment, the invention provides a compound of any one of formulas I, IA, IB, II or III wherein the compound has an IC in a cellular assay of less than 5 μ M₅₀Inhibition of JAK3, wherein IC of JAK2₅₀JAK 3-deficient IC₅₀At least 5 times higher. In another embodiment, the compound has an IC of less than 1 μ M in a cellular assay₅₀Inhibition of JAK3, wherein IC of JAK2₅₀JAK 3-deficient IC₅₀At least 5 times higher. In another embodiment, the compound has an IC of less than 5 μ M in a cellular assay₅₀Inhibition of JAK3, wherein IC of JAK2₅₀JAK 3-deficient IC₅₀At least 10 times higher. In another embodiment, the compound has an IC of less than 1 μ M in a cellular assay₅₀Inhibition of JAK3, wherein IC of JAK2₅₀JAK 3-deficient IC₅₀At least 10 times higher. In yet another embodiment, the present invention provides a compound of any one of formulas I, IA, IB, II or III, wherein the compound has an IC in a cellular assay of less than 1 μ M₅₀Inhibition of JAK3, wherein IC of JAK2₅₀JAK 3-deficient IC₅₀At least 5 fold higher, and wherein the compound has a K of less than 0.01 μ M_iInhibiting JAK3 and increasing K compared with JAK3_iAt least 5 times higher K_iInhibit Aurora-2. In yet another embodiment, the compound is at an IC of less than 1 μ M in a cellular assay₅₀Inhibition of JAK3, wherein IC of JAK2₅₀Compared with JAK3IC₅₀At least 10 fold higher, wherein the compound has a K of less than 0.01 μ M_iInhibiting JAK3 and increasing K compared with JAK3_iAt least 10 times higher K_iInhibit Aurora-2.

In another embodiment, the present invention provides compounds of table 1, table 2 or table 3:

TABLE 1

TABLE 2

TABLE 3

Use, formulation and administration

Pharmaceutically acceptable compositions

In another embodiment, the present invention provides a composition comprising a compound of formula I, IA, IB, II or III.

In another embodiment, the composition further comprises a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, a drug for treating cardiovascular disease, a drug for treating destructive bone disorders, a drug for treating liver disease, an antiviral agent, a drug for treating hematologic disease, a drug for treating diabetes, or a drug for treating immunodeficiency disorders.

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of compound in the compositions of the invention is sufficient to measurably inhibit protein kinases, particularly JAK family kinases, in a biological sample or patient. Preferably, the compositions of the present invention are formulated for administration to a patient in need thereof, and most preferably, the compositions of the present invention are formulated for oral administration to a patient.

As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

Thus, in another aspect of the invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound described elsewhere herein or a metabolite or residue thereof. As used herein, the term "an inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of JAK family kinases.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

Pharmaceutically acceptable salts are well known in the art. For example, S.M.Berge et al describe in detail pharmaceuticals in J.pharmaceutical Sciences, 1977, 66, 1-19The above acceptable salts, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N⁺(C_1-4Alkyl radical)₄And (3) salt. The present invention also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include the non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate, as appropriate.

As noted above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents or other liquid excipients, dispersing or suspending agents, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack Publishing co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for preparing them. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as any other carrier medium that produces any undesirable biological effect or otherwise interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition, its use is contemplated to be within the scope of the present invention.

Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower seed oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

As used herein, the term "measurably inhibits" means a measurable change in kinase activity, particularly JAK kinase activity, between a sample comprising a compound of the invention and a JAK kinase and an equivalent sample comprising a JAK kinase in the absence of the compound.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oleaginous suspension. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable excipients and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants may also be used for the purpose of the formulation, such as tweens, spans and other emulsifiers or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms.

The pharmaceutically acceptable compositions of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. The suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, especially when the target of treatment includes diseases of the region or organ accessible by topical application, including the eye, skin or lower intestinal tract. For each of these regions or organs, suitable topical formulations are readily prepared.

Topical application to the lower intestinal tract may be achieved in rectal suppositories (see above) or in suitable enema preparations. Topical transdermal patches may also be used.

For topical application, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, pharmaceutically acceptable compositions may be formulated, for example, as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solutions, or preferably as solutions in isotonic, pH adjusted sterile saline or other aqueous solutions, with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment, such as petrolatum. The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration.

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

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a non-toxic parenterally-acceptable diluent or solvent, for example, as a sterile injectable solution, suspension or emulsion in 1, 3-butanediol. Acceptable excipients and solvents that can be used are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile, solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of crystalline or amorphous materials which have poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which in turn may depend on the size of the crystals and the crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming microencapsule matrices of the compounds in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by embedding the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore dissolve in the rectum or vaginal cavity and release the active compound.

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

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also have compositions that release the active ingredient(s) only, or preferentially, in a particular portion of the intestinal tract, optionally, in a delayed manner. Examples of useful embedding components include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form with one or more of the excipients mentioned above. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, in accordance with standard practice, other substances in addition to the inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally also contain opacifying agents and may also have compositions that release the active ingredient(s) only, or preferentially, in a particular portion of the intestinal tract, optionally, in a delayed manner. Examples of useful embedding components include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions and may require any preservatives or buffers required. Ophthalmic formulations, ear drops and eye drops are also contemplated as being within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of controlled release of the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of a compound across the skin. The rate can be controlled by providing a rate controlling film or by dispersing the compound in a polymer matrix or gel.

The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the expression "dosage unit form" refers to physically discrete units of a drug suitable for the patient being treated. It will be understood, however, that the total daily amount of the compounds and compositions of this invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disease being treated and the severity of the disease; the activity of the particular compound employed; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed and similar factors well known in the medical arts.

The amount of a compound of the present invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, the compositions are formulated so that the inhibitor dose administered to a patient receiving the compositions is from 0.01 to 100 mg/kg body weight/day.

Depending on the particular condition or disease being treated or prevented, other therapeutic agents commonly administered to treat or prevent the condition may also be present in the compositions of the present invention. As used herein, other therapeutic agents commonly administered for the treatment or prevention of a particular disease or disorder are referred to as "appropriate for the disease or disorder being treated.

For example, chemotherapeutic or other antiproliferative agents may be used in combination with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include, but are not limited to, Gleevec^TMDoxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferon, and platinum derivatives.

Other examples of drugs that may also be administered in combination with the inhibitors of the invention include, but are not limited to, therapeutic agents for Alzheimer's disease such asAndtherapeutic agents for Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenylene, and amantadine; agents for treating Multiple Sclerosis (MS) such as interferon-beta (e.g.,andand mitoxantrone; therapeutic agents for asthma such as albuterol and its derivativesAgents for treating schizophrenia such as reprenol, visfate, serekan and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-parkinson's disease agents; agents for the treatment of cardiovascular diseases such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for treating liver diseases such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for treating hematological disorders such as corticosteroids, anti-leukemia agents, and growth factors; and agents such as gamma globulin for the treatment of immunodeficiency disorders.

The amount of the other therapeutic agent present in the compositions of the present invention will not exceed that which would normally be administered in a composition containing the therapeutic agent as the only active agent. Preferably, the amount of the other therapeutic agent in the presently disclosed compositions is from about 50% to 100% of the amount typically present in compositions containing that agent as the sole therapeutically active agent.

Use of compounds and compositions

In one embodiment, the present invention provides a method of inhibiting JAK kinase activity in a patient comprising administering to the patient a compound or composition of the invention.

In another embodiment, the invention comprises a method of treating or lessening the severity of a JAK-mediated condition or disease in a patient. As used herein, the term "JAK-mediated disease" refers to any disease or other deleterious condition in which JAK family kinases, particularly JAK2 or JAK3, are known to play a role. In another embodiment, the invention comprises a method of treating a JAK 3-mediated disease. Such conditions include, but are not limited to, immune responses such as allergic or type I allergies, asthma, autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative diseases such as Familial Amyotrophic Lateral Sclerosis (FALS), and solid and hematologic malignancies such as leukemias and lymphomas.

In another embodiment, the invention provides a method of treating or lessening the severity of a condition selected from the group consisting of a proliferative disease, a cardiac disease, a neurodegenerative disease, an autoimmune disease, a condition associated with organ transplantation, an inflammatory disease, an immune disease, or an immune-mediated disease, comprising administering to said patient a compound or composition of the invention.

In another embodiment, the method comprises the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disorder being treated and said additional therapeutic agent is administered with said composition as a single dosage form or separately from said composition as part of multiple dosage forms.

In one embodiment, the disease or disorder is allergic or type I hypersensitivity, asthma, diabetes, alzheimer's disease, huntington's disease, parkinson's disease, AI DS-related dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Multiple Sclerosis (MS), schizophrenia, myocardial hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic malignancies such as leukemia and lymphoma. In another embodiment, the disease or disorder is asthma. In another embodiment, the disease or disorder is transplant rejection. In another embodiment, the disease or disorder is rheumatoid arthritis.

In another embodiment, the compounds or compositions of the present invention may be used to treat myeloproliferative disorders. In one embodiment, the myeloproliferative disorder is polycythemia, essential thrombocythemia, or chronic idiopathic myelofibrosis. In another embodiment, the myeloproliferative disorder is myelometaplasia with myelofibrosis, Chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, systemic mastocytosis, atypical CML, or juvenile myelomonocytic leukemia.

In another embodiment, the invention provides the use of a compound of formula I, IA, IB, II or III for the treatment of JAK-mediated diseases. In another embodiment, the invention provides the use of the compound for the treatment of any of the above-mentioned diseases. In another embodiment, the present invention provides the use of a compound of formula I, IA, IB, II or III for the preparation of a medicament for the treatment of a JAK-mediated disease. In another embodiment, the invention provides the use of the compound for the manufacture of a medicament for the treatment of any of the diseases described above.

In another embodiment, the invention provides a method of inhibiting JAK kinase activity in a biological sample comprising contacting the biological sample with a compound or composition of the invention.

As used herein, the term "biological sample" means an ex vivo sample and includes, without limitation, cell cultures or extracts thereof; a tissue or organ sample or extract thereof; biopsy material or extract thereof from a mammal; blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

Inhibition of kinase activity, particularly JAK kinase activity, in a biological sample can be used for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

In certain embodiments of the invention, an "effective amount" of a compound or pharmaceutically acceptable composition refers to an amount effective to treat or reduce the severity of one or more of the above conditions. The compounds and compositions, according to the methods of the present invention, can be administered using any amount and any route of administration effective to treat or reduce the severity of the condition or disease. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular drug, its mode of administration, and the like.

In an alternative embodiment, the method of the invention comprises the additional step of separately administering to the patient an additional therapeutic agent. When these additional therapeutic agents are administered separately, they may be administered to the patient prior to, sequentially with, or after administration of the compositions of the present invention.

The compounds of the present invention or pharmaceutical compositions thereof may also be used to coat implantable medical devices such as prostheses, artificial valves, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (restenosis of the vessel wall after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These undesirable effects can be prevented or alleviated by pre-coating the device with a pharmaceutically acceptable composition comprising a compound of the invention.

General preparation of suitable coatings and coated implantable devices is described in U.S. Pat. nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coating may optionally be further covered by a suitable outer coating of fluorosilicone, polysaccharide, polyethylene glycol, phospholipid or combinations thereof to impart controlled release characteristics to the composition. Implantable devices coated with the compounds of the present invention are another embodiment of the present invention. The compounds may also be applied to implantable medical devices such as beads, or co-formulated with polymers or other molecules to provide a "drug depot" thereby allowing the drug to be released for a longer period of time than when an aqueous solution of the drug is administered.

Methodology for compound synthesis and characterization

The compounds of the present invention may generally be prepared by methods known to those skilled in the art for analogous compounds, or by those methods described in the examples below. See, for example, the examples described in WO 2005/095400, the entire contents of which are incorporated herein by reference.

All references provided in the examples are incorporated herein by reference. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S.Dodd, The ACS Style Guide, American for authors and Editors, second edition, Washington, American chemical society, 1997, The entire contents of which are incorporated herein by reference.

Detailed Description

Examples

EXAMPLE 1 preparation of the Compounds of the invention

General synthetic schemes

Step 1

To a stirred Boc-valine (1; R) in 100 ml DCM₁Is Me; to a solution of 3.8 g, 0.02 mol), EDC (4.63 g, 0.024 mol), HOBt (4.0 g, 0.026 mol), DIEA (10.5 ml, 0.06 mol) was added trifluoroethylamine HCl salt (2.92 g, 0.022 mol). The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated to dryness and redissolved in EtOAc and washed with 0.5N HCl, NaHCO₃The saturated aqueous solution and brine were washed successively. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo to give 5.4 g of 2 (98%) as a white solid.

Step 2

Compound 2(5.32 g, 0.0197 mol) was deprotected with a 1:1 mixture of DCM/TFA at room temperature for 45 min. Concentration to dryness afforded the intermediate amine, which was used directly in the next step. A mixture of 5-fluoro-2, 4-dichloropyrimidine (3, R is F; 3.28 g, 0.0197 mol), the TFA salt of the crude amine (5.25 g, 0.0197 mol), and DIEA (10.27 mL, 0.059 mol) was stirred in isopropanol at room temperature for 16 h. The reaction mixture was concentrated in vacuo and redissolved in EtOAc with 0.5N HCl, NaHCO₃Is washed continuously with brine. The organic layer was dried (Na)₂SO₄) And concentrated in vacuo to give a crude oil which was chromatographed (50% EtOAc/50% hexanes) to give the desired compound 4.

Step 3

5(30 mg, 0.075 mmol; prepared according to WO 2005/095400), 4(23 mg, 0.075 mmol), Pd (Ph) in 1 ml of DME₃P)₄(9 mg, 0.0078 mmol) and sodium carbonate 2M (115. mu.L, 0.23 mmol) were heated in a microwave oven at 150 ℃ for 10 minutes. The reaction mixture was filtered through a short pad of silica gel with 30% EtOAc-70% hexanes as the eluent, and concentrated to dryness to give the crude intermediate, which was used directly in the next step.

The crude intermediate was dissolved in 1 ml of dry ethanol and 200 μ l of 25% sodium methoxide-methanol solution was added. The reaction mixture was stirred at 60 ℃ for 1 hour and quenched with 6N HCl (154. mu.l). The mixture was dried under a stream of nitrogen and purified by reverse phase HPLC (10-60 MeCN/water w/0.5% TFA) to afford the desired material of formula 6 a.

The compounds of formulae 6b and 6c can be prepared in a similar manner using suitable starting reagents. For example, compounds of formula 6b can generally be prepared by replacing compound 1 with tert-butyl 2- (2, 2, 2-trifluoroethylcarbamoyl) pyrrolidine-1-carboxylate, while compounds of formula 6c can generally be prepared by replacing compound 1 with tert-butyl 2- (2, 2, 2-trifluoroethylcarbamoyl) propan-2-ylcarbamate.

Example 2 analytical results

Tables 4, 5 and 6 below describe exemplary compounds of certain of the present invention¹H-NMR data (NMR) and liquid chromatography mass spectrometry data reported as mass + protons (M + H) determined by electrospray, and Retention Time (RT), wherein the compound numbers in tables 4, 5 and 6 correspond to the compounds described in tables 1, 2 and 3, respectively (blank cells indicate no experiment):

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	(d 4-methanol) 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	(d 4-methanol) 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	(d 4-methanol) 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	(d 4-methanol) 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	(d 4-methanol) 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，10H)
42	508.10	1.80	(d 4-methanol) 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，10H)
				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, methanol-d 4)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, methanol-d 4), 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，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＝2.0Hz，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＝1.9Hz，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＝2.0Hz，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, methanol-d 4)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 ═ 7.2Hz, 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＝2.1Hz，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＝2.1Hz，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 equivp-TsOH)，7.37(d，J＝8.0Hz，2H*0.7 equivp-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＝1.2Hz，1H)，8.05(d，J＝7.2Hz，1H)，6.7(d，J＝7.2Hz，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 ═ 9.5Hz, 1H), 8.57(m, 2H), 8.33(s, 1H), 8.03(m, 1H), 7.89(d, J ═ 8.4Hz, 1H), 7.74(t, J ═ 7.7Hz, 1H), 3.82(m, 2H), 2.66(s, 1.3H), 1.88(s, 6H). (2.66 peaks not identified)
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，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)，3.86-3.71(m，2H)，2.40-2.34(m，1H)，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). The multiplet (0.47H), 8.71, was identified as an incompletely exchanged exchangeable proton, which decreased to 0.38H after 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＝7.0Hz，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＝2.2Hz，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，DMSO)12.32(s，1H)，8.69(m，2H)，8.28-8.13(m，3H)，4.9-4.75(m，1H)，4.7-4.5(m，1H)，3.95-3.75(m，3H)，2.15-1.95(m，1H)，1.87(m，2H)，1.6(s，1H)，1.44-1.41(m，1H)，1.1-0.85(m，3H)
217	439	1.8	(500MHz，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)，2.43-2.38(m，1H)，2.27-2.16(m，2H)，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)，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，MeOD)8.76(s，1H)，8.21-8.17(m，3H)，6.40(d，J＝5.9Hz，1H)，4.90(d，J＝9.1Hz，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)，1.60-1.45(m，1H)，1.08(t，J＝7.2Hz，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)，9.07-8.61(br，1H)，8.93(s，1H)，8.37(s，1H)，8.07-7.54(m，2H)，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，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, 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), 4.77-4.75(m, 1H), 3.3(m overlaps with meoh signal, 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，MeOD)8.49(s，1H)，8.41(d，J＝7.9Hz，1H)，8.33-8.32(m，1H)，8.04(d，J＝6.9Hz，1H)，6.70(d，J＝6.6Hz，1H)，5.84(t，J＝55.8Hz，1H)，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＝7.0Hz，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)，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＝6.5Hz，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＝7.5Hz，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＝10.2Hz，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) (warmed at 100 ℃)12.26(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 ═ 6.3Hz, 1H),3.93-3.83(m，2H)，1.62-1.60(m，2H)，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	(500MHz, MeOD, rt, containing conformers) 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), 1.28-1.24(m, 2H), 1.09(t, J ═ 7.1, 0.98H), 0.96(t, J ═ 2H), 1.96 (t, 2H).
245	359.1	1.6	(500MHz, MeOD, rt, containing conformers) 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	(500MHz, MeOD, rt, containing conformers) 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	(500MHz, MeOD, rt, containing conformers) 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, 7.2Hz, 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 ═ 4, 7.92, t, 0.7H), 7.67 (t, 2H), 3.7.67 (t, 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＝1.8Hz，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). Undetermined peak at d 1.94.
				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，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 (approximate d, 1H), 4.86 (approximate 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，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) (optical rotation mixture about 1.3:1):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) (optical rotation mixture about 1.3:1):12.6(m, 1H); 8.7-8.25m, 5H); 5.5-5.3(m, 1H); 4.9(d, 0.6H); 4.75(d is,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) (optical rotation mixture about 1.3:1):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＝47.4，5.1Hz，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	(d 4-methanol) 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＝7.9，4.7Hz，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＝4.7，7.7Hz，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＝6.3Hz，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)，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，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，DMSO)12.81(s，1H)，8.65-8.56(m，3H)，8.36(d，J＝4.4Hz，1H)，8.22(d，J＝6.9Hz，1H)，7.26(dd，J＝4.7，7.9Hz，1H)，6.85(d，J＝6.4Hz，1H)，3.80(bm，4H)，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, 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), 3.35-3.32(m, 2H), 1.87(s, 6H), 1.38-1.29(m, 2H, impurities).
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＝6.7Hz，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 (optical rotation mixture about 1.3:1):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 (optical rotation mixture about 1.3:1):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

Example 3 JAK3 inhibition assay

Compounds were screened for their ability to inhibit JAK3 using the assay shown below. In a medium containing 100mM HEPES (pH7.4), 1mM DTT, 10mM MgCl₂25mM NaCl and 0.01% BSA in kinase buffer. Substrate concentrations in the assay were 5. mu.M ATP (200 uCi/. mu.mole ATP) and 1. mu.M poly (Glu)₄Tyr. The reaction was carried out at 25 ℃ and 1nM JAK 3.

To each well of a 96-well polycarbonate plate, 1.5 microliters of a candidate JAK3 inhibitor and a solution containing 2. mu.M poly (Glu)₄Tyr and 10. mu.M ATP in 50. mu.l kinase buffer. Then, they were mixed and 50 μ l of kinase buffer containing 2nM JAK3 enzyme was added to start the reaction. After 20 minutes at room temperature (25 ℃), the reaction was stopped with 50 microliters of 20% trichloroacetic acid (TCA) also containing 0.4mM ATP. The entire contents of each well were then transferred to a 96-well glass fiber filter plate using a TomTek Cell Harvester. After washing, 60. mu.l of scintillation fluid was added and detected using a Perkin Elmer TopCount³³And (4) doping P.

Example 4 JAK2 inhibition assay

The assay was as described in example 3 above, except that JAK-2 enzyme, poly (Glu) was used₄The final concentration of Tyr was 15. mu.M, and the final concentration of ATP was 12. mu.M.

All compounds described in tables 1, 2 and 3 were found to inhibit JAK3 with a Ki of less than 0.1 μ M, except compounds 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 tables 1, 2 and 3, except compounds 68 and 319, inhibited JAK3 with a Ki of less than 2.0 μ M. All compounds in tables 1, 2 and 3 were found to inhibit JAK2 with a Ki of less than 0.5 μ M, except compounds 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 tables 1, 2 and 3, except compounds 68, 318 and 319 inhibited JAK2 with a Ki of less than 5.0 μ M.

Example 5 JAK3 cytostatic assay

HT-2 clone A5E cells (ATCC Cat. # CRL-1841) were grown and maintained in cell culture medium (RPMI1640, supplemented with 2mM L-glutamine, adjusted with Con A to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10mM HEPES, 1.0mM sodium pyruvate, 0.05mM 2-mercaptoethanol, 10% fetal bovine serum, and 10% by volume of rat T-STIM factor [ Fisher Scientific Cat # CB40115 ] in a humidified incubator at 37 deg.C]). On the day of the experiment, HT-2 cells were washed at 5X 10 per ml⁶Density of cells they were resuspended in fresh cell culture medium without T-STIM and cultured for 4 hours without T-STIM. After 4 hours, 50 microliters (0.25 x 10) was added to each well of the 96-well plate⁶Cells) in a suspension. Serial dilutions of the compounds were prepared in DMSO and then added to RPMI. 100 microliters of the diluted compound was added to each well, and the plate was incubated at 37 ℃ for 1 hour. 50 microliters of 40 ng/ml recombinant murine interleukin-2 (rmIL-2) (R) was added&D systems inc. cat # 402-ML) and plates were incubated at 37 ℃ for 15 minutes.

The plates were then centrifuged at 1000rpm for 5 minutes, the supernatant aspirated off, and 50 μ l of 3.7% formaldehyde in Phosphate Buffered Saline (PBS) was added to each well. The plates were incubated on a plate shaker at room temperature for 5 minutes. Plates were centrifuged again at 1000rpm for 5 minutes. The supernatant was aspirated, 50 microliters of 90% methanol was added to each well, and the plates were incubated on ice for 30 minutes. The supernatant was aspirated and the plate was washed with PBS. PhosphoSTAT-5(Y694) PE conjugated antibody (PS-5PE antibody; Becton-Dickinson Cat. #61256) was added at a 1:10 dilution to the plates at 25. mu.l per well and the plates were incubated for 45 minutes at room temperature on a plate shaker. 100 microliters of PBS was added and the plate was centrifuged. The supernatant was aspirated and the cells were resuspended in 100 microliters PBS. The plates were then read on a 96-well FACS reader (Guava PCA-96).

As a result, the compounds of the present invention were found to inhibit JAK3 in this assay.

Example 6 JAK2 cytostatic assay

TF-1 cells (ATCC Cat. # CRL-2003) were grown and maintained in cell culture medium (RPMI1640, supplemented with 2mM L-glutamine, adjusted to contain 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10mM HEPES, 1.0mM sodium pyruvate, 10% fetal bovine serum and recombinant human granulocyte macrophage colony stimulating factor [ rhGMCSF, R ] in a humidified incubator at 37 deg.C&D Systems Inc.Cat.# 215-GM]) In (1). On the day of the experiment, TF-1 cells were washed at 5X 10 per ml⁶Density of cells they were resuspended in fresh cell culture medium without rhGMCSF and cultured in the absence of rhGMCSF for 4 hours. After 4 hours, 50 microliters (0.25 x 10) was added to each well of the 96-well plate⁶Cells) in a suspension. Serial dilutions of the compounds were made in DMSO and then added to RPMI. 100 microliters of the diluted compound was added to each well, and the plate was incubated at 37 ℃ for 1 hour. 50 μ l of 10 ng/ml rhGMCSF was added and the plates were incubated at 37 ℃ for 15 min. The plates were then processed for FACS analysis according to the details in example 5 above. As a result, the compounds of the present invention were found to inhibit JAK2 in the present cellular assay.

While we have described a number of embodiments of this invention, it is apparent that our basic examples can be altered to provide other embodiments that utilize the compounds and methods of this invention. It is, therefore, to be understood that the scope of the invention is to be determined by the appended claims rather than by the specific embodiments shown by way of example above.

Claims (50)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

R³is H, Cl or F;

X¹is N or CR⁴；

R²Is H, F, R ', OH, OR', COR ', COOH, COOR', CONH₂、CONHR’、CON(R’)₂Or CN;

R⁴is H, F, R ', OH, OR', COR ', COOH, COOR', CONH₂、CONHR’、CON(R’)₂Or CN;

or R²And R⁴Taken together to form optionally substituted 1-4R¹⁰A substituted 5-7 membered aryl or heteroaryl ring;

r' is optionally substituted by 1-4R⁵Substituted C_1-3An aliphatic group;

each R⁵Independently selected from halogen, CF₃、OCH₃、OH、SH、NO₂、NH₂、SCH₃、NCH₃CN or unsubstituted C_1-2Aliphatic radical, or two R⁵Taken together with the carbon to which it is attached to form a cyclopropyl ring or C ═ O;

each R¹⁰Independently selected from halogen, OCH₃、OH、NO₂、NH₂、SH、SCH₃、NCH₃CN or unsubstituted C_1-2An aliphatic group;

R¹is thatOr

R' is H, or is optionally substituted with 1-3R¹¹substituted-C_1-2An aliphatic group;

each R¹¹Independently selected from halogen, OCH₃、OH、SH、NO₂、NH₂、SCH₃、NCH₃、CN、CON(R¹⁵)₂Or unsubstituted C_1-2Aliphatic radical, or two R¹¹The group taken together with the carbon to which it is attached forms a cyclopropyl ring or C ═ O;

R⁶is optionally substituted by 1-5R¹²Substituted C_1-4An aliphatic group;

each R¹²Independently selected from halogen, OCH₃、OH、NO₂、NH₂、SH、SCH₃、NCH₃CN or unsubstituted C_1-2An aliphatic radical, orTwo of R¹²The groups together with the carbon to which they are attached form a cyclopropyl ring;

ring A is a 4-to 8-membered saturated nitrogen-containing ring containing up to two additional heteroatoms selected from N, O or S, optionally substituted with 1-4R¹³Substitution;

each R¹³Independently selected from halogen, R', NH₂、NHR’、N(R’)₂、SH、SR’、OH、OR’、NO₂、CN、CF₃COOR ', COOH, COR', OC (O) R 'or NHC (O) R'; or any two R on the same substituent or different substituents¹³Radical and each R¹³The atoms to which the groups are attached together form a 3-7 membered saturated, unsaturated or partially saturated carbocyclic or heterocyclic ring optionally substituted with 1-3R⁵Substitution;

R⁸is optionally substituted by 1-5R¹²Substituted C_1-4An aliphatic group;

R⁹is C_1-2An alkyl group; or

R⁸And R⁹Taken together to form an optionally substituted 1-5R¹²A substituted 3-7 membered carbocyclic or heterocyclic saturated ring;

R¹⁴is H or unsubstituted C_1-2An alkyl group;

R¹⁵is H or unsubstituted C_1-2An alkyl group; and

R⁷is C optionally substituted by up to 6F_2-3Aliphatic or cycloaliphatic radicals.

2. The compound according to claim 1, wherein the compound has the formula I-a:

3. a compound according to any one of claims 1 or 2, wherein R³Is H or Cl.

4. A compound according to claim 3, wherein R³Is Cl.

5. A compound according to claim 3, wherein R³Is H.

6. A compound according to any one of claims 1 to 5, wherein R is²Is H, F, R ', OH OR OR'.

7. A compound according to claim 6, wherein R²Is H or F.

8. A compound according to any one of claims 1 to 5, wherein the compound is a compound of formula I-A, and R⁴Is H, F, R ', OH OR OR', OR R²And R⁴Taken together to form a 6-membered aryl ring.

9. A compound according to claim 8, wherein R⁴Is H or F.

10. A compound according to claim 9, wherein if R is⁴Is F, then R²Is H, and if R is²Is F, then R⁴Is H.

11. A compound according to claim 9, wherein R²And R⁴Are all H.

12. A compound according to any one of claims 10 or 11, wherein R³Is Cl.

13. A compound according to any one of claims 10 or 11, wherein R³Is H.

14. The compound according to any one of claims 1-13, wherein R⁷Is CH₂CH₃、CH₂CF₃、CH₂CHF₂、CH₂CH₂F、CH₂CH₂CH₃、CH₂CH₂CF₃、CH₂CH₂CH₂F or CH₂CH₂CHF₂。

15. A compound according to claim 14, wherein R⁷Is CH₂CH₃、CH₂CF₃、CH₂CH₂CH₃Or CH₂CH₂CF₃。

16. A compound according to claim 15, wherein R⁷Is CH₂CF₃。

17. The compound according to any one of claims 1-16, wherein R "is H or CH₃。

18. The compound according to claim 17, wherein R "is H.

19. The compound according to any one of claims 1-18, wherein R¹⁴Is H.

20. The compound according to any one of claims 1-19, wherein R¹⁵Is H.

21. The compound according to claim 1, wherein the compound is of formula II or III:

wherein X^1AIs N, CH or CF, and R^1AIs that

Or

22. A compound according to claim 21, wherein R⁷Is CH₂CH₃、CH₂CF₃、CH₂CH₂CH₃Or CH₂CH₂CF₃。

23. A compound according to claim 22, wherein R⁷Is CH₂CF₃。

24. The compound according to any one of claims 1-23, wherein R⁶Is selected from

25. A compound according to claim 24, wherein R⁶Is selected from

26. A compound according to claim 25, wherein R⁶Is selected from

Or

27. The compound according to any one of claims 1-23, wherein ring a is

And R is¹³' is H or R¹³。

28. The compound according to claim 27, wherein ring a is

Or

29. The compound according to claim 28, wherein ring a is

30. A compound according to claim 29, which isIn R¹³Is absent.

31. The compound according to claim 29, wherein ring a is substituted with 1R¹³And (4) substitution.

32. The compound according to claim 31, wherein R¹³Is OH, CH₃F, OR 'or NHR'.

33. The compound according to claim 32, wherein R' is C_1-2Alkyl or C_2-3An alkenyl group.

34. The compound according to claim 32, wherein R¹³Is OH.

35. The compound according to any one of claims 1-23, wherein R⁸And R⁹Taken together to form a ring selected from:

wherein one or more carbon atoms in the ring are optionally and independently replaced by N, O or S.

36. The compound according to any one of claims 1-23, wherein R⁸And R⁹Is that

Or

37. A compound according to claim 36, wherein R⁸And R⁹Is that

Or

38. A compound according to claim 37, wherein R⁸And R⁹Is that

Or

39. A compound according to any one of claims 21 to 38, wherein X^1AIs CH or CF.

40. A compound selected from table 1, table 2 or table 3.

41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

42. The composition of claim 41, further comprising a therapeutic agent selected from the group consisting of: a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an antiviral agent, an agent for treating hematologic disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

43. A method of inhibiting JAK kinase activity in a biological sample, comprising contacting the biological sample with a compound according to any one of claims 1-40 or a composition according to any one of claims 41 or 42.

44. A method of inhibiting JAK kinase activity in a patient comprising administering to the patient a compound according to any one of claims 1-40 or a composition according to any one of claims 41 or 42.

45. A method of treating or lessening the severity of a disease or disorder selected from a proliferative disease, a cardiac disease, a neurodegenerative disease, an autoimmune disease, a condition associated with organ transplantation, an inflammatory disease, or an immune-mediated disease in a patient comprising the step of administering to said patient a compound according to any one of claims 1-40 or a composition comprising said compound.

46. The method of claim 45 comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disorder being treated.

47. The method according to claim 45, wherein said disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Multiple Sclerosis (MS), schizophrenia, cardiac hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, solid malignancies, hematologic malignancies, leukemias, lymphomas, and myeloproliferative disorders.

48. The method according to claim 47, wherein the disease or disorder is asthma.

49. The method according to claim 47, wherein the disease or disorder is transplant rejection.

50. The method according to claim 47, wherein the disease or disorder is rheumatoid arthritis.