HK1111690A - Pyrid-2-ones useful as inhibitors of tec family protein kinases for the treatment of inflammatory, proliferative and immunologically-mediated diseases - Google Patents

Description

Pyridones useful as kinase inhibitors

Technical Field

[0100] The present invention relates to compounds useful as inhibitors of protein kinases. 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. The invention also provides processes for preparing the compounds of the invention and intermediate compounds useful in these processes.

Background

[0101] In recent years, better understanding of the structure of enzymes and other biomolecules associated with disease has greatly facilitated the search for new therapeutic agents. One important class of enzymes that has been the subject of extensive research is protein kinases.

[0102] Protein kinases constitute a large family of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells (see Hardie, G.and Hanks, S.ThePR ° protein Kinase computers Book, I and II, Academic Press, San Diego, CA: 1995). Protein kinases are thought to have evolved from a common genetic gene by preserving their structure and catalytic function. Almost all kinases contain a similar 250-300 amino acid catalytic domain. Kinases can be classified into several families according to the substrates they phosphorylate (e.g. protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs that generally correspond to each kinase family have been identified (see, e.g., Hanks, s.k., Hunter, t., FASEB j.1995, 9, 576-596; Knighton et al, Science1991, 253, 407-23414; Hiles et al, Cell 1992, 70, 419-429; Kunzet al, Cell 1993, 73, 585-596; Garcia-Bustos et al, EMBO j.1994, 13, 2352-2361).

[0103]In general, protein kinases mediate intracellular signaling by affecting the transfer of phosphoryl groups from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular switches, capable of modulating or regulating the biological function of the target protein. These phosphorylation events are ultimately stimulated in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress response signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H₂O₂) Cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), and growth factors such as granulocyte macrophage colony stimulating factor (GM-CSF) and Fibroblast Growth Factor (FGF). Extracellular stimuli can affect one or more cellular responses involving cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, carbohydrate metabolism, protein synthesis control, and cell cycle regulation.

[0105] Many diseases are associated with abnormal cellular responses triggered by the aforementioned protein kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergy and asthma, alzheimer's disease, and hormone-related diseases. Accordingly, there is a continuing effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.

[0106] The Tec family of non-receptor tyrosine kinases play a central role in antigen-receptor signaling, for example, the TCR, BCR and Fc epsilon receptors (described in Miller A, et al, Current Opinion in Immunology 14; 331-340 (2002). Tec family kinases are essential for T-cell activation.the three members of the Tec family, Itk, Rlk and Tec, are activated downstream of antigen receptor engagement in T-cells, transmitting signals to downstream effectors, including PLC- γ. deletion of Itk in mice results in reduced proliferation and secretion of the T-cell receptor (TCR) -induced cytokines IL-2, IL-4, IL-5, IL-10 and IFN- γ (Schaeffer et al, Science 284; 638-641)), Fowewell et al, Immunity 11; 399-409(1999), Schffer et al Nature Immunology2, 12; 1183-1188(2001))). The immunological symptoms of allergic asthma were attenuated in Itk-/-mice. In response to allergen OVA challenge, lung inflammation, eosinophil infiltration and mucus production were dramatically reduced in Itk-/-mice (Mueller et al, Journal of Immunology 170: 5056-5063 (2003)). Itk is also implicated in atopic dermatitis. This gene has been reported to be more highly expressed in T-cells from peripheral blood of patients with moderate and/or severe atopic dermatitis than in control or patients with mild atopic dermatitis (Matsumoto et al, International archives of Allergy and Immunology 129; 327-340 (2002)).

[0107] In response to TCR engagement, spleen cells from Rlk-/-mice secrete half as much IL-2 as wild-type animals (Schaeffer et al, Science 284; 638 + 641(1999)), whereas the combined deletion of Itk and Rlk in mice causes profound inhibition of TCR-induced responses, including proliferation and production of cytokines IL-2, IL-4, IL-5 and IFN- γ (Schaeffer et al Nature Immunology2, 12; 1183 + 1188(2001)), Schaeffer et al, Science 284; 638-641(1999)). Intracellular signaling after TCR engagement occurs in Itk/Rlk deficient T-cells; the production of inositol triphosphate, calcium mobilization, activation of MAP kinase and activation of the transcription factors NFAT and AP-1 are all reduced (Schaeffer et al, Science 284; 638: 641(1999), Schaeffer et al Nature Immunology2, 12; 1183: 1188 (2001)).

[0108] Tec family kinases are also essential for B-cell development and activation. Btk mutant patients have a profound block of B-cell development, resulting in almost complete depletion of B lymphocytes from plasma cells, severe reduction in Ig levels, and profound inhibition of humoral responses to recall antigens (reviewed in Vihine et al FRontiers in Bioscience 5: d 917-928). Btk deficient mice also have a reduced number of peripheral B-cells and greatly reduced levels of IgM and IgG 3. Btk deletion in mice has profound effects on anti-IgM-induced B-cell proliferation, suppressing the immune response to thymus-independent type II antigens (Ellmei er et al, J Exp Med 192: 1611-.

[0109] Tec kinases also play a role in mast cell activation through the high affinity IgE receptor (fcsri). Itk and Btk are expressed in mast cells and activated by cross-coupling with Fc ε RI (Kawakami et al, Journal of Immunology; 3556-3562 (1995)). Btk deficient murine mast cells have reduced degranulation and decreased pro-inflammatory cytokine production following Fc ε RI cross-coupling (Kawakami et al, journal of leukcytebiogy 65: 286-. Btk deficiency also leads to a reduction in macrophage effector function (Mukhopadhyay et al, Journal of Immunology; 168, 2914-.

[0110] Therefore, there is a great need to develop compounds useful as inhibitors of protein kinases. Specifically, there is a need to develop compounds that are useful as inhibitors of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases, particularly in view of the fact that the treatment currently available for most disorders involving their activation is inadequate.

Disclosure of Invention

[0111] It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as inhibitors of protein kinases. In certain embodiments, these compounds are effective as inhibitors of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinases. These compounds have the general formula I as defined herein or a pharmaceutically acceptable salt thereof.

[0112] These compounds and pharmaceutically acceptable compositions thereof are useful for treating or preventing a variety of diseases, disorders, or conditions, including but not limited to autoimmune, inflammatory, proliferative, or hyperproliferative diseases, or immunologically-mediated diseases. These compositions are also useful in methods of preventing thrombin-induced platelet aggregation. The compounds provided by the invention are also useful in kinase studies in biological and pathological phenomena; studies of intracellular signal transduction pathways mediated by such kinases; and comparative evaluation of novel kinase inhibitors.

[0113] The invention also provides processes for preparing the compounds of the invention and intermediate compounds useful in these processes.

Detailed description of the invention

[0114] The present invention describes compounds of formula I:

formula I

Or a pharmaceutically acceptable salt thereof, wherein

Each R³And R⁴Independently H, halogen or optionally halogen, C_1-2Aliphatic radical, OCH₃、NO₂、NH₂、CN、NHCH₃、SCH₃Or N (CH)₂Substituted C_1-4An aliphatic group;

R²is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r²Optionally J is^RSubstitution;

each X¹And X²Independently is-C (O) -, -NR-or-SO₂-, wherein X¹Or X²One is-NR-, X¹Or X²is-C (O) -or-SO₂-；

R is H, unsubstituted C_1-6An aliphatic group;

R¹is-T-Q;

t is a bond or C_1-6An aliphatic radical in which up to three methylene units of the chain are optionally andindependently by G or G', wherein G is-NR⁵-、-O-、-S-、-SO-、SO₂-, -CS-or-CO-; g' is cyclopropyl, C ≡ C, or C ═ C; t is optionally J^TSubstitution;

q is independently hydrogen, C_1-6An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; q is optionally J^QSubstitution;

R⁵is optionally substituted R, C_6-10Aryl radical, C_3-10A cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵The groups, together with the atoms to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring;

optional substituent J^R、J^TAnd J^QAs defined herein.

[0115] Certain embodiments of the invention provide

If R is²Is 4-pyridyl or 3-pyridyl, R³Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not CH (CH)₃)OC(＝O)CH₃、CH₂OC(＝O)CH₃Or CH₂C(＝O)CH₃；

b)R¹Is not C_1-6Alkyl or O (C)_1-6Alkyl groups);

if R is²Is 4-pyridyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not methyl, imidazole, OCH₃Or H;

b) when T is-CH₂When Q is not 3-OH-phenyl, 4-OH-phenyl, 4-pyridyl, 3-NO₂-phenyl, OH, -O (C ═ O) CH₃or-C (═ O) CH₃；

c) When T is-CH (CH)₃) When Q is not-OC (═ O) CH₃；

d) When T is-CH₂CH₂-when Q is not 2-pyridyl or-COOH;

e) when T is CH (CH)₃) When OC (O) -, Q is not CH₃；

If R is²Is 4-pyridyl, R³Is H, R⁴Is not H, X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not CH₃；

b)R¹Is not CH (CH)₃)OC(＝O)CH₃；

If R is²Is 2, 4-pyrimidinyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not methyl, NHCH₃or-NHC (═ O) NH₂；

If R is²Is 4-pyridyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-SO₂-, then

a) When T is a bond, Q is not optionally substituted C_6-10Aryl or C_5-10A heteroaryl group;

if R is²Is 4-thiazolyl, R³Is H, R⁴Is CH₃，X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is-CH₂CH₂When Q is not N (CH)₃)₂；

If R is²Is unsubstituted phenyl, R³And R⁴Is a compound of formula (I) wherein the compound is H,X¹is-NR-, R is H, X²is-C (O) -, then

If T is C₁An aliphatic radical in which 1 methylene unit of the chain is replaced by G; g is-NR⁵-；R⁵Is H; then Q is not 2, 6-di-isopropylphenyl;

if R is²Is unsubstituted phenyl, R³Is H, R⁴Is CH₃，X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is a bond, Q is not CH₃Or CH₂CH₃；

b) When T is-CH₂CH₂When Q is not unsubstituted phenyl or N (CH)₂CH₃)₂；

c) When T is-CH₂CH₂CH₂When Q is not N (CH)₂CH₃)₂；

d)R¹Is not NH₂；

If R is²Is unsubstituted phenyl, R³Is H, R⁴Is CH₃，X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is-O-CH₂-when Q is not unsubstituted phenyl;

if R is²Is 4-OCH₃Phenyl radical, R³Is H, R⁴Is CH₃，X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not CH₃；

If R is²Is a 6-membered heteroaryl group with 2 nitrogens, R³Is H, methyl or ethyl, R⁴Is methyl or ethyl, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not CH₃；

If X¹is-C (O) -, X²is-NR-, R is H, then R¹Is not H or methyl;

if R is²Is that，R³And R³Is H, X¹is-NR-, R is H, X²is-C (O) -, then R¹Is not CH₃；

If R is²Is unsubstituted phenyl, R³And R⁴Is H, X¹is-C (O) -, X²is-NR-, R is H, then R¹Is not provided with

[0116] Other embodiments of the invention provide

If R is²Is 4-pyridyl, 3-pyridyl or，R³Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not H, C_1-6Alkyl, O (C)_1-6Alkyl), CH (CH)₃)OC(＝O)CH₃Or an imidazole;

b) when T is-CH₂When Q is not 3-OH-phenyl, 4-pyridyl, 3-NO₂-phenyl, OH, OC (═ O) CH₃or-C (═ O) CH₃；

c) When T is-CH₂CH₂-when Q is not 2-pyridyl or-COOH;

if R is²Is 2, 4-pyrimidinyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not methyl, NHCH₃or-NHC (═ O) NH₂；

If R is²Is 4-pyridyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-SO₂-, then

a) When T is a bond, Q is not optionally substituted C_6-10Aryl or C_5-10A heteroaryl group;

if R is²Is 4-thiazolyl, R³Is H, R⁴Is CH₃，X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is-CH₂CH₂When Q is not N (CH)₃)₂；

If R is²Optionally substituted phenyl, R³Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is C₁Aliphatic radicals, in which 1 methylene unit of the chain is replaced by G; g is-NR⁵-；R⁵Is H; then Q is not 2, 6-di-isopropylphenyl;

b) when T is-O-CH₂-when Q is not unsubstituted phenyl;

c) when T is a bond, Q is not CH₃；

If R is²Is unsubstituted phenyl, R³Is H, X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is a bond, Q is not CH₃Or CH₂CH₃；

b) When T is-CH₂CH₂When Q is not unsubstituted phenyl or N (CH)₂CH₃)₂；

c) When T is-CH₂CH₂CH₂When Q is not N (CH)₂CH₃)₂；

d)R¹Is not NH₂Or

If R is²Is a 6-membered heteroaryl group with 2 nitrogens, R³Is H, methyl or ethyl, R⁴Is methyl or ethyl, X¹is-NR-, R is H, X²is-C (O) -, then R¹Is not CH₃；

If X¹is-C (O) -, X²is-NR-, R is H, then R¹Is not H or methyl.

[0117]The compounds of the present invention include those generally described above, further illustrated as major classes, minor classes, and species disclosed herein. Unless otherwise indicated, the following definitions will apply. For the purposes of the present invention, the chemical elements will be according to the CAS version of handbook of Chemistry and Physics, 75^thAnd Ed is identified. 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^thEd, ed.: smith, M.B.and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0118] As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as those set forth generally above, or as exemplified by particular classes, subclasses, and species of the invention. It is to be understood that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". In general, the term "substituted," whether preceded by the term "optionally," means that a hydrogen radical in a given structure is replaced with a radical that is designated as a substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and if more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. Substituent combinations contemplated by the present invention are preferably those that form stable or chemically feasible compounds. The term "stable" as used herein means compounds that are substantially unchanged when subjected to the conditions used for their preparation, detection, preferably recovery, purification, and for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that remains substantially unchanged in the absence of moisture or other chemically reactive conditions at a temperature of 40 ℃ or less for at least one week.

[0119]The term "optionally interrupted" denotes the replacement of one atom by another atom within the alkylene chain. Unless otherwise specified, a second atom may replace a first atom at any position, including the terminal atom. For example, C optionally interrupted by-O-)_1-3The alkyl chain can form-OCH₂CH₃、-CH₂-OCH₃Or CH₂CH₂And (5) OH. Unless otherwise specified, the terminal group is bonded to hydrogen on the terminal side.

[0120]As used herein, the term "aliphatic" or "aliphatic radical" refers to 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, or to a monocyclic or bicyclic hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as a "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has a single point of attachment to the remainder of the molecule. 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. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") denotes monocyclic C₃-C₈Hydrocarbons or bicyclic radicals C₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but is not aromatic, which has a single point of attachment to the rest of the molecule, wherein any single ring in said bicyclic ring system is a 3-7 membered ring. Suitable aliphatic groups include, but are not limited to, linear or branched substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl, or (cycloalkyl) alkenyl.

[0121] It is to be understood that the ring systems herein may be linearly fused, bridged or spiro.

[0122] The term "heteroaliphatic" as used herein, refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, straight or branched chain, cyclic or acyclic, and include "heterocyclic", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" groups.

[0123] The term "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" as used herein, refers to a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, a "heterocycle", "heterocyclyl", "heterocycloaliphatic", or "heterocyclic" group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

[0124]The term "heteroatom" means one or more oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized forms of any basic nitrogen or heterocyclic ring substitutable nitrogen, e.g. N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl)).

[0125] The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

[0126] The term "alkoxy" or "thioalkyl" as used herein means an alkyl group, as defined above, attached to the bulk carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

[0127] The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" denote alkyl, alkenyl or alkoxy groups, as the case may be, substituted with one or more halogen atoms. The term "halogen" denotes F, Cl, Br or I.

[0128] The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", denotes monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring".

[0129] The term "heteroaryl", used alone or as part of a larger portion of "heteroaralkyl" or "heteroarylalkoxy", denotes monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

[0130]Aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroaralkoxy, and the like) may contain one or more substituents. Suitable substituents on unsaturated carbon atoms of aryl or heteroaryl groups (e.g. J)^R、J^TAnd J^Q) Selected from halogens; -R^o(ii) a Is optionally substituted by R^oSubstituted C_1-6Alkyl, wherein up to three methylene units of the chain are optionally and independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-or-CO-is replaced by a chemically stable arrangement; -OCF₃；-SCF₂；C_1-4A haloalkyl group; -CH₂-a halogen; is optionally substituted by R^oSubstituted C_6-10An aryl group; is optionally substituted by R^oSubstituted 5-12 membered heteroaryl; is optionally substituted by R^oA substituted 3-12 membered heterocyclic ring; is optionally substituted by R^oSubstituted-o (ph); is optionally substituted by R^osubstituted-CH ═ CH (ph); is optionally substituted by R^osubstituted-CH ≡ CH (ph); is optionally substituted by R^osubstituted-C_1-6Alkyl- (5-12 membered heterocyclyl); is optionally substituted by R^osubstituted-C_1-6Alkyl radical- (C)_6-10Aryl groups); is optionally substituted by R^osubstituted-C_1-6Alkyl- (5-10 membered heteroaryl); is optionally substituted by R^oSubstituted C_3-10A cycloaliphatic group; is optionally substituted by R^osubstituted-C_1-6Alkyl radical- (C)_3-10A cycloaliphatic group); is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -OR^o(ii) a Is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -N (R)^o)₂(ii) a Is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -SR^o；-NO₂；-CN；-OR^o；-SR^o；-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)₂；-P(O)₂R^o；-PO(R^o)₂；-OPO(R^o)₂(ii) a And- (CH)₂)_0-2NHC(O)R^o。

[0131]Each R^oIndependently selected from hydrogen, NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic group) 2, halogen, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group), halogenated C_1-4Aliphatic radical, optionally substituted C_1-6An aliphatic group (wherein up to 2 methylene units are optionally replaced by O, N or S), an optionally substituted 5-8 membered heterocyclic group, an unsubstituted 5-6 membered heteroaryl group, an unsubstituted 3-6 membered cycloaliphatic group, an unsubstituted phenyl group, an unsubstituted-O (Ph), an unsubstituted-CH₂(Ph), unsubstituted-CH₂(5-7 membered heterocyclic group) or unsubstituted-CH₂(5-6 membered heteroaryl); or R independently occurs twice on the same substituent or different substituents, although as defined above^oAnd each R^oThe atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0132]R^oOn an aliphatic radical or from two R^oThe optional substituents on the ring formed by the radicals 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) and halogeno C_1-4An aliphatic radical, in which R^oEach of the above C_1-4Aliphatic groups are unsubstituted.

[0133]The aliphatic or heteroaliphatic group or the non-aromatic heterocycle may contain one or more substituents. Suitable substituents on saturated carbon atoms of aliphatic or heteroaliphatic groups or of non-aromatic heterocycles (e.g. J)^R、J^TAnd J^Q) Selected from those listed above for aryl or heteroaryl unsaturated carbons, and additionally comprising the following groups: o, S, NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl), - (NOH) and- (NR)^*Wherein each R is^*Independently selected from hydrogen or optionally substituted C_1-6An aliphatic group. R^*Is 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) and halogeno C_1-4Aliphatic radical, wherein R^*Each of the above C_1-4Aliphatic groups are unsubstituted.

[0134]Optional substituents on non-aromatic heterocyclic nitrogen (e.g. J)^R、J^TAnd J^Q) Is selected from-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⁺)₂and-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6An aliphatic group, an optionally substituted phenyl group, an optionally substituted-O (Ph), an optionally substituted-CH₂(Ph); optionally substituted- (CH₂)₂(Ph); optionally substituted-CH ═ CH (ph), or unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or R independently occurring twice on the same substituent or on different substituents, although as defined above⁺And each R⁺The atoms to which the groups are bonded together form a 5-8 membered heterocyclyl, aryl or heteroaryl ring, or a 3-8 membered cycloaliphatic ring, having 0-3 atoms independently selected from nitrogen, oxygenOr a heteroatom of sulfur. R⁺Is selected from NH or an optional substituent on the phenyl ring₂、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) and halogeno C_1-4Aliphatic radical, wherein R⁺Each of the above C_1-4Aliphatic groups are unsubstituted.

[0135]The term "alkylene chain" denotes a straight or branched carbon chain which may be fully saturated or have one or more units of unsaturation, and has two points of attachment to the rest of the molecule, wherein one or more methylene units may optionally and independently be replaced by a group including, but not limited to, CO₂、COCO、CONR、OCONR、NRNR、NRNRCO、NRCO、NRCO₂、NRCONR、SO、SO₂、NRSO₂、SO₂NR、NRSO₂NR, O, S or NR.

[0136]As noted above, in some embodiments, two independent occurrences of R^o(or R)⁺Or any other variable similarly defined herein) together with the atom to which each variable is bonded form a 5-8-membered heterocyclyl, aryl or heteroaryl ring or a 3-8-membered cycloalkyl ring, having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Two independently occurring R^o(or R)⁺Or any other variable similarly defined herein) along with the atom to which each variable is bonded include, but are not limited to, the following: a) two independently occurring R^o(or R)⁺Or any other variable similarly defined herein) to the same atom and together with that atom form a ring, e.g. N (R)^o)₂In which two R are present^oTogether with the nitrogen atom, form piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b) two independent occurrences of R^o(or R)⁺Or any other variable similarly defined herein) key(s)To different atoms and forming a ring with these atoms, e.g.OR in which the phenyl radical is present twice^oSubstitution, R of both occurrences^oTogether with the oxygen atoms to which they are bonded form a fused 6-membered oxygen containing ring:. It will be appreciated that two independent occurrences of R^o(or R)⁺Or any other variable similarly defined herein) may form a variety of other rings along with the atom to which each variable is bonded, and the above detailed examples are not intended to be limiting.

[0137]Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of these compounds 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. In addition, unless otherwise indicated, the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except that hydrogen is replaced by deuterium or tritium or carbon is replaced by¹³C-or¹⁴C-enriched carbon instead of compounds having the structure of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0138] Unless otherwise indicated, the structures depicted herein are also meant to include N-oxide derivatives or pharmaceutically acceptable salts of each compound of formula I.

[0139]According to one embodiment of the invention, T is C_1-3Aliphatic radical, optionally interrupted by zero to one G group, wherein G is selected from O, NR⁵And S.

[0140]In some embodiments, T is-C_1-2An aliphatic radical-G-wherein G is O or NR⁵And G is bonded to Q in a chemically stable arrangement. In other embodiments, G is bonded to X in a chemically stable arrangement². In other embodiments, T is C_1-3Aliphatic groups, optionally interrupted by zero G groups.

[0141]In some embodiments, T is C_1-3Aliphatic groups, optionally interrupted by zero to one G' group. In other embodiments, T is C_1-3Aliphatic groups, optionally interrupted by zero to one G or G' group.

[0142]In some embodiments, T is-CH₂-; in other embodiments, T is a bond.

[0143]According to one embodiment of the invention, each R³And R⁴Independently is H. In some embodiments, R³And R⁴Are all H.

[0144]According to some embodiments, R²Is optionally at most five J^RA group-substituted 5-8 membered monocyclic ring. In certain embodiments, R²Is optionally at most five J^RA group-substituted 5-6 membered aryl or heteroaryl. In other embodiments, R²Is optionally at most five J^RA group-substituted 5-6 membered heteroaryl, preferably, R²Is a 6-membered heteroaryl having 1 or 2 nitrogen atoms, wherein R²Optionally up to five J^RAnd (4) substituting the group.

[0145]In some embodiments, R²Is optionally at most five J^RRadical substituted C_3-8A cycloaliphatic group. In other embodiments, R²Is optionally at most five J^RRadical substituted C_3-8A cycloalkyl group. In certain embodiments, R²Is optionally at most five J^RRadical substituted C_3-8A cycloalkenyl group. In other embodiments, R²Is optionally at most five J^RA cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, or cycloheptenyl group substituted with a group.

[0146]In some embodiments, R²Is optionally at most five J^RA group-substituted pyridine ring. In some embodiments, R²Is optionally at most five J^RA group-substituted 2-pyridyl, 3-pyridyl or 4-pyridyl group. In certain embodiments, R²Is optionally at most five J^RA group-substituted pyrimidine ring. In some embodiments, R²Is a 2, 4-pyrimidinyl group. In other embodiments, R²Is optionally at most five J^RA group-substituted 5-membered heteroaryl ring. In some embodiments, R²Is optionally at most five J^RGroup-substituted thiophenes or pyrazoles. In other embodiments, R²Is optionally at most five J^RA phenyl group substituted with a group.

[0147]In some embodiments, R²Optionally up to five J^RSubstituted by groups; in other embodiments, is up to 3J^RSubstituted by groups; in other embodiments, is 0 or 1J^RAnd (4) substituting the group.

[0148]In some embodiments of the invention, J^RIs selected from C_1-6Alkyl radical, C_6-10Aryl radical, -C_1-6alkyl-C_6-10Aryl radical, C_1-4Haloalkyl, -OR^o、-N(R^o)₂、-SR^o3-12 membered heterocyclic group, - (C)_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂、-(C_1-6Alkyl) -SR^o、-C(O)OR^o、-NR^oCOR^o、-COR^o、-CON(R^o)₂、-SO₂R^o、-SO₂N(R^o)₂And C_1-6Alkyl, wherein up to three methylene units of the chain are independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-or-CO-is replaced by a chemically stable arrangement.

[0149]In certain embodiments, J^RSelected from oxo or ═ NOH.

[0150]In other embodiments, J^Ris-OR^o、-N(R^o)₂、-SR^o、NO₂、CN、-(C_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂Or- (C)_1-6Alkyl) -SR^o。

[0151]In some embodiments, each J is^RIs independently selected from the group consisting of an optionally substituted 5-8 membered heterocyclic group, an optionally substituted-NR (C)_1-4Alkyl) N (R)^o)₂Optionally substituted-NR (C)_1-4Alkyl) OR^o、-N(R^o)₂Or an optionally substituted-NH (5-6 membered heterocyclyl). In certain embodiments, J^Ris-NH (C)_1-4Alkyl) N (R)^o)₂(ii) a In other embodiments is-NH (C)_1-4Alkyl) NHR^oor-NH (C)_1-4Alkyl) NH₂. In some embodiments, J^Ris-NR (CH)₂CH₂)N(R^o)₂(ii) a In other embodiments, J^Ris-N (CH)₃)CH₂CH₂N(R^o)₂。

[0152]In other embodiments, each J is^RIndependently selected from optionally substituted-NH (5-6 membered heterocyclyl).

[0153]In certain embodiments, each J is^RIs a 5-6 membered heterocyclic group containing 1-2 nitrogen atoms. In some embodiments, the 5-6 membered heterocyclyl is selected from pyrrolidine, piperidine, or piperazine.

[0154]In some embodiments, J^ROptionally and independently by R^oAnd (4) substitution.

[0155]In one embodiment of the invention, each X is¹And X²Independently is-C (O) -or-NR-, wherein X¹Or X²One is-NR-, X¹Or X²is-C (O) -.

[0156]In some embodiments, X¹is-C (O) -, X²is-NR-.

[0157]In other embodiments, X¹is-NR-, X²is-C (O) -.

[0158] In one embodiment of the invention, Q is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having O-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0159]In certain embodiments, Q is C_6-10Aryl radical, C_3-10A cycloaliphatic group, a 5-14 membered heteroaryl group, or a 5-14 membered heterocyclic group. In other embodiments, Q is C_6-10Aryl or 5-14 membered heteroaryl. In other embodiments, Q is a 5-6 membered aryl or heteroaryl. In some embodiments, Q is a 5-8 membered heterocyclyl; and in certain embodiments 5-6 membered heterocyclyl. In certain embodiments, Q is phenyl.

[0160]In some embodiments of the invention, Q is up to five J^QIs substituted by radicals in which J^QIs CN, C_1-6Alkyl radical, C_6-10Aryl radical, -C_1-6alkyl-C_6-10Aryl radical, C_1-4Haloalkyl, -OR^o、-N(R^o)₂、-SR^o、-(C_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂、-(C_1-6Alkyl) -SR^o、-C_1-6Alkyl radical- (C)_3-10Heterocyclyl), -C (O) OR^o、-NR^oCOR^o、-COR^o、-CON(R^o)₂、-SO₂R^o、-SO₂N(R^o)₂Or C_1-6Alkyl, wherein up to three methylene units are optionally and independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-or-CO-is replaced by a chemically stable arrangement.

[0161]In some embodiments, J^QIs selected from C_1-6Alkyl, CN, C_1-4Haloalkyl, -OR^o、-N(R^o)₂、-SR^o、-(C_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^O)₂、-(C_1-6Alkyl) -SR^o、C_6-10Aryl radical, -C_1-6alkyl-C_6-10Aryl radical, C_3-10Cycloaliphatic radical, -C_1-6Alkyl radical- (C)_3-10Cycloaliphatic radical), C_3-10Heterocyclyl radical, -C_1-6Alkyl radical- (C)_3-10Heterocyclyl), -C (O) OR^o、-NR^oCOR^o、-COR^o、-CON(R^o)₂、

-SO₂R^o、-SO₂N(R^o)₂Or C_1-6Alkyl, wherein up to three methylene units are optionally and independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-, -CO-, cyclopropyl, C ≡ C or C ═ C is replaced by a chemically stable arrangement; each J^QOptionally and independently by R^oAnd (4) substitution.

[0162]In some embodiments, J^Qis-SO₂N(R^o)₂、-SO₂R^o、-NR^oC(O)OR^o、-C≡C-R^o、-C＝C-R^oPhenyl, -O-Ph, -O-CH₂Ph、C_5-6Heteroaryl group, C_3-7Heterocyclyl or C_3-7A cycloaliphatic group.

[0163]In certain embodiments, J^QIs CN, C_1-6Alkyl, -CF₃、-OCF₃、-OR^o、-N(R^o)₂、-SR^o、-CH₂-halogen, -SCF₂、-(C_1-6Alkyl) -N (R)^o)₂、C₆Aryl radical, C_5-6Heteroaryl, -C (O) OR^o、-NR^oCOR^o、-COR^oor-CON (R)^o)₂。

[0164]In some embodiments, R²Optionally up to five J^QSubstituted by groups; in other embodiments, is up to 3J^QSubstituted by groups; in other embodiments, is O or 1J^QAnd (4) substituting the group.

[0165]In some embodiments, R^oSelected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, tert-butyl, OH, halogen, -CH₂-pyrrolidine, COCH₃、-(C_1-4Alkyl radical)_0-1-O(C_1-4Alkyl), - (C)_1-4Alkyl radical)_0-1-O(C_1-4Alkyl) OH, - (C)_1-4Alkyl radical)_0-1-O(C_1-4Alkyl) OH, - (C)_1-4Alkyl radical)_0-1-NH(C_1-4Alkyl), - (C)_1-4Alkyl radical)_0-1-N(C_1-4Alkyl radical)₂Or- (C)_1-4Alkyl radical)_0-1-NH₂。

[0166] In some embodiments, the variables are as depicted for the compounds of table I.

[0167] Thus, representative examples of compounds of formula I are depicted in table I.

TABLE I

[0168] The compounds of the invention can generally be prepared by methods known to those skilled in the art for analogous compounds, as illustrated by the following general schemes and the following preparation examples.

Scheme I

[0169]Reagents and conditions: (a) pyridine, RT, 16 h.

[0170]Scheme I above shows a general synthetic route for the preparation of compound 3a of the present invention, when R is¹As described herein. Compounds of formula 3a can be prepared according to scheme I, step (a), by reacting amrinone 1 with an acid chloride in pyridine. The reaction is applicable to a variety of acid chlorides.

[0171] Compounds I-1 through I-67 and I-82 and I-85 were prepared according to the general procedure described in scheme I.

Scheme II

[0172]Reagents and conditions：(a)NMP，xs(R⁰)₂NH, 160 ℃, 2 hours and microwave.

[0173]Scheme II above shows a general synthetic route for the preparation of compound 3b of the present invention, when R is⁰As described herein. The compound of formula 3b can be prepared by reacting I-20 with an excess of amine in NMP according to step (a) of scheme II. This reaction is applicable to a variety of amines.

[0174] Compounds I-68 to I-81 were prepared according to the general procedure described in scheme II.

Scheme III

[0175]Reagents and conditions：(a)MeI，Ag₂CO₃、CHCl₃RT, 48 hours; (b) bis (pinacolato) diboron, Pd (Oac)₂KOAc, DMF, 85 ℃ for 3 hours; (c) r²-Hal，Pd(Pph₃)₄，aq.Na₂CO₃Toluene, EtOH, reflux, 4 hrs.

[0176]Scheme III above shows a general synthetic route for the preparation of Compound 7 of the present invention, when R is²As described herein. Feed 4 can be prepared by the method described in Warner, et al, j.med.chem.1994, 37, 3090, methylated according to step (a) of scheme II. The iodide 5 is reacted with bis (pinacolato) diboron in the presence of a palladium catalyst to produce the compound of formula 6. Boronic ester derivatives 6 are prepared with halides R in the presence of palladium catalysts using Suzuki coupling procedures well known in the art²-Hal treatment to effect the formation of derivative 7. The reaction is applicable to a variety of substituted halides R²-Hal。

Procedure IV

[0177]Reagents and conditions: (a) hcl, 1, 4-dioxane, reflux, 30 min; (b) h₂10% Pd/C, MeOH, EtOAc, 2 h; (c) pyridine, RT, 16 h.

[0178]Scheme IV above shows a general synthetic route for the preparation of Compound 10 of the present invention, when R is¹And R²As described herein. Demethylation of compound 7 under acidic conditions leads to the formation of compound 8, which is then deprotected according to step (b). Finally, the compound of formula 10 can be prepared by reacting derivative 9 with acid chloride 2 in pyridine. This reaction is applicable to a variety of acid chlorides 2.

Procedure V

[0179]Reagents and conditions：(a)H₂10% Pd/C, MeOH, EtOAc, 2 h; (b) pyridine, RT, 16 hours; (c) hcl, 1, 4-dioxane, reflux, 30 min.

[0180]Scheme V above shows another general synthetic route for the preparation of Compound 10 of the present invention, when R is¹And R²As described herein. Deprotection of the amine 7 affords intermediate 11, which is reacted with acid chloride 2 in pyridine. This reaction is applicable to a variety of acid chlorides 2. After demethylation of intermediate 12 in an acidic medium, pyridone 10 is obtained.

Scheme VI

[0181]_{Reagents and conditions}：(a)H₂，Pd(OH)₂C, MeOH, RT, 5 h; (b) et (Et)₃N, DCM, RT, 10 min; (c) r²-Hal，Pd(Pph₃)₄，aq.Na₂CO₃Toluene, EtOH, reflux for 4 hours; (d) hc1, 1, 4-dioxane, at reflux for 30 min.

[0182]Scheme VI above shows another general synthetic route for the preparation of Compound 10 of the present invention, when R is¹And R²As described herein. Deprotection of the amine 6 affords intermediate 13, which is reacted with acid chloride 2 to yield the compound of formula 14. This reaction is applicable to a variety of acid chlorides 2. Boronic ester derivative 14 is reacted with halide R in the presence of a palladium catalyst using Suzuki coupling methods well known in the art²-Hal treatment to effect the formation of derivative 12. The reaction is applicable to a variety of substituted halides R²-Hal. After demethylation of intermediate 12 in an acidic medium, pyridone 10 is obtained.

Scheme VII

[0183]Reagents and conditions：(a)(a)NMP，xs(R⁰)₂NH, 160 ℃, 2 hours and microwave.

[0184]Scheme VII above shows a general synthetic route for the preparation of Compound 16 of the present invention, when R²And R⁰As described herein. The compound of formula 16 can be prepared by reacting compound 15 with an excess of amine in NMP according to scheme VII, step (a). This reaction is applicable to a variety of amines.

[0185] Compounds II-1 to II-182 were prepared according to the general procedures described in schemes III, IV, V, VI and VII.

[0186]Scheme VIII

[0187]Reagents and conditions: (a) HOBt, DMAP, EDC, THF, RT, 16 h.

[0188]Scheme VIII above shows a general synthetic route for the preparation of compound 19 of the present invention, at point R, R¹And R²As described herein. Starting material 17 can be prepared by methods substantially similar to those described in the literature (Church et al J. org. chem.1995, 60,3750). A compound of formula 19 is prepared according to step (a) of scheme VIII.

[0189] Compounds III-1 to III-54 were prepared according to the general procedure described in scheme VIII.

Procedure IX

[0190]Reagents and conditions: (a) pyridine, 0 ℃, 2 hours.

[0191]Scheme IX, supra, shows a general synthetic route for the preparation of Compound 21 of the present invention, when R¹And R²As described herein. The compound of formula 21 can be prepared by reacting derivative 9 with sulfonyl chloride 20 in pyridine. This reaction is applicable to a variety of sulfonyl chlorides 20.

[0192] Compound IV-1 is prepared according to the general procedure described in scheme IX.

[0193] The present invention also provides compounds that can be used as intermediates in the synthesis of the compounds of the invention. In addition, the present invention provides methods of using these intermediate compounds to prepare the compounds of the present invention.

[0194] In particular, compound 22 can be used as an intermediate compound in the process of preparing compound 23. Compound 23 can then proceed to produce the compound of formula I.

Procedure X

Wherein:

R¹⁰is an amino protecting group;

R¹¹is H or C_1-6Alkyl, or R¹⁰And R¹¹Together with the nitrogen atom to which they are bonded, form an amine protecting group;

R¹²is a hydroxy protecting group; and

R²as defined herein.

[0195]In one embodiment, compound 22 is combined with an appropriate compound comprising R²Under appropriate reaction conditions to produce compound 23. Suitably comprises R²An example of a compound of (1) is R²-X, wherein X is a suitable leaving group, such as a halo group. Suitable reaction conditions are those which allow the boronic ester (or boronic acid) to react with R²-coupling conditions for bonding between X. Suitable leaving groups and suitable coupling conditions are known to the skilled worker (see, for example, March, supra).

[0196]Boronic ester derivative 22 is reacted with halide R in the presence of a palladium catalyst using coupling methods well known in the art, for example, using a Suzuki coupling²-Hal treatment to prepare compound 23.

[0197]Scheme XI depicts an example of using Suzuki coupling conditions in the methods of the invention. In scheme XI, R¹⁰Is a Cbz group, R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it should be understood that the reactions depicted in scheme XI can employ chemical combinationsCompound 22 is used in place of compound 6 and compound 23 is used in place of 7.

Scheme XI

(a)R²-Hal，Pd(Pph₃)₄，aq.Na₂CO₃Toluene, EtOH, reflux.

[0198]The boronate ester derivative 22 is substituted with a nitrogen-containing saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring (e.g., R) in the presence of a copper catalyst²Definitions described) compound 23 can also be prepared by reaction of a nitrogen atom in the ring, for example using coupling methods well known in the art (see chernich et al.j. org. chem.2005, 1486) to give 23 (where R is²Is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having at least one nitrogen heteroatom; or an 8-12 membered saturated, partially unsaturated or fully unsaturated bicyclic ring system having at least one nitrogen heteroatom, R²Optionally J is^RSubstitution). Scheme XII depicts an example of copper-mediated coupling conditions in the methods of the invention. In scheme XII, R¹⁰Is a Cbz group, R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it is understood that reaction scheme XII depicted therein can employ compound 22 in place of compound 6 and compound 23 in place of 7.

Scheme XII

(a)Cu(OAc)₂，Et₃N，O₂、CH₂Cl₂，r.t.，20h。

[0199]In the methods of the present invention, compound 23 (and related compounds, e.g., compound 7) is converted to a compound of formula I by methods known to the skilled artisan, including but not limited to those disclosed herein. In certain intermediates, the hydroxyl protecting group is removed from compound 23, followed by removal of the amino protecting group. The resulting amines with appropriate radicals containing R¹To obtain the compound of formula I. For a specific example of this embodiment, see scheme IV and scheme IX. In scheme IV, R¹⁰Is a Cbz group, R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it will be appreciated that compound 23 can be employed in place of compound 7 in the reaction depicted in scheme IV.

[0200]In another embodiment, the amino protecting group in compound 23 is removed and the resulting amine is reacted with a compound containing the appropriate R¹To obtain compound X. Removing the hydroxy protecting group from compound X to provide the compound of formula I. For a specific example of such an implementation, see scheme V. In scheme V, R¹⁰Is a Cbz group, R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it will be appreciated that compound X may be employed in place of compound 11 and compound XX may be employed in place of compound 12 in the reaction depicted in scheme V.

[0201]In which X is¹In an embodiment where it is-NR-, the amino protecting group R¹¹May be a group R¹-X²-. As will be appreciated, in such embodiments, it will not be necessary to remove the amino protecting group and use a compound containing R¹The group is substituted. Thus, to obtain a compound of formula I, compound 23 will be reacted under conditions suitable to remove the hydroxy protecting group (thereby obtaining a compound of formula I). In which R is¹In embodiments in which the C (═ O) -group forms an incompatibility with the boronic ester, embodiments may be formed in which R forms¹⁰Is a boronate ester of Cbz, then substitutedAfter the formation of the boronic acid ester, the reaction is carried out with a compound containing R¹A group replaces the Cbz group. For a specific example of this embodiment, see scheme VI. In scheme VI, R¹⁰(in compound 14) is R¹C(＝O)-，R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it will be appreciated that compound 22 can be employed in place of compound 6 in the reaction depicted in scheme VI.

[0202]Or, R in 23¹⁰Can be converted into R¹-X²-. That is, R¹⁰The functional group in (A) can be converted to the desired R-containing¹A group. The hydroxy protecting group will then be removed to provide the compound of formula I. For a specific example of this embodiment, see scheme II and scheme VII.

[0203]Compound 22 may be prepared by methods known to the skilled artisan, including but not limited to those disclosed herein. In one embodiment, iodo compound 24 is reacted under conditions to form boronic ester 22 (scheme XIII). For specific examples of such conditions, see scheme III. In scheme III, R¹⁰Is a Cbz group, R¹¹Is hydrogen, R¹²Is methyl. Nevertheless, it is understood that reaction scheme XII depicted therein can employ compound 22 in place of compound 6 and compound 23 in place of 7.

Scheme XIII

[0204] It will be appreciated that in the process of the invention, the boronic ester 22 may not be used and the corresponding boronic acid may be used (scheme XIV). The boronic acid may be used as a starting material or may be generated in situ. Compound 25 can be prepared by methods including, but not limited to, the conversion of boronic ester 22 to boronic acid 25.

Scheme XIV

[0205]Protecting groups protecting amino and hydroxy functional groups from being converted into boronates or acids R²Under the condition of the group. Many amino protecting groups and hydroxyl protecting groups are known to the skilled person. Examples of such protecting GRoups can be found in T.W.Greene and P.G.M.Wutz, "reactive GRoups in Organic Synthesis", 3^rdEdition, John Wiley & Sons, Inc. (1999) and earlier versions of the book, and J.W.F.McOmie, "PR^otective GR^oups in Organic Synthesis”，Plenum Press(1973)。

[0206]In certain embodiments, R¹⁰is-C (O) R¹³OR-C (O) OR¹³Wherein:

R¹³the method comprises the following steps:

unsubstituted C_1-6An alkyl group, a carboxyl group,

quilt C₆-C₁₀Aryl substituted C_1-6Alkyl, or

C₆-C₁₀Aryl radical, each of which is C₆-C₁₀Aryl being optionally halogenated, -CN, -NO₂、-N(R¹⁴)₂Unsubstituted C_1-6Alkyl or-CF₃Substitution; and R is¹⁴Is H or unsubstituted C_1-6An alkyl group.

[0207]Preferably, R¹⁰Is Cbz (carbobenzoxy) or Boc (tert-butyloxycarbonyl).

[0208]In certain embodiments, R¹¹Is hydrogen.

[0209]In certain embodiments, R¹²Is C_1-6An alkyl group. Preferably, R¹²Is methyl or ethyl.

[0210]In a preferred embodiment, R¹⁰Is Cbz (carbobenzoxy) or Boc (tert-butyloxycarbonyl); r¹¹Is hydrogen; r¹²Is methyl.

[0211] While certain exemplary embodiments are depicted and described above and herein, it will be appreciated that the compounds of the invention may be prepared according to the methods generally described above, by means of methods generally available to those of ordinary skill in the art, using appropriate starting materials.

[0212] As disclosed herein, the present invention provides compounds that are inhibitors of protein kinases and, thus, are useful in the treatment of diseases, disorders, and conditions including, but not limited to, autoimmune, inflammatory, proliferative, or hyperproliferative diseases, or immunologically-mediated diseases. 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. Such additional therapeutic agents include, but are not limited to, agents for the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases or immunologically-mediated diseases, including rejection of transplanted organs or tissues and Acquired Immune Deficiency Syndrome (AIDS).

[0213] It will also be appreciated that certain compounds of the invention can be present in free form for use in therapy, or as pharmaceutically acceptable derivatives thereof, as appropriate. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative capable of providing, directly or indirectly, a compound as described herein or a metabolite or residue thereof upon administration to a patient in need thereof.

[0214] The term "pharmaceutically acceptable salt" as used herein, means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" means any non-toxic salt or ester salt of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitorily active metabolite or residue thereof. The term "its inhibitory active metabolite or residue" as used herein means that its metabolite or residue is also an inhibitor of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase.

[0215]Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences, 1977, 66, 1-19, by s.m.berge et al, which is 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 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, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, Propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄And (3) salt. The invention also encompasses quaternization of any basic nitrogen-containing group of the compounds as disclosed herein. By means of such quaternization, products which are soluble or dispersible in water or oil can be obtained. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine cations, generated using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0216] As noted above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, as described herein, including any and all solvents, diluents or other liquid excipients, dispersing or suspending aids, 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.ma rtin (Mack Publishing co., Easton, Pa., 1980) disclose various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, e.g., any other component that produces any undesirable biological effect or interacts in a deleterious manner with a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention. Some examples of materials capable of serving as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as 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, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinylpyrrolidone; a polyacrylate; waxes; polyethylene-polypropylene oxide-block polymers; lanolin; sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; crushed tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol 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; a phosphate buffer solution; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

[0217] In certain embodiments, the composition comprises an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In particular embodiments, the amount of compound detectably inhibits a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) protein kinase.

[0218] The invention also provides pharmaceutical compositions made by combining a compound of the invention with a pharmaceutically acceptable carrier, adjuvant, or vehicle, and methods of making pharmaceutical compositions comprising combining a compound of the invention with a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0219] In another aspect, methods of treating or lessening the severity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) -mediated disease are provided, comprising administering to a subject in need thereof an effective amount of a compound or a pharmaceutically acceptable composition comprising a compound. These methods may employ the compounds of formula I of the present invention or any other compound:

formula I

Or a pharmaceutically acceptable salt thereof, wherein

Each R³And R⁴Independently H, halogen or optionally halogen, C_1-2Aliphatic radical, OCH₃、NO₂、NH₂、CN、NHCH₃、SCH₃Or N (CH)₂Substituted C_1-4An aliphatic group;

R²is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r²Optionally J is^RSubstitution;

each X¹And X²Independently is-C (O) -, -NR-or-SO₂-, wherein X¹Or X²One is-NR-, X¹Or X²is-C (O) -or-SO₂-；

R is H, unsubstituted C_1-6An aliphatic group;

R¹is-T-Q;

t is a bond or C_1-6An aliphatic radical in which up to three methylene units of the chain are optionally and independently replaced by G or G', wherein G is-NR⁵-、-O-、-S-、-SO-、SO₂-, -CS-or-CO-; g' is cyclopropyl, C ≡ C, or C ═ C; t is optionally J^TSubstitution;

q is independently hydrogen, C_1-6An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfurA heteroatom selected from nitrogen, oxygen or sulfur; q is optionally J^QSubstitution; and

R⁵optionally substituted R, C_6-100Aryl radical, C_3-10A cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵The groups, together with the atoms to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring;

optional substituent J^R、J^TAnd J^QAs defined herein.

[0220] In certain embodiments of the invention, an "effective amount" of a compound or pharmaceutically acceptable composition is an amount effective to treat or reduce the severity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) -mediated disease. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route of administration effective to treat or reduce the severity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) -mediated 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, the manner in which it is administered, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein denotes physically discrete pharmaceutical units, as appropriate for the patient to be treated. It will be understood, however, that the total daily amount of the compounds and compositions of the present invention will be decided 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 disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and other factors well known in the medical arts. The term "patient" as used herein means an animal, preferably a mammal, most preferably a human.

[0221] The pharmaceutically acceptable compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), bucally, as an oral or nasal spray, etc., to humans and other animals, depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of from about 0.01mg/kg to about 50mg/kg, preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day, one or more times a day, to achieve the desired therapeutic effect.

[0222] 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. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0223] 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 sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed 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, may be used in the preparation of injectables.

[0224] The injectable formulations can be sterilized, for example, by filtration through a bacterial-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.

[0225] In order to prolong the effect of the compounds of the invention, it is often desirable to delay absorption of the compounds following subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of a compound depends on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered compound form is achieved by dissolving or suspending the compound in an oil carrier. Injectable depot forms are prepared by forming a microencapsulated matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, 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 entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

[0226] Rectal or vaginal compositions 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 ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity to release the active compound.

[0227] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, for example starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, for example glycerol, d) disintegrants, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders, for example paraffin, f) absorption accelerators, for example quaternary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerol monostearate, h) absorbents, for example kaolin and bentonite, and i) lubricants, for example talc, calcium stearate, sodium silicate, and the like, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0228] Solid compositions of a similar type may also be employed as fillers in soft or hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as polymeric polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided 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 be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used 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 sugar as well as polymeric polyethylene glycols and the like.

[0229] The active compound may also be in microencapsulated form, containing one or more of the above-mentioned excipients. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be provided with coatings and shells such as enteric coatings, release controlling 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, for example sucrose, lactose or starch. Such dosage forms may also contain, under normal circumstances, other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0230] 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 under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as appropriate. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of controlling the delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0231] As generally described above, the compounds of the present invention are useful as inhibitors of protein kinases. In one embodiment, the compounds and compositions of the present invention are inhibitors of one or more Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases, and thus, without wishing to be bound by any particular theory, compounds and compositions are particularly useful for treating or lessening the severity of a disease, disorder or condition in which activation of one or more Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases is implicated. When activation of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in a particular disease, disorder or condition, the disease, disorder or condition may also be referred to as a "Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) -mediated disease" or disease symptom. Thus, in another aspect, the invention provides methods of treating or lessening the severity of a disease, disorder or condition in which activation of one or more Tec families (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) is implicated in the disease state.

[0232] Also not wishing to be bound by any particular theory, the compounds and compositions of the invention are particularly useful for treating or lessening the severity of a disease, condition or disorder in which activation of Itk kinase is implicated, and are particularly useful for inhibiting Itk selectively relative to Btk and Rlk (see examples 14-16 and 18).

[0233] The activity of compounds useful as inhibitors of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases in the present invention may be assayed in vitro, in vivo, or in cell lines. In vitro assays include determining the inhibition of phosphorylation activity or ATPase activity of activated Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinases. A selective in vitro assay can quantify the ability of an inhibitor to bind to a kinase of the Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk). Binding of the inhibitor can be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) complexes, and determining the amount of bound radiolabel. Alternatively, binding of the inhibitor can be determined by incubating the novel inhibitor with a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase that is known to bind to a radioligand in a competition experiment.

[0234] The term "measurably inhibits" as used herein means that there is a measurable change in the kinase activity of a Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase between a sample containing the composition and the Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase and an equivalent sample containing the Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase without the presence of the composition.

[0235] The term "Tec family tyrosine kinase-mediated disorder" as used herein denotes any disease or other deleterious disorder in which a Tec family kinase is known to play a role. Such conditions include, without limitation, autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases, including rejection of transplanted organs or tissues and Acquired Immune Deficiency Syndrome (AIDS).

[0236] For example, Tec family tyrosine kinase-mediated disorders include respiratory diseases including, without limitation, reversible obstructive airway diseases including asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or refractory asthma (e.g., late asthma airway hyperreactivity) and bronchitis. In addition, Tec family tyrosine kinase diseases include, without limitation, those conditions characterized by mucositis, including acute, allergic and atopic and chronic rhinitis, including rhinitis caseosa, hypertrophic, purulent, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis, including croup, fibrinous and pseudomembranous rhinitis and scrofula rhinitis; seasonal rhinitis, including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; a fibroid lung; and idiopathic interstitial pneumonia.

[0237] Tec family tyrosine kinase-mediated disorders also include bone and joint diseases including, without limitation, rheumatoid arthritis (pannus formation in), seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and reiter's disease), becker's disease, sjogren's syndrome, and systemic sclerosis.

[0238] Tec family kinase-mediated disorders also include diseases and conditions of the skin including, without limitation, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, xeroderma, vasculitis nodosa, erythroderma, cutaneous eosinophilia, uveitis, alopecia, cluster and vernal conjunctivitis.

[0239] Tec family tyrosine kinase-mediated conditions also include diseases and disorders of the gastrointestinal tract including, without limitation, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, crohn's disease, ulcerative colitis, gastrointestinal remote food-related allergies such as migraine, rhinitis and eczema.

[0240] Tec family tyrosine kinase-mediated disorders also include diseases and conditions of other tissues and systemic diseases including, without limitation, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper IgE syndrome, leprosy, sexil syndrome and idiopathic thrombocytopenic purpura, post-angioplasty restenosis, tumors (e.g., leukemia, lymphoma), atherosclerosis, and systemic lupus erythematosus.

[0241] Tec family tyrosine kinase-mediated disorders also include allograft rejection, including, without limitation, acute and chronic allograft rejection, e.g., secondary to post-transplantation of the kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft-host disease.

[0242] It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention may be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions may be administered simultaneously, prior to, or subsequent to one or more other desired therapeutic agents or pharmaceutical procedures. The particular combination of therapies (therapeutic agents or procedures) used in the combination regimen will take into account the compatibility of the desired therapeutic agent and/or procedure with the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may achieve the desired effect on the same condition (e.g., the compounds of the invention may be administered simultaneously with another drug used to treat the same condition), or they may achieve different effects (e.g., control of any side effects). As used herein, an additional therapeutic agent that is normally administered to treat or prevent a particular disease or condition is said to be "appropriate for the disease or condition being treated.

[0243] Additional therapeutic agents that may be used in the methods of the invention include, but are not limited to, therapeutic agents for autoimmune, inflammatory, proliferative, or hyperproliferative diseases, or immunologically-mediated diseases, including rejection of transplanted organs or tissues and Acquired Immune Deficiency Syndrome (AIDS), where the additional therapeutic agent is appropriate for the disease being treated; the additional therapeutic agent is administered either together with the composition as a single dosage form or separately from the composition as part of multiple dosage forms.

[0244]For example, chemotherapeutic agents or other antiproliferative agents may be combined with the compounds of the invention to treat proliferative diseases and cancer. Other therapies or anti-cancer agents that may be used in combination with the anti-cancer agents of the present invention include surgery, radiation therapy (some examples are gamma irradiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy and systemic radioisotopes, to name a few), endocrine therapy, biological response modifiers (interferons, interleukins and Tumor Necrosis Factor (TNF), to name a few), hyperthermia and cryotherapy, drugs that attenuate any side effects (e.g., antiemetics) and other approved chemotherapeutic drugs including, but not limited to, alkylating drugs (nitrogen mustards, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (methotrexate), purine and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, gemcitabine), fusioninhibitors (vinblastine, gemcitabine), and other chemotherapeutic agents, Vincristine, vinorelbine, paclitaxel), podophyllotoxin (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), nitrosoureas (nitrosourea mustard, cyclohexylnitrosourea), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), hormones (tamoxifen, leuprorelin acetate, flutamide, and megestrol), Gleevec^TMDoxorubicin, dexamethasone, and cyclophosphamide. For a more complete discussion of the latest cancer therapies, see http:// www.nci.nih.gov/, FDA approved list of tumor drugsTable http:// www.fda.gov/cd/cancer/drug frame. htm and The Merck Manual, seven eenth ed.1999, The entire contents of which are incorporated herein by reference.

[0245]Other examples of drugs that may also be combined with the inhibitors of the invention include, but are not limited to: therapeutic agents for Alzheimer's disease, e.g. Aricept^®And Excelon^®(ii) a Therapeutic agents for parkinson's disease, such as levodopa/carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; drugs for treating Multiple Sclerosis (MS), e.g. interferon-beta (e.g. Avonex)^®And Rebif^®)、Copaxone^®And mitoxantrone; therapeutic agents for asthma, e.g. albuterol and Singulair^®(ii) a Drugs for the treatment of schizophrenia, such as reptile, visfate, serekon and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immune modulating 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 antiparkinson agents; drugs for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; drugs for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; drugs for treating hematological disorders, such as corticosteroids, antileukemic agents and growth factors; and drugs for the treatment of immunodeficiency disorders, such as gamma globulin.

[0246] The amount of additional therapeutic agent in the compositions of the present invention will not exceed the amount normally administered in compositions containing the therapeutic agent as the only active ingredient. Preferably, the amount of the additional therapeutic agent in the presently disclosed compositions will be from about 50% to 100% of the content in typical compositions containing the drug as the sole therapeutically active ingredient.

[0247] The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, prosthetic valves, vascular grafts, stents and catheters. Thus, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as generally described above and as described in classes and subclasses herein, and a carrier suitable for coating said implantable device. In another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device.

[0248] Vascular stents, for example, 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 mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Suitable coatings and general methods of making coated implantable devices are 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 copolymers and mixtures thereof. The coating may optionally be further covered with a surface layer of a suitable fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof to impart controlled release characteristics to the composition.

[0249] Another aspect of the invention relates to a method of inhibiting Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) activity in a biological sample or in a patient, comprising administering to said patient or contacting said biological sample with a compound of formula I or a composition comprising said compound. The term "biological sample" as used herein refers to a sample that is external to a living organism, including without limitation cell cultures and extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0250] Inhibition of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

Examples

[0251] The term "rt (min)" as used herein means the HPLC retention time in minutes associated with a compound. Unless otherwise indicated, the HPLC method used to obtain the reported retention times was as follows:

column: ace 5C 8, 15cm × 4.6mm id

Gradient: 0-100% acetonitrile + methanol (50: 50) (20mM Tris phosphate, pH7.0)

Flow rate: 1.5ml/min

And (3) detection: 225nm

Example 1

[0252] 4-tert-butyl-N- (6-oxo-1, 6-dihydro- [3, 4' ] bipyridinyl-5-yl) -benzamide I-11

[0253]Aminolone (Aminonone) (200mg, 1.07mmol) was suspended in pyridine (5mL) and 4-tert-butylbenzoyl chloride (209. mu.L, 1.07mmol) was added. The reaction mixture was stirred at room temperature overnight. The solid was filtered, washed with MeOH to give the title compound as a pink solid (33mg, 9% yield). MS (ES)⁺)m/e＝348.¹H NMR(DMSO-d₆)δH1.43(9H，s)，7.57-7.62(4H，m)，7.81(1H，s)，7.88(2H，d)，8.59(2H，d)，8.78(1H，d)，9.32(1H，s)，12.61(1H，s).

Example 2

[0100] N- (1, 2-dihydro-2-oxo-5- (pyridin-4-yl) pyridin-3-yl) -4- (piperidin-1-yl) benzamide I-68

[0254] 4-bromo-N- (1, 2-dihydro-2-oxo-5- (pyridin-4-yl) pyridin-3-yl) benzamide (30mg, 0.081mmol) I-20 was placed in a microwave tube equipped with a stir bar. NMP (0.75mL) was added followed by piperidine (1.5 mL). The reaction vessel was heated in a microwave at 160 ℃ for 2 hours. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (13mg, 43% yield).

MS(ES⁺)m/e＝375.¹H NMR(DMSO-d₆)δH 1.54-1.65(6H，m)，3.30-3.38(4H，m)，7.02(2H，d)，7.61(2H，d)，7.72-7.80(1H，m)，7.78(2H，d)，8.59(2H，d)，8.77(1H，d)，9.13(1H，s)，12.58(1H，bs).

[0255]A variety of other compounds of formula I are prepared by methods substantially similar to those described herein. The identification data for these compounds are summarized in Table I-A below, including HPLC, LC/MS (Observation) and¹h NMR data.

[0256]¹The H NMR data are summarized in Table I-A below, in which¹H NMR data were obtained in DMSO at 400MHz and were found to be consistent with the structure unless otherwise indicated. The compound numbers correspond to the compound numbers listed in table 1.

Table I-a. identification data for selected compounds of formula I

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
				1	292	7.5	(CDCl3)7.02-7.65(6H，m)，7.95-7.99(2H，m)，8.69-8.70(2H，m)，9.11(1H，brs)，9.16(1H，brs)，11.43(1H，brs)
2	322	7.7	3.85(3H，s)，7.10(2H，d)，7.61(2H，d)，7.80(1H，s)，7.93(2H，d)，8.58(2H，d)，8.75(1H，m)，9.28(1H，s)，12.60(1H，s)
				3	306	7.5	3.85(2H，s)，7.19-7.34(5H，m)，7.52(2H，d)，7.70(1H，s)，8.54(1H，d)，8.72(1H，s)，9.58(1H，s)，12.45(1H，s)

Compound number I-	M+1(obs)	Rt(nin)	1H-NMR
				4	298	8.1	1.25-1.40(5H，m)，1.64(1H，brd)，1.72(2H，brd)，1.80(2H，brd)，2.60-2.67(1H，m)，7.55(2H，d)，7.71(1H，s)，8.55(2H，d)，8.72(1H，s)，9.18(1H，s)，12.40(1H，brs)
5	340	8.2	4.86(2H，s)，7.58-7.65(4H，m)，7.83(1H，s)，7.97(2H，m)，8.59(2H，m)，8.76(1H，s)，9.44(1H，s)，12.63(1H，brs)
				6	320	8.7	1.22(3H，t)，2.70(2H，q)，7.41(2H，d)，7.61(2H，d)，7.81(1H，d)，7.87(2H，d)，8.58(2H，d)，8.77(1H，d)，9.33(1H，s)，12.62(1H，brs)
7	342	8.7	7.62-7.69(4H，m)，7.84(1H，s)，8.02(2H，t)，8.10(1H，d)，8.16(1H，d)，8.59-8.62(3H，m)，8.82(1H，s)，9.59(1H，s)，12.65(1H，s)
				8	306	8.0	2.40(3H，s)，7.37(2H，d)，7.86(2H，d)，8.01(2H，d)，8.09(1H，s)，8.75(2H，d)，8.83(1H，d)，9.39(1H，s)，12.88(1H，s)
9	317	7.4	7.62(2H，d)，7.87(1H，s)，8.04(2H，d)，8.11(2H，d)，8.59(2H，d)，8.72(1H，s)，9.72(1H，s)，12.63(1H，s)
				10	334	9.2	0.91(3H，t)，1.62(2H，m)，2.64(2H，t)，7.38(2H，d)，7.61(2H，d)，7.81(1H，s)，7.87(2H，d)，8.59(2H，d)，8.77(1H，d)，9.33(1H，s)，12.61(1H，s)
12	368	9.3	7.44(1H，t)，7.53(2H，t)，7.63(2H，d)，7.77(2H，d)，7.84(1H，d)，7.88(2H，d)，8.05(2H，d)，8.60(2H，d)，8.79(1H，d)，9.47(1H，d)，12.64(1H，brs)
				13	306	8.2	2.41(3H，s)，7.44-7.48(2H，m)，7.74-7.78(2H，m)，8.21-8.25(3H，m)，8.82-8.86(3H，m)，9.41(1H，s)，13.02(1H，s)
14	336	8.3	1.37(3H，t)，4.12(2H，q)，7.19(1H，d)，7.44-7.51(3H，m)，7.61(2H，d)，7.83(1H，d)，8.59(2H，d)，8.74(1H，d)，9.37(1H，s)，12.61(1H，s)
				15	374	8.6	7.60-7.84(3H，m)，8.05-8.26(5H，m)，8.76-8.84(3H，m)，9.73(1H，s)，13.00(1H，s)
16	376	9.0	7.66(1H，d)，7.72(1H，t)，7.93(1H，s)，8.02(1H，d)，8.20(2H，d)，8.26(1H，s)，8.81-8.83(3H，m)，9.78 1H，s)，12.99(1H，s)

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
				17	390	8.8	4.00(3H，s)，7.43(1H，d)，8.14-8.28(5H，m)，8.74-8.82(3H，m)，9.75(1H，s)，12.93(1H，brs)
18	376	9.0	7.55-7.57(2H，m)，8.09-8.11(2H，m)，8.18-8.19(2H，m)，8.23(1H，m)，8.81-8.83(3H，m)，9.66(1H，s)，12.97(1H，s)
				19	320	8.0	2.79-2.92(4H，m)，7.18(1H，m)，7.28-7.30(4H，m)，8.13-8.14(3H，m)，8.75-8.79(2H，m)，8.87(1H，s)，9.64(1H，s)，12.82(1H，s)
20	372	8.6	7.61(2H，dd)，7.77(2H，d)，7.84(1H，d)，7.90(2H，d)，8.58(2H，dd)，8.73(1H，d)，9.52(1H，s)，12.61(1H，brs)
				21	350	8.7	1.30(6H，s)，4.75(1H，m)，7.07(2H，d)，7.91(2H，d)，8.20-8.21(3H，m)，8.82-8.86(3H，m)，9.32(1H，s)，12.98(1H，s)
22	384	9.3	7.11-7.15(4H，m)，7.25(1H，m)，7.45-7.49(2H，m)，7.94-8.02(4H，m)，8.09(1H，s)，8.70-8.82(2H，m)，8.82(1H，m)，9.40(1H，s)，12.86(1H，s)
				23	332	8.5	1.31(1H，m)，1.48(1H，m)，2.37(1H，m)，2.79(1H，m)，7.16-7.22(3H，m)，7.28-7.32(2H，m)，8.12-8.14(3H，m)，8.80(2H，d)，8.87(1H，m)，9.99(1H，s)，12.81(1H，s)
24	374	10.3	1.27(1H，m)，1.40-1.49(4H，m)，1.72(1H，m)，1.80-1.82(4H，m)，2.60(1H，m)，7.41-7.44(3H，m)，7.86-7.92(6H，m)，8.79(1H，s)，9.33(1H，s)，12.70(1H，s)
				25	326	7.7	7.40-7.67(6H，m)，7.83(1H，s)，8.59(2H，d)，8.80(1H，d)，9.67(1H，s)，12.6(1H，s)
26	293	6.1	7.58-7.63(3H，m)，7.86(1H，s)，8.31(1H，d)，8.59(2H，d)，8.74(1H，d)，8.78(1H，d)，9.10(1H，s)，9.74(1H，s)，12.6(1H，s)
				27	326	8.4	7.61-7.65(4H，m)，7.84(1H，d)，7.98(2H，d)，8.58(2H，d)，8.73(1H，d)，9.52(1H，s)，12.62(1H，bs)
28	426	6.7	2.93(3H，s)，3.17(3H，s)，7.62(2H，d)，7.77(1H，d)，7.85(2H，d)，7.93(2H，d)，8.27(1H，s)，8.59(2H，d)，8.75(1H，d)，9.60(1H，s)，12.61(1H，bs)
				29	293	7.4	7.62(2H，d)，7.74(1H，m)，7.83(1H，

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
							m)，8.13(1H，m)，8.20(1H，m)，8.60(2H，d)，8.78(1H，d)，8.92(1H，d)，10.76(1H，s)，12.68(1H，s)
30	327	7.1	7.61(2H，dd)，7.70(1H，d)，7.86(1H，d)，8.34(1H，dd)，8.58(2H，d)，8.71(1H，d)，8.93(1H，d)，9.87(1H，s)，12.60(1H，brs)
				31	327	-	7.35(1H，m)，7.70(2H，m)，7.80(2H，m)，8.00(1H，s)，8.68(2H，m)，8.90(1H，s)，9.80(1H，m)
32	327	-	7.55(2H，m)，7.70(1H，m)，7.90(2H，brs)，8.05(1H，brs)，8.70(2H，m)，8.90(1H，s)，9.80(1H，m)
				33	327	-	7.55(1H，m)，7.65(2H，m)，7.90(2H，m)，8.09(1H，s)，8.74(3H，m)，9.7(1H，s)
34	297	-	7.23(1H，m)，7.90(1H，s)，8.05(1H，s)，8.20(3H，m)，8.75(1H，s)，8.80(2H，m)，9.57(1H，s)
				35	281	-	6.75(1H，m)，7.35(1H，m)，7.90(2H，m)，8.05(2H，m)，8.70(2H，m)，8.75(1H，s)，9.23(1H，s)
36	377	-	7.65(1H，m)，8.15(2H，m)，8.20(1H，m)，8.80(2H，m)，8.85(1H，s)，10.00(1H，s)7.75(2H，m)，
				37	316	-	7.60(2H，s)，7.76(1H，m)，7.85(1H，s)，8.10(1H，m)，8.25(1H，m)，8.41(1H，s)，8.58(2H，m)，8.75(1H，s)，9.85(1H，s)
38	369	-	(CD3OD)3.20(3H，s)，7.20(1H，s)，7.70(1H，s)，8.20-8.40(6H，m)，8.70(2H，d)，8.80(1H，d)
				39	310	-	7.40(2H，m)，8.10(2H，m)，8.20(3H，m)，8.80(3H，m)，9.60(1H，s)
40	372	8.6	7.54(1H，t)，7.58-7.65(2H，m)，7.80-7.88(2H，m)，794(1H，d)，8.13(1H，s)，8.57-8.63(2H，m)，8.73(1H，s)，9.62(1H，s)
				41	335	-	-
42	359	-	-
				43	360	-	7.80(1H，m)，8.00(1H，m)，3.18(2H，m)，8.25(3H，m)，8.80(3H，m)，9.85(1H，s)
44	309	-	7.42(2H，m)，7.55(2H，m)，7.65(1H，m)，7.80(1H，s)，8.00(1H，m)，8.60(2H，m)，8.90(1H，s)，9.70(1H，m)

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
				45	335	8.0	3.02(6H，s)，6.80(2H，d)，7.60(2H，dd)，7.75-7.80(3H，m)，8.58(2H，d)，8.77(1H，d)，9.11(1H，s)，12.57(1H，brs)
46	398	-	(CDCl3)5.20(2H，s)，7.10(3H，d)，7.50(5H，m)，8.00(3H，m)，8.70(2H，d)，9.10(2H，d)
				47	307	-	6.70(2H，d)，7.40(2H，d)，7.60(2H，m)，8.00(1H，s)，8.40(2H，d)，8.50(1H，s)，9.50(1H，s)，
48	348	-	2.10(3H，s)，7.60(2H，d)，7.70(3H，m)，7.90(2H，d)，8.60(2H，d)，8.80(1H，s)，9.30(1H，s)，10.30(1H，s)
				49	348	-	2.10(3H，s)，7.50(1H，m)，7.60(3H，s)，7.80(1H，s)，7.90(2H，d)，8.20(1H，s)，8.60(2H，d)，8.80(1H，s)，9.30(1H，s)，10.20(1H，s)
50	372	-	9.00(1H，s)，8.70(1H，s)，8.60(2H，d)，7.80(2H，d)，7.75(2H，d)，7.60(2H，d)，7.40-7.50(3H，m)，7.30(1H，t)，2.70(3H，s)
				51	382	-	7.10(1H，d)，7.45(2H，d)，7.50(3H，m)，7.60(2H，m)，7.70(2H，d)，7.80(1H，d)，8.60(2H，d)，8.70(1H，d)，9.30(1H，s)
52	376	-	-
				53	358	-	-
54	373	-	-
				55	-	-	-
56	256	-	0.80(4H，m)，2.20(1H，m)，7.90(2H，m)，7.95(1H，s)，8.70(2H，m)，8.78(1H，s)，9.75(1H，s)
				57	311	-	7.55(1H，m)，7.90(2H，m)，8.10(1H，m)，8.40(2H，m)，8.70(2H，m)，9.90(1H，s)，10.0(1H，s)
58	359	-	7.43(1H，m)，7.65(1H，m)，7.85(3H，m)，8.05(1H，m)，8.25(1H，m)，8.70(4H，m)，8.95(1H，brs)，10.20(1H，s)
				59	311	-	7.65(1H，s)，7.80(1H，m)，7.92(2H，m)，8.10(1H，brs)，8.45(1H，m)，8.75(3H，m)，9.90(1H，s)
60	324	-	1.35(3H，t)，2.20(3H，s)，4.45(2H，q)，6.80(1H，s)，7.95(2H，m)，8.05(1H，brs)，8.70(3H，m)，9.20(1H，s)
				61	409	-	-
62	-	-	3.90(3H，s)，6.90(1H，d)，7.40(2H，d)，7.50(1H，s)，7.90(2H，d)，8.00(1H，s)，

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
							8.70(2H，d)，8.80(1H，s)，9.20(1H，s)，9.80(1H，s)
63	327	-	2.60(2H，s)，6.70(1H，s)，8.00(1H，s)，8.10(2H，d)，8.60(1H，s)，8.80(2H，d)
				64	254	-	3.00(3H，s)，7.80(1H，s)，7.95(1H，s)，8.00(2H，d)，8.50(1H，s)，8.70(2H，d)
65	359	-	1.30(3H，t)，2.80(2H，q)，6.80(1H，s)，7.10(1H，m)，7.40(2H，d)，7.50(1H，s)，7.60(2H，d)，7.80(1H，m)，8.60(2H，d)，11.40(1H，s)
				66	407	-	1.50(9H，s)，7.40(1H，m)，7.50(1H，d)，7.60(2H，d)，7.70(1H，m)，7.80(1H，s)，8.10(1H，s)，8.60(2H，d)，8.80(1H，s)，9.30(1H，s)，9.60(1H，s)
67	412	-	3.80(2H，s)，5.20(2H，s)，6.90(1H，m)，7.10(1H，d)，7.20-7.30(5H，m)，7.40(2H，d)，7.50(2H，d)，7.70(1H，s)，8.60(2H，d)，8.70(1H，s)，9.25(1H，s)
				69	361	8.8	1.96-2.00(4H，m)，3.29-3.35(4H，m)，6.63(2H，d)，7.60(2H，d)，7.75-7.79(3H，m)，8.58(2H，d)，8.77(1H，d)，9.08(1H，s)，12.45(1H，brs)
70	390	7.4	2.23(3H，s)，2.43-2.48(4H，m)，3.28-3.34(4H，m)，7.05(2H，d)，7.60(2H，d)，7.76-7.84(3H，m)，8.58(2H，d)，8.77(1H，d)，9.16(1H，s)，12.58(1H，brs)
				71	376	6.3	2.81-2.86(4H，m)，3.20-3.26(4H，m)，7.02(2H，d)，7.60(2H，d)，7.75-7.82(3H，m)，8.58(2H，d)，8.77(1H，d)，9.14(1H，s)
72	391	7.1	1.38-1.48(2H，m)，1.76-1.84(2H，m)，3.00-3.07(2H，m)，3.66-3.76(3H，m)，4.73(1H，bs)，7.03(2H，d)，7.54(2H，d)，7.75(2H，d)，7.85(1H，d)，8.52(2H，d)，8.68(1H，d)，9.28(1H，brs)
				73	377	7.5	3.25-3.29(4H，m)，3.72-3.77(4H，m)，7.06(2H，d)，7.60(2H，dd)，7.78(1H，d)，7.82(2H，d)，8.58(2H，dd)，8.76(1H，d)，9.18(1H，s)，12.56(1H，brs)
74	476	7.0	0.95(6H，t)，2.39-2.56(12H，m)，3.26-3.39(4H，m)，7.03(2H，d)，7.60(2H，d)，7.75-7.82(3H，m)，8.58(2H，d)，8.77(1H，d)，9.15(1H，s)
				75	444	6.8	1.47-1.59(2H，m)，1.63-1.86(4H，m)，1.92-2.06(2H，m)，2.89(2H，t)，3.26-3.39(5H，m)，3.82-3.98(2H，m)，7.06

Compound number I-	M+1(obs)	Rt(min)	1H-NMR
							(2H，d)，7.60(2H，d)，7.76-7.82(3H，m)，8.59(2H，d)，8.77(1H，d)，9.15(1H，s)，12.58(1H，brs)
76	389	9.5	1.44-1.49(4H，m)，1.70-1.77(4H，m)，3.50-3.56(4H，m)，6.79(2H，d)，7.59(2H，d)，7.73-7.77(3H，m)，8.57(2H，d)，8.76(1H，d)，9.08(1H，s)
				77	449	7.8	1.69(2H，quintet)，2.36(2H，t)，3.22(3H，s)，3.27-3.38(10H，m)，7.04(2H，d)，7.60(2H，d)，7.76-7.82(3H，m)，8.58(2H，d)，8.76(1H，d)，9.16(1H，s)，12.42(1H，vbrs)
78	390	6.4	1.74-1.81(2H，m)，2.62(2H，t)，2.85(2H，t)，3.29-3.37(2H，m)，3.53(2H，t)，3.61(2H，t)，6.81(2H，d)，7.59(2H，d)，7.72-7.76(3H，m)，8.58(2H，d)，8.77(1H，d)，9.07(1H，s)
				79	392	6.5	1.68(2H，m)，2.14(6H，s)，2.29(2H，t)，3.09(2H，dt)，6.41-6.48(1H，m)，6.63(2H，d)，7.50-7.54(2H，m)，7.66(2H，d)，7.82-7.86(1H，m)，8.46-8.51(2H，m)，8.63-8.68(1H，m)，9.21(1H，brs)
80	364	6.0	1.63(2H，m)，2.65(2H，t)，3.13(2H，dt)，6.50(1H，t)，6.65(2H，d)，7.58(2H，d)，7.68(2H，d)，7.76(1H，d)，8.57(2H，d)，8.75(1H，d)，9.05(1H，s)
				81	464	7.0	2.50-2.58(6H，m)，3.25-3.29(4H，m)，3.42(2H，t),3.46-3.52(2H，m)，3.56(2H，t)，4.62(1H，brs)，7.04(2H，d)，7.60(2H，d)，7.77-7.82(3H，m)，8.58(2H，d)，8.76(1H，d)，9.17(1H，s)
82	391	7.4	3.19(4H，m)，3.5-4.0(maskedprotons)，4.43(2H，s)，7.67-7.71(2H，m)，7.97(2H，m)，8.04-8.10(3H，m)，8.74-8.82(3H，m)，9.51(1H，s)，12.87(1H，brs)
				83	390	6.4	(DMSO+D2O)3.00(4H，m)，3.22(4H，m)，4.03(2H，s)，7.58(2H，d)，7.96(2H，d)，8.09-8.12(3H，m)，8.69(2H，d)，8.79(1H，s)
84	392	6.7	(D2O)2.68(3H，s)，2.77(3H，s)，3.43-3.51(4H，m)，4.41(2H，s)，7.58(2H，d)，7.90(2H，d)，8.04(1H，m)，8.09(2H，m)，8.60(2H，m)，8.70(1H，m)
				85	406	6.7	(D2O)2.08(2H，m)，2.60(3H，s)，2.73(3H，s)，2.98(2H，m)，3.19(2H，m)，

TransformingCompound number I-	M+1(obs)	Rt(min)	1H-NMR
							4.35(2H，m)，7.55(2H，m)，7.88(2H，m)，8.01-8.10(3H，m)，8.59-8.69(3H，m)

[0257]Example 3

[0258] (5-iodo-2-methoxy-pyridin-3-yl) -carbamic acid benzyl ester

[0259] Benzyl (5-iodo-2-oxo-1, 2-dihydro-pyridin-3-yl) -carbamate (3.68g, 9.94mmol) was dissolved in chloroform (50mL) at room temperature under nitrogen in a dark place (foil wrap). Silver carbonate (3.70g, 13.2mmol) was added followed by methyl iodide (6.2mL, 99.4 mmol). The reaction mixture was stirred at room temperature for 48 hours. The silver salt was removed by filtration through a celite pad, washed with more chloroform, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound as a white solid (3.14g, 82% yield).

MS(ES⁺)m/e＝385.¹H NMR(CDCl₃)δH 3.97(3H，s)，5.23(2H，s)，7.15(1H，brs)，7.35-7.47(5H，m)，8.00(1H，s)，8.64 (1H，brs)

[0260]Example 4

[0261] [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridin-3-yl ] -carbamic acid benzyl ester

[0262]Benzyl (5-iodo-2-methoxy-pyridin-3-yl) -carbamate (1g, 2.6mmol), bis (pinacolato) diboron (727mg, 2.86mmol), KOAc (766mg, 7.81mmol) and Pd (Oac)₂(18mg, 3 mol%) was suspended in anhydrous DMF (20 mL). The system was degassed by slowly bubbling nitrogen through it for 30 minutes and then heated to 85 ℃ for 3 hours. The reaction was cooled to room temperature and diluted with water. The reaction mixture was extracted with EtOAc (× 3), over MgSO₄Dried, filtered and concentrated in vacuo. Purification by column chromatography gave the title compound as a white solid (501mg, 50% yield).

MS(ES⁺)m/e＝385.¹H NMR(DMSO-d₆)δH1.34(12H，s)，4.03(3H，s)，5.24(2H，s)，7.15(1H，brs)，7.34-7.46(5H，m)，8.21(1H，s)，8.63(1H，brs).

[0263]Example 5

[0264] [ 2-methoxy-5- (2-methylsulfanyl-pyrimidin-4-yl) -pyridin-3-yl ] -carbamic acid benzyl ester

[0265]Mixing [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2]]Bioxaborolan-2-yl) -pyridin-3-yl]Benzyl carbamate (377mg, 0.98mmol), 4-chloro-2-thiomethylpyrimidine (171. mu.L, 1.47mmol) and Pd (Pph)₃)₄(113mg, 10 mol%) was dissolved in toluene (15mL) and EtOH (3 mL). Adding Na₂CO₃(717mg, 6.77mmol) in water (6mL) and the reaction mixture was heated to reflux for 4 hours. After leaving to rt, the reaction mixture was diluted with water and extracted with EtOAc (× 3). The combined organic extracts were then dried over MgSO₄Dried, filtered and concentrated in vacuo. The residue was adsorbed on silica and purified by column chromatography to give the title compound as an off-white solid (261mg, 70% yield).

MS(ES⁺)m/e＝383.¹H NMR(DMSO-d₆)δH2.67(3H，s)，4.09(3H，s)，5.27(2H，s)，7.30-7.47(7H，m)，8.54(1H，d)，8.67(1H，s)，9.01(1H，brs).

[0266]Example 6

[0267] [5- (2-methylsulfanyl-pyrimidin-4-yl) -2-oxo-1, 2-dihydro-pyridin-3-yl ] -carbamic acid benzyl ester II-3

[0268] Benzyl [ 2-methoxy-5- (2-methylsulfanyl-pyrimidin-4-yl) -pyridin-3-yl ] -ate (20mg, 0.05mmol) was dissolved in 1, 4-dioxane (1mL) and water (300. mu.L). Concentrated HCl (100. mu.L) was added and the reaction mixture was heated to reflux for 30 min. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was isolated by filtration and dried under vacuum to give the title compound as a yellow solid (12.9mg, 67% yield).

MS(ES⁺)m/e＝369.¹HNMR(DMSO-d₆)δH2.56(3H，s)，5.20(2H，s)，7.38-7.46(5H，m)，7.60(1H，d)，8.10(1H，brd)，8.56(1H，d)，8.61(1H，s)，8.69(1H，s)，12.52(1H，brd).

[0269]Example 7

[0270] 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridin-3-ylamine

[0271]Mixing [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2]]Bioxaborolan-2-yl) -pyridin-3-yl]Benzyl carbamate (506mg, 1.32mmol) is dissolved in methanol (10 mL). Adding Pd (OH) in₂Carbon (51mg, 10 mol%), the reaction was degassed with nitrogen. The nitrogen atmosphere was replaced with hydrogen and the reaction mixture was stirred at room temperature for 5 hours. The palladium residue was removed by filtration through a celite pad, rinsing with more methanol. The filtrate was concentrated in vacuo to give the title compound as an off-white solid (319mg, 97% yield).

MS(ES⁺)m/e＝251.¹H NMR(DMSO-d₆)δH1.27(12H，s)，3.88(3H，s)，4.89(2H，brs)，7.13(1H，s)，7.64(1H，s).

[0272]Example 8

[0273] 4-tert-butyl-N- [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridin-3-yl ] -benzamide

[0274] [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -pyridin-3-ylamine (319mg, 1.28mmol) was dissolved in dichloromethane (5 mL). Triethylamine (117. mu.L, 1.40mmol) and 4-tert-butylbenzoyl chloride (274. mu.L, 1.40mmol) were added and the reaction stirred at room temperature for 10 min. The crude mixture was adsorbed on silica and purified by column chromatography to give the title compound as an off-white solid (274mg, 52% yield).

MS(ES⁺)m/e＝411.¹H NMR(CDCl₃)δH1.36(12H，s)，1.39(9H，s)，4.10(3H，s)，7.55(2H，d)，7.86(2H，d)，8.28(1H，s)，8.36(1H，brs)，9.07(1H，s).

[0275]Example 9

[0276] 4-tert-butyl-N- [ 2-methoxy-5- (2-methylsulfanyl-pyrimidin-4-yl) -pyridin-3-yl ] -benzamide

[0277]4-tert-butyl-N- [ 2-methoxy-5- (4, 4, 5, 5-tetramethyl- [1, 3, 2)]Bioxaborolan-2-yl) -pyridin-3-yl]Benzamide (274mg, 0.67mmol), 4-chloro-2-thiomethylpyrimidine (116. mu.L, 1.00mmol) and Pd (Pph)₃)₄(77mg, 10 mol%) was dissolved in toluene (10mL) and EtOH (2 mL). Adding Na₂CO₃(488mg, 4.61mmol) in water (4mL) and the reaction mixture was heated to reflux for 2 hours. After cooling to rt, the reaction mixture was diluted with water and extracted with EtOAc (× 3). The combined organic extracts were then dried over MgSO₄Dried, filtered and concentrated in vacuo. The residue was adsorbed on silica and purified by column chromatography to give the title compound as a yellow solid (120mg, 44% yield).

MS(ES⁺)m/e＝409.¹H NMR(CDCl₃)δH1.40(9H，s)，2.69(3H，s)，4.17(3H，s)，7.41(1H，d)，7.57(2H，d)，7.87(2H，d)，8.45(1H，brs)，8.56(1H，d)，8.76(1H，d)，9.46(1H，d).

[0278]Example 10

[0279] 4-tert-butyl-N- [5- (2-methylsulfanyl-pyrimidin-4-yl) -2-oxo-1, 2-dihydro-pyridin-3-yl ] -benzamide II-4

[0280] 4-tert-butyl-N- [ 2-methoxy-5- (2-methylsulfanyl-pyrimidin-4-yl) -pyridin-3-yl ] -benzamide (120mg, 0.29mmol) was dissolved in 1, 4-dioxane (6mL) and water (1.2 mL). Concentrated HCl (600. mu.L) was added and the reaction mixture was heated to reflux for 30 min. The reaction mixture was cooled to room temperature and water was added. The resulting precipitate was isolated by filtration and dried under vacuum. The crude solid was purified by flash chromatography to give the title compound as a pale tan solid (29mg, 25% yield).

MS(ES⁺)m/e＝395.¹H NMR(DMSO-d₆)δH1.33(9H，s)，2.58(3H，s)，7.59(2H，d)，7.64(1H，d)，7.88(2H，d)，8.21(1H，s)，8.58(1H，d)，9.11(1H，s)，9.30(1H，s)，12.72(1H，brs).

[0281]Example 11

[0282] N- (1, 2-dihydro-5- (2- (methylamino) pyrimidin-4-yl) -2-oxopyridin-3-yl) -4- (piperidin-1-yl) benzamide II-40

[0283] 4-bromo-N- (2-methoxy-5- (2- (methylamino) pyrimidin-4-yl) pyridin-3-yl) benzamide (50mg, 0.121mmol) was placed in a microwave tube equipped with a stir bar. NMP (1.5mL) was added followed by piperidine (1.5 mL). The reaction vessel was heated in a microwave at 160 ℃ for 2 hours. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (22mg, 45% yield).

MS(ES⁺)m/e＝405.¹H NMR(DMSO-d₆)δH 1.54-1.61(6H，m)，2.85(3H，brs)，3.28-3.36(4H，m)，6.95-7.12(4H，m)，7.77(2H，d)，8.00(1H，s)，8.27(1H，d)，9.02(IH，br s)，9.09(1H，s)，12.53(1H，brs).

[0284]By substantially similar to that described hereinMethods prepare a variety of other compounds of formula II. The identification data for these compounds are summarized in Table II-A below, including HPLC, LC/MS (Observation) and¹h NMR data.

[0285]¹The H NMR data are summarized in Table II-A below, in which¹H NMR data were obtained at 400Mhz in DMSO and were found to be consistent with the structure unless otherwise stated. The compound numbers correspond to the compound numbers listed in table 1.

Identification of selected Compounds of formula I in Table II-A

Compound number II-	M+1(obs)	Rt(nin)	1H-NMR
				1	321	9.5	5.26(2H，s)，7.28-7.51(11H，m)，7.85(1H，s)，8.56(1H，s)，12.49(1H brs)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				2	291	8.9	7.33-7.62(9H，m)，7.95(2H，m)，8.71(1H，s)，9.36(1H，s)，12.34(1H，brs)
3	See, example 6
				4	See, example 10
5	432	9.8	1.38(9H，s)，3.804.14(8H，brm)，6.85(1H，d)，7.16(1H，d)，7.54(2H，d)，7.60(1H，t)，7.88(2H，d)，7.94(1H，brs)，8.94(2H，brs)，9.01(1H，s)，9.28(1H，s)，12.47(1H，brd)
				6	391	10.4	1.33(9H，s)，3.11(6H，s)，6.62(1H，brd)，7.00(1H，d)，7.58(3H，d)，7.88(3H，d)，9.05(1H，brs)，9.27(1H，brs)，12.45(1H，brs)
7	377	9.8	1.33(9H，s)，2.91(3H，s)，6.94(1H，brd)，7.36-7.46(1H，m)，7.53-7.69(3H，m)，7.88(3H，d)，8.90(1H，brs)，9.36(1H，brs)，12.56(1H，brs)
				8	365	-	(CDCl3)1.25(9H，s)，7.05(2H，m)，7.25(1H，s)，7.45(2H，d)，7.50(2H，d)，7.85(2H，d)，8.95(1H，s)，9.05(1H br，s)
9	391	-	(MeOH-d4)1.35(1H，m)，1.47(4H，m)，1.80(1H，m)，1.90(4H，m)，2.62(1H，m)，7.15(2H，m)，7.40(3H，m)，7.55(2H，m)，7.90(2H，d)，8.85(1H，s)
				10	362	-	1.31(9H，s)，6.80(2H，m)，7.30(3H，m)，7.55(3H，m)，7.85(2H，m)，6.65(1H，m)，9.30(1H，brs)
11	372	-	1.33(9H，s)，7.58(2H，m)，7.75(2H，m)，7.80(1H，d)，7.85(4H，m)，8.70(1H，s)，9.40(1H，brs)
				12	353	-	1.33(9H，s)，7.05(2H，m)，7.18(1H，m)，7.30(1H，m),7.55(2H，m)，7.60(1H，s)，7.83(2H，m)，8.50(1H，m)，9.45(1H，brs)
13	392	-	1.30(9H，s)，7.55(3H，m)，7.80(1H，brs)，7.90(4H，m)，8.30(2H，m)，8.80(1H，s)，9.30(1H，s)
				14	378	9.5	1.33(9H，s)，2.91(3H，brs)，7.14(1H，brs)，7.59(2H，d)，7.88(2H，d)，8.17(1H，brs)，8.29(1H，d)，9.07(1H，brs)，9.30(1H，s)，12.70(1H，brs)
15	351	-	1.33(9H，s)，3.85(3H，s)，7.40(1H，s)，7.60(2H，d)，7.65(1H，s)，7.85(2H，d)，8.00(1H，s)，8.50(1H，s)，9.30(1H，brs)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				16	426	-	1.32(9H，s)，7.33(1H，s)，7.57(2H，d)，7.65(1H，m)，7.78(2H，d)，7.90(4H，m)，8.75(1H，s)，9.30(1H，s)
17	378	9.2	(80℃)3.01(3H，s)，6.90(1H，s)，7.60(2H，d)，7.88(2H，d)，8.04(1H，d)，8.34(1H，s)，8.81(1H，s)，9.22(1H，s)，12.58(1H，brs)
				18	392	9.6	1.32(9H，s)，3.30(6H，s)，7.16(1H，s)，7.59(2H，d)，7.90(2H，d)，8.18(1H，d)，8.73(1H，s)，8.80(1H，s)，9.40(1H，s)，12.99(1H，brs)
19	520	10.1	1.19(3H，t)，1.32(9H，s)，1.46(2H，m)，1.96(2H，m)，2.85-3.10(2H，m)，3.92-4.10(6H，m)，7.33(1H，brs)，7.58(2H，d)，7.88(2H，d)，8.32(3H，m)，9.06-9.16(1H，m)，9.29(1H，s)，12.87(1H，s)
				20	421	9.4	1.32(9H，s)，2.62(3H，m)，3.19(2H，m)，3.74(2H，m)，7.32(1H，brs)，7.59(2H，d)，7.89(2H，d)，8.17(1H，vbrs)，8.37(1H，brs)，8.87(2H，vbrs)，9.08(1H，s)，9.33(1H，s)，12.87(1H，brs)
21	392	10.0	1.33(9H，s)，3.23(6H，s)，7.16(1H，brs)，7.58(2H，d)，7.88(2H，d)，8.19(1H，brs)，8.34(1H，d)，9.12(1H，s)，9.29(1H，s)，12.70(1H，brs)
				22	392	9.8	1.21(3H，t)，1.32(9H，s)，3.50(3H，brm)，7.31(1H，brd)，7.58(2H，d)，7.88(2H，d)，8.30(1H，s)，8.31(1H，brs)，9.08(1H，s)，9.31(1H，s)，12.86(1H，brs)
23	406	10.1	1.24(6H，d)，1.33(9H，s)，4.12(2H，brm)，7.24(1H，brs)，7.58(2H，d)，7.88(2H，d)，8.26(1H，brs)，8.29(1H，d)，9.06(1H，s)，9.31(1H，s)，12.82(1H，brs)
				24	454	10.3	1.32(9H，s)，4.66(2H，brs)，7.22-7.35(4H，m)，7.49(1H，brs)，7.59(2H，d)，7.89(2H，d)，8.28(1H，brs)，8.32(1H，brs)，9.10(1H，brs)，9.31(1H，s)，12.84(1H，brs)
25	433	9.7	1.33(9H，s)，3.22(4H，brm)，4.04(4H，brm)，7.19(1H，d)，7.59(2H，d)，7.88(2H，d)，8.14(1H，brd)，8.43(1H，d)，8.93(1H，brs)，9.04(1H，s)，9.31(1H，s)，12.71(1H，brd)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				26	348	9.6	7.45(1H，t)，7.58(2H，d)，7.85(2H，d)，7.94-8.04(3H，m)，8.65(1H，d)，9.04(1H，s)，9.31(1H，s).
27	519	10.4	1.20(3H，t)，1.32(9H，s)，1.96-2.05(2H，m)，2.95-3.12(2H，m)，3.30-3.36(2H，m)，3.90-4.06(5H，m+q)，6.37(1H，d)，6.52-6.58(1H，m)，6.85(1H，d)，7.40(1H，t)，7.57(2H，d)，7.76-7.84(1H，m)，7.84(1H，d)，9.07(1H，s)，9.20(1H，s).
				28	448	9.5	1.32(9H，s)，1.76-7.82(2H，m)，2.07-2.20(2H，m)，3.07(2H，brm)，3.33-3.39(2H，m)，4.10(1H，m)，7.29(1H，brs)，7.49(2H，d)，7.88(2H，d)，8.27(1H，brs)，8.34(1H，s)，9.01-9.23(1H，brm)，12.82(1H，brs)
29	448	9.5	1.32(9H，s)，1.61-2.07(4H，m)，2.82-2.99(2H，brm)，3.19(1H，m)，3.39(1H，m)，4.21(1H，m)，7.23(1H，brs)，7.59(2H，d)，7.89(2H，d)，8.08-8.28(2H，brm)，8.35(1H，s)，9.06(1H，s)，12.79(1H，brs)
				30	433	9.5	1.32(9H，s)，2.07(1H，m)，2.25(1H，m)，3.28(2H，m)，3.37(1H，m)，3.47(1H，m)，4.55(1H，m)，7.25(1H，s)，7.59(2H，d)，7.88(2H，d)，8.16(1H，s)，8.35(1H，d)，9.08(1H，s)，9.14-9.26(1H，brm)，12.76(1H，brs)
31	433	9.5	1.32(9H，s)，2.09(1H，m)，2.27(1H，m)，3.27(2H，m)，3.39(1H，m)，3.45(1H，m)，4.49(1H，m)，7.28(1H，s)，7.61(2H，d)，7.88(2H，d)，8.19(1H，s)，8.36(1H，d)，9.12(1H，s)，9.14-9.35(1H，brm)，12.80(1H，brs)
				32	447	9.8	1.22-1.30(2H，m)，1.33(9H，s)，1.86-1.95(2H，m)，2.51-2.60(2H，m)，2.91-2.97(2H，m)，3.75-3.85(1H，m)，6.35(1H，d)，6.47(1H，d)，6.83(1H，d)，7.36(1H，t)，7.59(2H，d)，7.80(1H，s)，7.85(2H，d)，9.02(1H，s)，9.22(1H，s).
33	433	9.5	1.32(9H，s)，3.23(4H，s)，4.05(4H，s)，7.36(1H，s)，7.59(2H，d)，7.89(2H，d)，8.22(1H，s)，8.71(1H，s)，8.96(1H，s)，9.35(1H，s)，9.38(1H，brs)，12.86(1H，brs)

Compound number II-	M+1(obs)	Rt(nin)	1H-NMR
				34	349	9.4	1.32(9H，s)，7，59(2H，d)，7.88(2H，d)，7.98(1H，d)，8.22(1H，s)，8.76(1H，d)，9.17(2H，d)，9.30(1H，s)，12.71(1H，brs)
35	420	9.1	1.35(9H，s)，2.65(3H，s)，3.16-3.25(2H，m)，3.63-3.70(2H，m)，7.03(1H，d)，7.60(2H，d)，7.90(2H，d)，8.80-8.95(2H，m)，9.00(1H，s)，9.32(1H，s)
				36	409	10.1	1.33(9H，s)，2.37(3H，s)，2.55(3H，s)，7.55(2H，d)，7.69(1H，s)，7.85(2H，d)，8.48(1H，s)，8.78(1H，s)，9.25(1H，s).
37	311	-	5.17(2H，s)，7.35(7H，m)，7.85(2H，brs)，8.10(1H，s)，8.37(1H，brs)
				38	421	8.7	1.32(9H，s)，2.58-2.60(3H，m)，3.13-3.15(2H，m)，3.75-3.76(2H，m)，6.94(1H，brs)，7.59(2H，d)，7.89(2H，d)，8.11(1H，brs)，8.69(1H，s)，8.84(1H，s)，8.93(2H，brs)，9.36(1H，s)，12.85(1H，brs)
39	433	8.7	1.32(9H，s)，1.99(1H，m)，2.38(1H，m)，3.16(1H，m)，3.30(1H，m)，3.37(1H，m)，3.52(1H，m)，4.64(1H，m)，6.93(1H，s)，7.61(2H，d)，7.88(2H，d)，8.09(1H，brs)，8.69(1H，s)，8.85(1H，s)，9.33(2H，brs)，9.36(1H，s)，12.82(1H，brs)
				41	424	10.1	1.31(9H，s)，2.83(3H，s)，6.49(1H，s)，7.46-7.61(3H，m)，7.81-7.98(3H，m)，8.90(1H，brs)，9.27(1H，s)，12.48(1H，brs)
42	376	9.7	1.31(9H，s)，2.11(3H，s)，4.95(2H)，6.41-6.51(2H，m)，6.89(1H，m)，7.05(1H，s))，7.58(2H，m)7.85(2H，m)，8.32(1H，s)，9.25(1H)
				43	390	10.2	1.36(9H，s)，2.15(3H，s)，2.67(3H，m)，5.55(1H，m)，6.36-6.51(2H，m)，6.97(1H，m)，7.08(1H，s))，7.58(2H，m)7.85(2H，m)，8.35(1H，s)，9.25(1H)
44	391	10.5	1.31(9H，s)，2.22(3H，s)，3.75(3H，s)，6.78-6.89(2H，m)，7.18-7.22(2H，m，7.58(2H，m)，7.85(2H，m)，8.35(1H，s)，9.29(1H)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				45	460	8.6	1.55-1.65(6H，m)，1.94(1H，m)，2.24(1H，m)，3.11(1H，m)，3.27-3.29(2H，m)，3.29-3.35(4H，m)，3.44(1H，m)，4.53(1H，m)，6.82(1H，s)，7.02(2H，d)，7.77(2H，d)，7.86-7.94(2H，m)，8.50(1H，s)，8.96-8.99(2H，m)，9.10(1H，s)，12.51(1H，brs)
46	405	8.9	1.50-1.60(6H，m)，2.84(3H，brs)，3.31-3.34(4H，m)，6.75(1H，s)，7.02(2H，d)，7.39(1H，brs)，7.77(2H，d)，7.92(1H，brs)，8.42(1H，s)，8.95(1H，s)，9.09(1H，s)，12.44(1H，brs)
				47	404	9.5	1.55-1.65(6H，m)，3.30-3.37(4H，m)，2.83(3H，s)，6.33(1H，d)，6.48-6.59(1H，brs)，6.84(1H，d)，7.00(2H，d)，7.43(1H，t)，7.72-7.80(3H，m)，9.00(1H，s)，9.06(1H，s).
48	432	10.1	1.21(6H，d)，1.55-1.63(6H，m)，3.30-3.38(4H，m)，3.99-4.09(1H，m)，6.33(1H，d)，6.38(1H，d)，6.76(1H，d)，6.99(2H，d)，7.36(1H，t)，7.72-7.78(3H，m)，8.93(1H，s)，9.05(1H，s).
				49	430	10.1	0.40-0.46(2H，m)，0.67-0.75(2H，m)，1.55-1.64(6H，m)，2.49-2.57(1H，m)，3.30-3.38(4H，m)，6.50(1H，d)，6.80(1H，s)，6.91(1H，d)，7.00(1H，d)，7.49(1H，t)，7.71-7.79(3H，m)，8.97(1H，s)，9.05(1H，s).
50	480	10.3	1.55-1.64(6H，m)，3.30-3.38(4H，m)，4.53(2H，d)，6.37(1H，d)，7.83(1H，d)，7.00(2H，d)，7.15-7.22(2H，m)，7.25-7.33(2H，m)，7.35-7.44(3H，m)，7.70-7.77(3H，m)，8.96(1H，s)，9.05(1H，s)
				51	447	8.7	1.53-1.64(6H，m)，2.30(3H，s)，2.63-2.70(2H，m)，3.30-3.44(6H，m)，6.35(1H，d)，6.45-6.52(1H，m)，6.80(1H，d)，7.00(2H，d)，7.38(1H，t)，7.70-7.78(3H，m)，8.95(1H，s)，9.05(1H，s).
52	422	9.8	1.59(6H，brs)，2.54(3H，s)，3.23(4H，brs)，7.01(2H，d)，7.36(1H，brs)，7.71(2H，d)，8.33(1H，brs)，8.39(1H，brs)，8.84(1H，brs)，9.39(1H，brs)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				53	432	10.2	1.30(6H，d)，1.60(6H，brs)，2.46(4H，brs)，3.10(1H，m)，3.31(3H，s)，7.02(2H，d)，7.60(1H，s)，7.77(2H，d)，8.10(1H，brd)，9.11(2H，brsd)，12.61(1H，brd)
54	377	10.3	1.34(9H，s)，3.85(3H，s)，6.91(1H，m)，7.10-7.16(2H，m)，7.36(1H，m)，7.58(3H，m)，7.89(2H，m)，8.71(1H，s)，9.30(1H)
				55	362	9.7	1.31(9H，s)，2.55(3H，s)，7.41(1H，s)，7.56(2H，m)，7.89(3H，m)，8.40(1H，s)，8.70-8.78(2H，m)，9.35(1H)
56	405	9.1	1.62(6H，m)，2.90(3H，m)，6.34(1H，d)，7.04(2H，d)，7.38(1H，brm)，7.75(2H，d)，8.09(2H，m)，9.08(1H，s)，9.22(1H，s)，12.35(1H，s)
				57	420	9.7	1.79(3H，t)，2.01(6H，brs)，3.70(4H，brs)，4.82(2H，m)，7.43(2H，d)，7.96(1H，m)，8.19(2H，d)，8.56(1H，brs)，8.96(1H，m)，9.50(2H，d)，13.06(1H，brs)
58	462	9.4	1.53(6H，m)，2.77(6H，m)，4.20-4.50(6H，m)，4.60-4.80(2H，m)，7.05(2H，m)，7.35(1H，m)，7.73(1H，m)，7.99(1H，m)，8.27(1H，m)，9.05(2H，m)，9.32(1H，brs)，9.93(1H，brs)，12.91(1H，brs)
				59	435	8.6	1.55-1.65(6H，m)，3.33-3.40(6H，m)，3.54(2H，m)，4.58(1H，brs)，6.90-7.02(4H，m)，7.76(2H，d)，7.98(1H，s)，8.26(1H，s)，8.99(1H，s)，9.08(1H，s)，12.50(1H，brs)
60	448	8.9	1.50-1.65(6H，m)，2.34(3H，s)，2.77-2.90(2H，m)，3.24-3.40(4H，m)，4.30-4.40(2H，m)，6.60(1H，m)，6.93-7.05(2H，m)，7.26-7.35(1H，m)，7.64-7.80(3H，m)，7.89(1H，s)，8.97(1H，s)，9.10(1H，s).
				61	476	9.7	1.56(6H，m)，2.46(3H，masked signal)，2.85(6H，m)，3.20-3.60(6H，m)，3.97(2H，m)，6.98-7.11(2H，m)，7.73(2H，brs)，8.04(1H，brs)，8.34(1H，brs)，9.07(2H，brs)，9.26(1H，brs)，12.6((brs)

Compound number II-	M+1(obs)	Rt(nin)	1H-NMR
				62	392	9.6	1.30(9H，s)，2.20(3H，s)，2.80(3H，d)，6.91(1H，brd)，7.55-7.61(3H，m)，7.85(2H，d)，8.16(1H，s)，8.75(1H，s)，9.26(1H，s)
63	448	8.7	1.60(6H，m)，2.62(3H，s)，3.16(2H，m)，3.33(4H，m)，3.62(2H，m)，7.01(1H，d)，7.10(1H，d)，7.16(1H，t)，7.77(2H，d)，8.04(1H，m)，8.33(1H，d)，8.58(2H，m)，9.06-9.09(2H，m)，12.6(1H，d)
				64	322	7.6	2.82-2.89(3H，m)，6.99(1H，d)，7.11(1H，d)，7.53-7.67(3H，m)，7.94(2H，d)，8.05(1H，s)，8.27(1H，d)，9.04(1H，s)，9.35(1H，s)，12.58(1H，d).
65	462	9.1	1.59(6H，m)，2.32(3H，s)，2.67(3H，s)，3.18(2H，m)，3.35-3.60(4H，m)，3.78(2H，m)，7.00-7.10(3H，m)，7.76(2H，d)，8.03(1H，s)，8.33(1H，d)，9.07(2H，m)
				66	433	9.8	1.21(3H，t)，1.59(6H，m)，2.54(2H，m)，2.85(3H，s)，3.39(4H，b m)，6.82(1H，s)，7.01(2H，d)，7.75(2H，d)，8.09(1H，s)，8.95(1H，s)
67	426	8.8	2.86(3H，br ss)，7.01(1H，d)，7.12(1H，d)，7.60(2H，dd)，7.66-7.76(1H，m)，7.79(2H，d)，7.88(2H，d)，8.06-8.12(3H，m)，8.28(1H，d)，9.05(1H，s)，9.55(1H，s)，12.60(1H，s)
				68	376	10.0	1.35(9H，s)，2.86(3H，s)，6.95(1H，m)，7.18(2H，m)，7.39(1H，m)，7.54(1H，s)，7.61(2H，d)，7.92(2H，d)，8.72(1H，s)，9.31(1H，s)
69	403	9.7	1.58(6H，s)，2.71(3H，s)，3.36(4H，m)，6.45(1H，m)，6.65-6.72(2H，m)，6.98(2H，d)，7.11(1H，t)，7.37(1H，s)，7.75(2H，d)，8.67(1H，s)
				70	434	9.0	1.53-1.62(6H，m)，3.30-3.42(4+2H，2xm)，3.51-3.60(2H，m)，4.72(1H，t)，6.38(1H，d)，6.53(1H，t)，6.80(1H，d)，6.99(2H，d)，7.37(1H，t)，7.72-7.78(3H，m)，8.92(1H，s)，9.06(1H，s).
71	448	9.6	1.54-1.65(6H，m)，3.27(3H，s)，3.30-3.37(4H，m)，4.46-4.55(4H，m)，6.2(1H，d)，6.63(1H，t)，6.85(1H，d)，7.01(2H，d)，7.41(1H，t)，7.72-7.82(3H，m)，8.99(1H，s)，9.06(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				72	403	-	(CDCl3)1.7-1.2(6H，m)，1，85(4H，m)，2.55(1H，m)，3.80(3H，s)，6.90(2H，d)，7.15(2H，m)，7.30(2H，d)，7.40(2H，d)，7.85(2H，d)，8.95(1H，brs)，9.05(1H，brs)
73	396	10.2	1.3(9H，s)，2.3(3H，s)，7.3(1H，d)，7.4(1H，s)，7.6(2H，d)，7.8(1H，d)，7.9(2H，d)，8.6(1H，s)
				74	389	9.1	1.6(6H，s)，3.4(4H，m)，7.0(2H，brm)，7.2(1H，brm)，7.4-7.6(4H，m)，7.8(2H，d)，8.7(1H，s)
75	446	9.1	1.6(6H，s)，2.6(3H，s)，3.1(2H，m)，3.3(4H，m)，3.4(2H，m)，6.6(1H，m)，6.8(2H，m)，7.0(2H，m)，7.2(1H，t)，7.4(1H，s)，7.8(2H，m)，8.6(1H，s)，9.1(1H，s)
				76	449	8.6	1.59(6H，brs)，2.49(5H，brs)，3.33(4H，brs)，4.53(2H，brs)，7.00(2H，brd)，7.63(1H，brs)，7.75(2H，brs)，8.17(1H，brs)，8.57(1H，brs)，9.08(2H，brd)
77	406	6.3	2.85(3H，s)，3.17-3.20(4H，m)，3.44-3.50(4H，m)，6.97(1H，d)，7.05-7.12(3H，m)，7.85(2H，d)，8.01(1H，s)，8.27(1H，d)，9.02(1H，bs)，9.15(1H，s).
				78	448	7.7	1.01(6H，d)，2.53-2.59(4H，m)，2.66-2.69(1H，m)，2.85(3H，bs)，3.26-3.36(4H，m)，6.97(1H，d)，7.03(2H，d)，7.09(1H，d)，7.78(2H，d)，8.00(1H，s)，8.27(1H，d)，9.03(1H，s)，9.10(1H，s)，12.51(1H，brs).
79	478	7.8	1.63-1.75(2H，m)，2.30-2.41(2H，m)，2.82-2.90(4H，m)，3.22(3H，s)，3.28-3.39(6H，m)，6.94-7.12(4H，m)，7.79(2H，d)，8.00(1H，s)，8.27(1H，d)，9.03(1H，s)，9.11(1H，s)，12.53(1H，d).
				80	474	7.9	1.66-1.73(4H，m)，1.89-2.09(4H，m)，2.31-2.54(4H，m)，2.57-2.68(2H，m)，2.88(3H，bs)，3.11-3.19(1H，m)，3.39-3.48(1H，m)，3.91-3.99(1H，m)，6.66(2H，d)，6.97(1H，d)，7.10(1H，d)，7.77(2H，d)，7.99(1H，s)，8.27(1H，d)，9.03(2H，s)，12.49(1H，bs).

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				81	448	7.1	2.05(3H，s)，2.85(3H，s)，3.28-3.40(4H，m)，3.56-3.61(4H，m)，6.97(1H，d)，7.02-7.11(3H，m)，7.81(2H，d)，8.01(1H，s)，8.26(1H，d)，9.02(1H，s)，9.12(1H，s)，12.52(1H，brs).
82	386	6.5	1.02(9H，s)，2.82(3H，s)，3.35-3.39(8H，m)，6.90(1H，m)，7.05(1H，m)，7.86(2H，m)，8.24(1H，m)，8.68(1H，m)，12.38(1H，brs)
				83	379	-	1.31(9H，s)，2.05(2H，m)，2.35(2H，m)，2，72(2H，m)，6.17(1H，s)，7.55(2H，m)，7.60(1H，m)，7.88(2H，m)，8.65(1H，s)，9.25(1H，brs)
84	382	-	-
				85	392	-	(CDCl3)1.70-1.50(6H，m)，2.05(2H，m)，2.40(2H，m)，2.60(2H，m)，3.25(4H，m)，6.35(1H，s)，6.90(2H，m)，7.30(1H，s)，7.80(2H，m)，8.90(2H，d)
86	407	-	1.60(6H，s)，1.80(4H，m)，2.45(4H，m)，3.35(4H，m)，6.35(1H，s)，7.00(2H，m)，7.25(1H，m)，7.75(2H，m)，8.70(1H，s)，9.10(1H，s)
				87	378	-	(CDCl3)1.50-1.70(6H，m)，2.50(2H，m)，2.90(2H，m)，3.30(4H，m)，6.43(s，1H)，6.85(2H，m)，7.35(1H，s)，7.80(2H，m)，8.90(2H，d)
88	365	-	(CDCl3)1.25(9H，s)，7.05(2H，m)，7.25(1H，s)，7.45(2H，d)，7.50(2H，d)，7.85(2H，d)，8.95(1H，s)，9.05(1H，brs)
				89	394	-	1.60(8H，m)，1.85(3H，m)，2.20(2H，m)，3.25(4H，m)，4.30(1H，brs)，6.05(1H，s)，6.85(2H，m)，7.00(1H，s)，7.75(2H，m)，8.80(1H，m)，8.90(1H，m)
90	364.	-	-
				91	496	-	-
92	406	-	-
				93	433	9.6	1.21(3H, t), 1.60(6H, m), 2.54(2H, q), 2.87(3H, s), 3.3(4 masked protons s), 6.17 (1)H，s)，7.02(2H，d)，7.77(2H，d)，8.07(1H，s)，9.21(1H，s)
94	400	9.5	1.60(6H，m)，3.3(4masked protons)，7.02(2H，d)，7.70(1H，d)，7.77(2H，d)，8.09(1H，d)，8.39(1H，s)，8.84(1H，d)，9.13(1H，d)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				95	461	9.4	1.52-1.62(6H，m)，2.30(3H，s)，2.70(2H，t)，3.05(3H，s)，3.24-3.36(4H，m)，3.61(2H，t)，6.51(1H，d)，6.90(1H，d)，6.97(2H，d)，7.47(1H，t)，7.70(2H，d)，7.85(1H，s)，9.03(1H，s)，9.05(1H，s)
96	503	9.3	0.93(6H，t)，1.55-1.60(6H，m)，1，62-1.71(2H，m)，2.38-2.54(6H，m)，3.25-3.37(6H，m)，6.32(1H，d)，6.57-6.63(1H，m)，6.80(1H，d)，7.00(2H，d)，7.37(1H，t)，7.71-7.80(3H，m)，8.95(1H，s)，9.03(1H，s)
				97	428	9.2	2.88(3H，brs)，5.21(2H，s)，7.09(1H，d)，7.17(2H，d)，7.30-7.48(5H，m)，7.92(2H，d)，8.12(1H，brs)，8.28(1H，d)，9.03(1H，brs)，9.25(1H，s)，12.65(1H，brs)
98	412	9.4	2.85(3H，brs)，4.04(2H，s)，6.97(1H，d)，7.09(1H，d)，7.16-7.34(5H，m)，7.42(2H，d)，7.86(2H，d)，8.04(1H，s)，8.25(1H，d)，9.02(1H，brs)，9.28(1H，brs)
				99	400	9.2	1.59(6H, m), 3.3(4 masked protons s)7.02(2H, d), 7.76-7.78(3H, m), 8.54(1H, s), 8.70(1H, d), 8.94(1H, s), 9.07(1H, d)
100	377	6.1	2.77(4H，t)，3.57(4H，t)，6.88(1H，d)，7.60(2H，d)，7.78(1H，d)，8.00(1H，dd)，8.57(2H，d)，8.68(1H，d)，8.73(1H，d)
				101	475	9.1	1.56-1.63(6H，m)，1.82(3H，s)，3.22-3.29(2H，m)，3.30-3.37(6H，m)，6.36(1H，d)，6.63(1H，t)，6.99(2H，d)，7.41(1H，t)，7.73(2H，d)，7.81(1H，s)，7.95(1H，t)，9.00(1H，s)，9.07(1H，s)
102	413	9.5	1.60(6H，brs)，3.34(4H，brs)，6.60(1H，d)，7.03(3H，t)，7.08(1H，t)，7.14(1H，d)，7.16(1H，d)，7.36(1H，d)，7.77(2H，d)，8.79(1H，d)
				103	503	9.7	0.91(6H，m)，1.59(6H，m)，2.40-2.60(6H，m)，3.04(3H，s)，3.30-3.45(4H，m)，3.65(2H，m)，6.48(1H，m)，6.91(1H，m)，7.01(2H，d)，7.44(1H，m)，7.75-7.781(3H，m)，9.03(2H，d)，12.30(1H，brs)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				104	487	9.7	1.60(6H，m)，1.87-1.91(2H，m)，2.02(2H，m)，3.15(2H，m)，3.28-3.30(4H，m)，3.43-3.46(2H，m)，3.53-3.56(4H，m)，6.45(1H，d)，6.91(1H，brs)，6.97-7.10(2H，m)，7.49(1H，m)，7.75-7.81(3H，m)，9.07-9.12(2H，m)，9.51(1H，brs)，12.35(1H，m)
105	487	9.2	1.29-1.38(2H，m)，1.60(6H，m)，1.91-2.03(4H，m)，2.90-2.93(2H，m)，3.24-3.25(2H，m)，3.30-3.34(5H，m)，6.43(1H，d)，6.901(1H，d)，6.97-7.03(2H，m)，7.44(1H，m)，7.75-7.78(3H，m)，8.15 (1H，d)，8.49(1H，d)，9.06-9.08(2H，m).12.48(1H，brs)
				106	443	9.3	1.60(6H，m)，2.84-2.87(2H，m)，3.30-3.50(4H，m)，3.56-3.60(2H，m)，6.45(1H，d)，6.92(1H，d)，7.01-7.05(3H，m)，7.48(1H，m)，7.76(2H，m)，7.81(1H，d)，9.00(1H，d)，9.07(1H，s)，12.30(1H，s)
107	394	6.0	1.78-1.86(2H，m)，2.65-2.70(2H，m)，2.85-2.91(3H，m)，3.18(1.4H，t)，3.30(0.6H，t)，6.67(2H，d)，7.06(1H，d)，7.72(2H，d)，8.03-8.09(1H，m)，8.28(1H，d)，9.01(1H，s)，9.02-9.06(1H，m)
				108	476	9.6	0.85-0.95(6H，m)，1.51-1.62(6H，m)，1.65-1.77(1H，m)，2.82-2.90(1H，m)，3.24-3.35(4H，m)，4.06-4.15(1H，m)，4.25-4.33(1H，m)，6.68(1H，d)，7.00(2H，d)，7.31(1H，d)，7.66-7.76(3H，m)，7.87(1H，s)，9.02(1H，s)，9.06(1H，s)
109	413	10.0	1.60(6H，brs)，3.25(4H，brs)，6.52(1H，d)，7.01-7.10(4H，m)，7.36(2H，d)，7.64(1H，d)，7.75(2H，d)，8.65(1H，d)
				110	482	9.9	1.60(6H，brs)，3.35(4H，brs)，7.02(2H，d)，7.50(1H，s)，7.78(2H，d)，7.83(1H，s)，8.41(1H，s)，8.47(1H，brs)，9.01(1H，brs)
111	433	9.9	1.65-1.77(6H，m)，2.65(6H，s)，3.40-3.50(4H，m)，6.84(1H，d)，7.06(1H，d)，7.14(2H，d)，7.36(1H，s)，7.66(1H，t)，7.85-7.90(3H，m)，9.07(1H，s)，9.18(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				112	461	9.1	1.07(6H，s)，1，53-1，62(6H，m)，3.23-3.37(6H，2xm)，6.43(1H，d)，6.47(1H，t)，6.80(1H，d)，6.99(2H，d)，7.37(1H，t)，7.72(2H，d)，7.76(1H，s)，8.9891H，s)，9.04(1H，s)
113	390	8.6	1.60(6H，brs)，3.34(4H，brs)，6.08(1H，brd)，6.38(1H，d)，6.84(1H，s)，7.02(2H，d)，7.72-7.77(3H，m)，8.01(1H，d)，8.95(1H，s)
				114	405	9.1	1.60(6H, m), 2.87(3H, s), 3.3(4 masked protons s), 7.02(2H, d), 7.76(2H, d), 7.78(1H, s), 7.90(1H, d), 8.08(1H, s), 8.98(1H, d)
115	404	9.2	1.60(6H，s)，2.47(3H，s)，3.34(4H，s)，6.57(1H，s)，6.68(1H，d)，7.02(2H，d)，7.59(1H，s)，7.75(2H，d)，7.97(1H，d)，8.66(1H，s)
				116	389	9.7	1.60(6H，s)，2.37(3H，s)，3.35(4H，s)，7.02(2H，d)，7.12(1H，d)，7.66(1H，s)，7.76(2H，d)，7.89(1H，d)，8.85(1H，d)，9.12(1H，s)
117	458	10.5	1.46-1.54(2H，m)，1.57-1.60(8H，m)，1.68-1.70(2H，m)，1.96-2.02(2H，m)，3.35(4H，m)，4.15(1H，m)，6.37(1H，m)，6.56(1H，m)，6.82(1H，d)，7.02(2H，d)，7.41(1H，m)，7.75-7.80(3H，m)，8.98(1H，s)，9.07(1H，s)，12.3(1H，s)
				118	378	8.6	1.60(6H，s)，3.35(4H，s)，3.64(3H，s)，7.01(3H，m)，7.28(1H，s)，7.75(3H，m)，8.38(1H，d)
119	517	10.0	0.86(3H，d)，0.94(3H，d)，1.45-1.55(2H，m)，1.52-1.64(6H，m)，1.65-1.75(1H，m)，2.57(3H，d)，3.32-3.42(4H，m)，4.29-4.38(1H，m)，6.45(1H，d)，6.65-6.74(1H，m)，6.81(1H，d)，7.00(2H，d)，7.40(1H，t)，7.72-.82(4H，m)，8.89(1H，s)，9.08(1H，s)
				120	501	9.7	0.95-1.10(3H，m)，1.53-1.75(9H，m)，1.78-2.65(4H，m)，2.85-3.18(3H，m)，3.30-3.37(4H，m)，3.55-3.68(1H，m)，6.38(1H，d)，6.5-6.85(1H，m)，7.00(2H，d)，7.37(1H，t)，7.69-7.78(3H，m)，8.93(1H，s)，9.04(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				121	405	8.9	1.60(6H，s)，3.34(4H，s)，4.60(2H，s)，7.02(2H，d)，7.34(1H，d)，7.63(1H，d)，7.76(2H，d)，7.82(1H，t)，7.93(1H，d)，9.02(1H，s)
122	348	8.3	2.87(3H，brs)，6.98(1H，d)，7.35-7.47(4H，m)，7.57(1H，d)，7.65(2H，d)，8.02(1H，s)，8.27(1H，d)，9.20(1H，brs)，9.62(1H，s)
				123	434	9.3	1.60(6H, m), 2.80(6H, 2s), 3.3(4 masked protons s), 6.05(1H, s), 6.41(1H, brs), 6.89(1H, brs), 7.02(2H, d), 7.77(2H, d), 7.85(1H, s), 8.88(1H, s)
124	432	9.2	1.54-1.63(6H，m)，2.85(3H，s)，3.25-3.40(4H，m)，7.00(2H，d)，7.70-7.82(4H，m)，7.91(1H，t)，8.40(1H，s)，8.89(1H，s)
				125	418	8.9	1.60(6H，s)，2.38(3H，s)，3.35(4H，s)，3.86(2H，s)，7.02(2H，d)，7.32(1H，d)，7.66(1H，d)，7.79(2H，d)，7.82(1H，t)，7.96(1H，d)，9.06(1H，d)
126	406	6.2	2.78-2.86(7H，m)，3.19-3.24(4H，m)，6.73(1H，s)，7.02(2H，d)，7.34(1H，brs)，7.77(2H，d)，7.98(1H，brs)，8.41(1H，s)，8.92(1H，brs)，9.16(1H，s)
				127	501	10.1	1.55-1.60(10H，m)，1.70(3H，s)，1.99(2H，m)，2.32(4H，m)，3.15(1H，m)，3.34(4H，m)，6.35(1H，d)，6.63(1H，s)，6.84(1H，d)，7.02(2H，d)，7.40(1H，m)，7.76-7.78(3H，m)，8.99(1H，s)，9.08(1H，s)，12.30(1H，s)
128	488	9.9	1.19-1.28(2H，m)，1.60(6H，m)，1.67-1.70(4H，m)，1.88-1.91(2H，m)，3.23-3.37(5H，m)，3.86-3.88(2H，m)，6.48(1H，s)，6.88(1H，m)，7.03(2H，d)，7.49(1H，m)，7.60-7.80(4H，m)，8.96(1H，s)，9.09(1H，s)，12.40(1H，s)
				129	447	9.1	1.16(3H，d)，1.53-1.63(6H，m)，2.55-2.73(2H，m)，3.25-3.40(4H，m)，3.85-3.96(1H，m)，6.35(1H，d)，6.82(1H，d)，7.01(2H，d)，7.39(1H，t)，7.70-7.80(3H，m)，8.97(1H，s)
130	419	9.4	-
				131	478	7.3	-

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				132	476	9.8	0.93-0.98(6H，m)，1.60(6H，m)，1.78(1H，m)，2.94(1H，m)，3.34(4H，m)，4.18(1H，m)，4.36(1H，m)，6.70(1H，d)，7.02(2H，d)，7.36(1H，d)，7.73-7.89(3H，m)，7.90(1H，s)，9.04(1H，s)，9.09(1H，s)
133	490	10.1	0.96-0.99(9H，m)，1.60(6H，m)，2.96(1H，m)，3.32-3.34(4H，m)，4.13(1H，m)，4.64(1H，m)，6.75(1H，m)，7.02(2H，d)，7.38(1H，d)，7.71-7.78(3H，m)，7.90(1H，d)，9.06-9.08(2H，m)
				134	448	7.7	1.10(2H，m)，1.48-1.78(5H，m)，2.40-2.47(2H，m)，2.85(3H，m)，2.89(2H，m)，4.10(2H，m)，6.31(1H，m)，6.52(NH)，6.85(1H，m)，7.09(2H，m)，7.42(1H，t)，7.81-7.91(3H，m)，9.00(1H，s)，9.12(1H，s)
135	434	6.3	1.28(6H，d)，2.76(2H，t)，2.93(3H，s)，3.34-3.52(2H，m)，4.08(2H，d)，6.85(1H，s)，7.15(2H，d)，7.85(2H，d)，7.94(1H，brs)，8.59(1H，brs)，8.85(1H，brs)，9.21(1H，s)，12.69(1H，brs)
				136	474	7.6	1.84-2.20(8H，m)，2.93(3H，s)，3.06-3.52(6H，m)，3.57-3.68(1H，m)，3.78-3.86(1H，m)，4.18-4.28(1H，m)，6.77(2H，d)，6.84(1H，brs)，7.83(2H，d)，7.93(1H，brs)，8.58(1H，brs)，8.87(1H，brs)，9.11(1H，s)
137	403	6.2	2.34-2.39(2H，m)，2.84(3H，s)，2.92(2H，t)，3.30-3.42(2H，m)，6.40(1H，s)，6.74(1H，s)，7.60(2H，d)，7.89(2H，d)，7.96-8.08(1H，m)，8.41(1H，s)，8.92(1H，brs)，9.38(1H，s)
				138	449	7.4	2.38-2.42(4H，m)，2.67(6H，m)，2.81(3H，m)，4.14(2H，m)，6.35(1H，m)，6.51(NH)，6.89(1H，m)，7.10(2H，m)，7.45(1H，t)，7.85-7.92(3H，m)，8.98(1H，s)，9.11(1H，s)
139	406	6.5	(MeOD)3.02(3H，s)，3.37(4H，t)，3.60(4H，t)，7.16(2H，d)，7.78(1H，s)，7.95(2H，d)，7.97(1H，d)，8.05(1H，s)，9.21(1H，d)
				140	375	9.3	1.55-1.62(6H，m)，3.25-3.40(4H，m)，6.98(2H，d)，7.16-7.22(1H，m)，7.71-7.80(4H，m)，7.95(1H，s)，8.54-8.57(1H，m)，9.00(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				141	462	9.0	1.1(6H，m)，1.6(6H，s)，3.2-3.4(6H，m)，7.0(3H，m)，7.7-7.8(2H，m)，7.8-7.9(2H，m)，8.0-8.1(1H，s)，9.0(1H，m)，9.1(1H，s)
142	449	6.8	1.21-1.36(2H，m)，1.72(3H，m)，1.83(2H，m)，2.71-2.85(5H，m)，3.10(2H，m)，4.11(2H，m)，6.75(1H，s)，7.10(2H，m)，7.39(NH)，7.91(2H，m)，8.45(1H，s)，8.95(1H，brs)，9.22(1H，s)
				143	449	7.2	1.18-1.30(2H，m)，1.69-1.85(5H，m)，2.68(2H，m)，2.86(3H，m)，3.11(2H，m)，4.13(2H，m)，7.09(2H，m)，7.12(NH)，7.80(1H，m)，7.90(3H，m)，8.10(1H，m)，9.00(1H，s)，9.21(1H，s)
144	379	5.8	2.81-2.82(4H，m)，3.19-3.21(4H，m)，3.61(3H，s)，6.89(1H，s)，7.02(2H，d)，7.33(1H，s)，7.64(1H，s)，7.75(2H，d)，8.31(1H，s)，9.26(1H，s)
				145	474	8.0	-
146	420	6.7	1.74-1.82(2H，m)，2.63(2H，t)，2.82-2.90(5H，m)，3.53(2H，t)，3.61(2H，t)，6.81(2H，d)，7.08-7.16(1H，m)，7.73(2H，d)，7.80(1H，s)，7.86(1H，d)，8.09(1H，s)，9.00(1H，d)
				147	421	7.6	1.85-2.08(4H，m)，2.88(3H，d)，3.09-3.18(1H，m)，3.20-3.28(1H，m)，3.40-3.52(2H，m)，3.78-3.84(1H，m)，6.70(2H，d)，7.07-7.15(1H，m)，7.76(2H，d)，7.80(1H，s)，7.87(1H，d)，8.09(1H，s)，9.00(1H，d)
148	450	6.7	2.44(2H，t)，2.55(4H，t)，2.88(3H，d)，3.26-3.37(4H，m)，3.54(2H，t)，7.04(2H，d)，7.08-7.14(1H，m)，7.78(2H，d)，7.80(1H，s)，7.88(1H，d)，8.10(1H，s)，9.00(1H，d)，9.12(1H，s)，12.42(1H，brs)
				149	478	9.1	1.04-1.13(3H，m)，1.50-1.62(6H，m)，3.78-3.85(1H，m)，3.63-3.83(1H，m)，4.10-4.34(2H，2xm)，6.54-6.61(1H，m)，7.01(2H，d)，7.21(1H，t)，7.66(1H，t)，7.71(2H，d)，8.01+8.11(1H，2xs)，8.90(1H，s)
150	488	9.8	1.37-1.43(2H，m)，1.50-1.66(12H，m)，1.70-1.80(2H，m)，3.22-3.36(4H，m)，4.18(2H，s)，6.60(1H，d)，7.01(2H，d)，7.20(1H，d)，7.65(1H，t)，7.73(2H，d)，8.02(1H，s)，8.85(1Hs)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				151	462	9.6	0.96(3H，t)，1.30-1.40(1H，m)，1.55-1.60(6H，m)，2.95-3.02(1H，m)，3.30-3.36(4H，m)，4.10-4.27(2H，m)，6.70(1H，d)，7.01(2H，d)，7.32(1H，d)，7.70-7.78(4H，m)，7.86(1H，s)，9.01(1H，s)
152	490	10.1	0.86(3H，t)，0.95(3H，d)，1.13-1.25(1H，m)，1.47-1.60(8H，m)，2.95-3.01(1H，m)，3.30-3.40(4H，m)，4.10-4.20(1H，m)，3.38-3.45(1H，m)，6.70(1H，d)，7.00(2H，d)，7.33(1H，d)，7.70-7.85(3H，m)，7.90(1H，s)，9.05(1H，s)
				153	435	7.0	1.41-1.52(2H，m)，1.96(2H，m)，2.13(1H，m)，2.89(3H，m)，3.01(4H，m)，3.97(2H，m)，7.09(2H，m)，7.11(1H，s)，7.81(1H，s)，7.94(3H，m)，8.16(1H，s)，9.00(1H，s)，9.24(1H，s)
154	469	8.2	1.65-1.75(4H，m)，1.94-2.09(4H，m)，2.41-2.51(4H，m)，2.61-2.62(2H，m)，3.16(1H，m)，3.42(1H，m)，3.93(1H，m)，6.67(2H，d)，7.72(2H，d)，7.88(1H，d)，8.35(1H，m)，8.54(1H，d)，8.76(1H，d)，8.97(1H，d)，9.42，(1H，d)
				155	420	7.5	2.35-2.52(4H，m)，2.62-2.86(3H，m)，2.87(3H，s)，3.28-3.48(4H，m)，7.07(2H，d)，7.80(1H，s)，7.82(2H，d)，7.89(1H，d)，8.10(1H，s)，9.00(1H，d)，9.14(1H，s)，12.45(1H，d)
156	449	7.8	1.12-1.24(2H，m)，1.38(2H，q)，1.56-1.69(1H，m)，1.74(2H，d)，2.80(2H，t)，2.87(3H，s)，3.46(2H，t)，3.91(2H，d)，7.02(2H，d)，7.08-7.14(1H，m)，7.76(2H，d)，7.80(1H，s)，7.88(1H，d)，8.09(1H，s)，9.00(1H，d)
				157	434	7.7	1.15-1.26(2H，m)，1.75(2H，m)，1.78(1H，m)，2.85(3H，m)，2.98(2H，m)，3.40(2H，m)，3.89(2H，m)，6.32(1H，m)，6.55(NH)，6.89(1H，m)，7.09(2H，m)，7.42(1H，m)，7.85(1H，s)，7.91(2H，m)，9.00(1H，s)，9.21(1H，s)
158	450	6.8	2.45(4H，m).2.71(2H，m)，2.81(4H，m)，2.89(3H，m)，4.18(2H，m)，7.08-7.12(3H，m)，7.80(1H，s).7.91(3H，m)，8.10(1H，s)，8.97(1H，s)，9.25(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				159	404	9.0	1.55-1.63(6H，m)，2.72(3H，s)，3.25-3.40(4H，m)，6.97(1H，s)，7.01(2H，d)，7.51(1H，s)，7.75(2H，d)，7.86(1H，s)，7.95(1H，s)，8.51(1H，s)
160	430	7.9	2.8-3.0(7H，m)，3.1(4H，m)，6.7(1H，s)，7.0(2H，m)，7.1-7.2(1H，m)，7.2-7.3(1H，s)，7.7-7.8(2H，m)，7.9(1H，m)，9.0(1H，m)，9.1(1H，s)
				161	401	7.2	2.8-2.9(4H，m)，3.2-3.3(4H，m)，7.0(2H，m)，7.7(1H，m)，7.8(2H，m)，8.0-8.1(1H，m)，8.4(1H，s)，8.8(1H，m)，9.1(2H，m)
162	434	6.7	1.84-1.94(2H，m)，1.98-2.07(2H，m)，2.88(3H，s)，3.02-3.10(2H，m)，3.30-3.42(2H，m)，3.48-3.54(2H，m)，3.56-3.64(2H，m)，6.75(2H，d)，7.76(2H，d)，7.81(1H，s)，7.88(1H，d)，8.10(1H，s)，9.00(1H，d)
				163	420	6.4	1.47-1.58(2H，m)，1.90-1.98(2H，m)，2.88(3H，s)，2.90-3.00(2H，m)，3.24-3.40(1H，m)，3.95-4.02(2H，m)，7.08(2H，d)，7.81(2H，d)，7.82(1H，s)，7.90(1H，d)，8.11(1H，s)，9.02(1H，d)
164	422	7.6	2.87(6H，s)，2.88(3H，s)，3.03(3H，s)，3.24-3.30(2H，m)，3.75-3.81(2H，m)，6.90(2H，d)，7.81(1H，s)，7.82(2H，d)，7.89(1H，d)，8.10(1H，s)，9.00(1H，d)
				165	431	6.8	2.87(3H，s)，2.92(2H，t)，3.43(2H，t)，6.70(2H，d)，7.50(1H，s)，7.72(2H，d)，7.81(1H，s)，7.87(1H，d)，8.09(1H，s)，8.97-9.01(2H，m)，9.03(1H，s)，12.43(1H，d)
166	434	7.9	2.14-2.26(2H，m)，2.88(6H，s)，2.90(3H，s)，3.30-3.64(3H，m)，3.72-3.78(1H，m)，3.98-4.08(1H，m)，6.73(2H，d)，7.81(1H，s)，7.84(2H，d)，7.89(1H，d)，8.10(1H，s)，9.01(1H，d)
				167	436	7.4	1.86-1.96(2H，m)，2.78(6H，s)，2.88(3H，s)，3.01(3H，s)，3.07-3.14(2H，m)，3.49(2H，t)，6.84(2H，d)，7.79(2H，d)，7.81(1H，s)，7.88(1H，d)，8.10(1H，s)，9.00(1H，d)
168	445	7.1	2.04(2H，quintet)，2.87(3H，s)，3.06(2H，t)，4.14(2H，t)，6.64(2H，d)，7.15(1H，s)，7.40(1H，s)，7.71(2H，d)，7.81(1H，s)，7.86(1H，d)，8.09(2H，s)，9.00(1H，d)，9.02(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				169	405	6.9	2.79-2.84(7H，m)，3.16-3.24(4H，m)，6.41(1H，m)，6.54(1H，s)，6.66(1H，d)，7.02-7.03(2H，m)，7.74(2H，d)，7.91(1H，d)，8.56(1H，d)，9.39(1H，d)
170	435	6.5	1.51(2H，m)，1.88(2H，m)，2.09(1H，m)，2.78-2.86(5H，m)，3.21(2H，m)，3.95(2H，m)，6.78(1H，s)，7.11(2H，m).7.45(1H，brs)，7.93(2H，m)，8.45(1H，s)，8.96(1H，s)，9.23(1H，s)
				171	490	9.2	1.68-1.75(4H，m)，1.90-2.12(4H，m)，2.35-2.65(6H，m)，2.70(3H，s)，3.10-3.20(1H，m)，3.40-3.50(1H，m)，3.90-3.99(1H，m)，6.27(1H，d)，6.45-6.55(2H，m)，6.70(2H，d)，7.43-7.61(2H，m)，7.75(2H，d)，8.68(1H，s)
172	473	7.9	1.70-1.80(4H，m)，1.98-2.07(4H，m)，2.401-2.49(2H，m)，2.61-2.62(2H，m)，2.80(3H，s)，3.16-3.17(2H，m)，3.42-3.44(2H，n)，3.95(1H，m)，6.52(1H，d)，6.58(1H，s)，6.66-6.70(3H，m)，7.62(1H，d)，7.76(2H，d)，7.97(1H，d)，8.67(1H，d)，9.16(1H，s)
				173	416	6.3	3.00-3.05(4H，m)，3.29-3.39(4H，m)，6.69(1H，d)，7.08(2H，d)，7.84(2H，d)，7.86-7.90(1H，m)，7.96(1H，d)，8.75(1H，s)，9.14-9.18(2H，m)，12.08(1H，brs)
174	464	8.8	1.55-1.70(6H，m)，3.30-3.53(4+2H，m)，4.13-4.25(2H，m)，4.62-4.72(1H，m)，6.71(1H，d)，7.03(2H，d)，7.33(1H，d)，7.70-7.80(3H，m)，7.88(1H，s)，9.00(1H，s)，9.07(1H，s)
				175	488	8.4	1.21(3H，t)，1.71(4H，brs)，1.91-2.07(4H，m)，2.33-2.40(1H，m)，2.61-2.68(4H，m)，3.12-3.19(1H，m)，3.35(3H，s)，3.38-3.46(1H，m)，3.93-3.97(1H，m)，6.67(2H，d)，7.11-7.14(1H，m)，7.76(1H，s)，7.78(2H，d)，7.85(1H，d)，8.07(1H，s)，8.97(1H，d)
176	500	8.6	0.41(2H，brs)，0.78(2H，brd)，1.71(3H，brs)，1.81-2.19(7H，brm)，2.65(2H，brs)，3.16(1H，brs)，3.36(3H，s)，3.45(1H，brs)，3.87-3.97(1H，m)，6.68(2H，brd)，7.78(2H，brs)，7.88(1H，s)，7.92(1H，s)，8.21(1H，s)，9.00(1H，s)，9.06(1H，s)

Compound number II-	M+1(obs)	Rt(min)	1H-NMR
				177	463	7.1	1.41-1.58(6H，brm)，1.91(2H，brm)，2.38(4H，m)2.90(3H，m)，3.35(4H，m)，4.11(2H，m)，7.07-7.15(NH and 2H，m)，7.82(1H，s).7.96(3H，m)，8.13(1H，s)，9.01(1H，s)，9.27(1H，s)
178	473	7.5	1.91(4H，m)，2.04(4H，m)，2，50-2.51(2H，m)，2.76(3H，s)，3.15-3.22(2H，m)，3.45-3.49(2H，m)，3.65(1H，m)，3.80(1H，m)，4.24(1H，m)，6.06(1H，m)，6.78(2H，d)，6.97(1H，m)，7.50(1H，m)，7.81(2H，d)，7.93(1H，m)，7.97(1H，m)，8.67(1H，m)，9.12(1H，s)，10.02(1H，brs)
				179	497	9.0	1.65-1.75(4H，m)，1.85-2.05(6H，m)，2.50-2.60(3H，m)，2.75(3H，d)，3.08-3.19(1H，m)，3.35-3.45(2H，m)，3.85-3.92(1H，m)，6.27-6..34(1H，m)，6.63(2H，d)，6.75(1H，s)，6.94(1H，s)，7.09(1H，s)，7.48(1H，s)，7.75(2H，d)，8.63(1H，s)，9.04(1H，s)
180	542	8.8	1.71(4H，brs)，1.94-2.19(4H，m)，2.38-2.51(4H，m)，2.61-2.68(2H，m)，3.16-3.18(1H，m)，3.44-3-47(1H，m)，3.92-3.95(1H，m)，4.20-4.32(2H，m)，6.67(2H，d)，7.71(1H，brt)，7.76(2H，d)，7.83(1H，s)，7.98(1H，s)，8.21(1H，s)，8，92(1H，s)，9.1591H，s)
				181	421	6.6	1.45(2H，m)，1.98(2H，m)，2.61(2H，m)2.95(3H，m)，3.00(2H，m)，4.55(2H，m)，7.10-7.15(NH and 2H，m)，7.86(1H，s).7.95(3H，m)，8.15(1H，s)，9.02(1H，s)，9.28(1H，s)
182	465	7.7	1.95(2H，m)，2.39(4H，m)，2.89(3H，m)3.35(2H，m)，3.59(4H，m)，4.12(2H，m)，7.08-7.14(3H，m)，7.80(1H，s).7.89(3H，m)，8.10(1H，s)，8.99(1H，s)，9.24(1H，s)

[0286]Example 12

[0287] 2-oxo-5-phenyl-1, 2-dihydro-pyridine-3-carboxylic acid phenylamide III-1

[0288] To a solution of 2-oxo-5-phenyl-1, 2-dihydro-pyridine-3-carboxylic acid (44g, 0.20mmol) in tetrahydrofuran (5mL) were added aniline (20 μ L, 0.23mmol), hydroxybenzotriazole (30mg, 0.23mmol), dimethylaminopyridine (27mg, 0.23mmol) and EDC (43mg, 0.23mmol) in succession. The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel, eluting with DCM containing 10% MeOH to give the title compound as a white solid (20mg, 34% yield).

MS(ES⁺)291.δH(DMSO-d₆)7.2(3H，m)，7.9(1H，t)，8.5(1H，d)，8.6(2H，m)，9.3(1H，s).

[0289]Various other compounds of formula III are prepared by methods substantially similar to those described herein. The identification data for these compounds are summarized in Table III-A below, including HPLC, LC/MS (Observation) and¹h NMR data.

[0290]¹The H NMR data are summarized in Table III-A below, in which¹H NMR data were obtained in DMSO at 400MHz and were found to be consistent with the structure unless otherwise indicated. The compound numbers correspond to the compound numbers listed in table 1.

Table III-a. identification data II for selected compounds of formula I

Compound number III-	M+1(pobs)	Rt(min)	1H-NMR
				2	305	8.6	4.56(2H，d)，7.28(1H，m)，7.34-7.37(5H，m)，7.46(2H，t)，7.62(2H，d)，8.06(1H，s)，8.66(1H，d)，10.20(1H，brt)，12.86(1H，brs).
3	306	7.4	4.51(2H，d)，7.20-7.40(5H，m)，7.60(2H，d)，8.40(1H，m)，8.50-8.70(3H，m)，11.10(1H，brs).
				4	334	9.2	1H NMR(DMSO)1.19-1.25(6H，m)，2.80-2.92(1H，m)，7.19-7.29(2H，m)，7.58-7.66(2H，m)，7.70-7.76(2H，m)，8.35-8.40(1H，m)，8.58-8.65(2H，m)，8.78-8.83(1H，m)，12.08(1H，brs)，13.22(1H，brs).
5	348	9.6	1.29(9H，s)，7.39(2H，d)，7.63(2H，d)，7.73(2H，d)，8.39(1H，d)，8.61(2H，d)，8.81(1H，d)，12.10(1H，brs)，13.24(1H，brs).
				6	320	7.6	2.84(2H，t)，3.58(2H，q)，7.18-7.34(5H，m)，7.65-7.69(2H，m)，8.29(1H，d)，8.57-8.61(2H，m)，8.70(1H，d)，9.78(1H，brt)，13.0(1H，brs).

Compound number III-	M+1(obs)	Rt(min)	1H-NMR
				7	320	8.8	1.18(3H，t)，2.59(2H，q)，7.21(2H，d)，7.62(2H，d)，7.73(2H，d)，8.39(1H，d)，8.61(2H，d)，8.80(1H，d)，12.10(1H，brs)，13.20(1H，brs).
8	371	8.9	7.57(2H，d)，7.68-7.75(4H，m)，8.41(1H，d)，8.61(2H，d)，8.81(1H，d)，12.20(1H，s)，13.30(1H，brs).
				9	384	9.3	6.96-7.18(5H，m)，7.32-7.46(2H，m)，7.62-7.81(4H，m)，8.35-8.45(1H，m)，8.56-8.66(2H，m)，8.77-8.84(1H，m)，12.19(1H，brs).
10	334	9.2	1.22(6H，d)，2.83-2.96(1H，m)，6.98-7.04(1H，m)，7.24-7.33(1H，m)，7.5 1-7.61(2H，m)，7.68-7.78(2H，m)，8.35-8.40(1H，m)，8.59-8.64(2H，m)，8.78-8.84(1H，m)，12.02(1H，brs).
				11	322	-	(300Mhz)3.75(3H，s)，6.95(2H，d)，7.64(2H，d)，7.72(21H，d)，8.36(1H，d)，8.61(2H，d)，8.80(1H，d)，11.92(1H，s)
12	322	-	(300Mhz)3.77(3H，s)，6.7(1H，d)，7.16(1H，d)，7.27(1H，t)，7.47(1H，s)，7.72(2H，d)，8.39(1H，s)，8.60(2H，d)，8.79(1H，d)，12.20(1H，s)，13.0(1H，brs)
				13	336	-	(300Mhz)1.33(3H，d)，4.7(1H，q)，5.2(1H，brs)，7.13(1H，d)，7.36(1H，t)，7.62(1H，d)，7.64(1H，s)，7.71(2H，d)，8.40(1H，d)，8.61(2H，d)，8.80(1H，d)，12.23(1H，s)，13.2(1H，brs)
14	336	-	(300Mhz)3.85(3H，s)，4.50(2H，d)，6.91(1H，t)，7.02(1H，d)，7.30-7.22(2H，m)，7.67(2H，dd)，8.29(1H，d)，8.59(2H，d)，8.71(1H，d)，10.09(1H，t)
				15	384	-	(300Mhz)6.83-6.79(1H，m)，7.08-7.05(2H，m)，7.28-7.18(2H，m)，7.47-7.39(3H，m)，7.59(1H，t)，7.70(2H，dd)，8.33(1H，d)，8.60(2H，dd)，8.78(1H，d)，12.11(1H，brs)，13.24(1H，brs)
16	352	-	(300Mhz)3.76(3H，s)，3.79(3H，s)，6.95(1H，d)，7.20(1H，dd)，7.45(1H，d)，7.72(2H，dd)，8.37(1H，d)，8.61(2H，d)，8.81(1H，d)，11.95(1H，brs)

Compound number III-	M+1(obs)	Rt(min)	1H-NMR
				17	334	-	(300Mhz)1.84(2H，quint.)，2.64(2H，t)，3.34(2H，q)，7.31-7.15(5H，m)，7.94(2H，d)，8.39(1H，d)，8.68(2H，d)，8.78(1H，d)，9.70(1H，t)，13.16(1H，brs)
18	410	-	(300Mhz)2.31(2H，q)，3.25(2H，t)，4.03(1H，t)，7.17(2H，t)，7.35-7.28(8H，m)，7.67(2H，dd)，8.28(1H，d)，8.58(2H，dd)，8.67(1H，d)，9.77(1H，t)，12.90(1H，brs)
				19	396	-	(300Mhz)7.48(1H，d)，7.79-7.55(8H，m)，7.89(1H，d)，8.23(1H，s)，8.40(1H，d)，8.60(2H，d)，8.80(1H，d)，12.40(1H，brs)，13.0(1H，brs)
20	350	-	(300Mhz)2.82(2H，q)，3.53(2H，q)，3.79(3H，s)，6.87(1H，t)，6.96(1H，d)，7.23-7.16(2H，m)，7.67(2H，d)，8.27(1H，d)，8.59(2H，d)，8.69(1H，d)，9.70(1H，t)，12.90(1H，brs)
				21	334	-	(300Mhz)1.25(3H，d)，3.0(1H，sext.)，3.55-3.49(2H，m)，7.34-7.18(5H，m)，7.66(2H，d)，8.26(1H，d)，8.58(2H，d)，8.68(1H，d)，9.74(1H，t)，12.86(1H，brs)
22	286	-	(300Mhz)0.92-0.88(6H，m)，1.10(3H，d)，1.76(1H，sext.)，3.90(1H，sext.)，7.67(2H，d)，8.27(1H，d)，8.59(2H，d)，8.70(1H，d)，9.73(1H，d)，12.94(1H，brs)
				23	382	-	(300Mhz)3.95(2H，s)，7.0(1H，d)，7.32-7.19(5H，m)，7.56(1H，s)，7.58(2H，d)，7.71(2H，d)，8.38(1H，d)，8.61(2H，d)，8.79(1H，d)，12.10(1H，brs)，13.20(1H，brs)
24	256	-	(300Mhz)0.55-0.49(2H，m)，0.79-0.70(2H，m)，2.90-2.84(1H，m)，7.67(2H，dd)，8.27(1H，d)，8.59(2H，d)，8.68(1H，d)，9.68(1H，s)，12.98(1H，brs)
				25	313	-	(300Mhz)9.79(1H，s)，8.70(1H，d)，8.59(2H，d)，8.28(1H，d)，7.67(2H，d)，3.48(2H，t)，2.79-2.69(6H，m)，1.80-1.60(4H，m)
26	328	-	(300Mhz)1.58-1.24(10H，m)，3.30(2H，s)，4.39(1H，s)，7.68(2H，d)，8.28(1H，d)，8.59(2H，dd)，8.71(1H，d)，9.84(1H，t)，12.89(1H，brs)

Compound number III-	M+1(obs)	Rt(min)	1H-NMR
				27	312	-	(300Mhz)1.57-1.43(10H，m)，1.91-1.85(2H，m)，4.04-3.99(1H，m)，7.66(2H，dd)，8.28(1H，d)，8.59(2H，dd)，8.68(1H，d)，9.82(1H，d)，12.40(1H，brs)
28	350	-	(300Mhz)2.79(1H，dd)，2.94(1H，dd)，3.45-3.32(2H，m)，4.17(1H，d)，4.95(1H，brs)，7.26-7.19(5H，m)，7.66(2H，dd)，8.28(1H，d)，8.58(2H，d)，8.68(1H，d)，9.82(1H，d)，12.20(1H，brs)
				29	348	-	(300Mhz)1.24(9H，s)，7.17(1H，d)，7.30(1H，t)，7.53(1H，d)，7.73(2H，d)，7.74(1H，s)，8.38(1H，d)，8.61(2H，d)，8.82(1H，d)，12.07(1H，brs)，13.19(1H，brs)
30	272	-	(300Mhz)0.82(3H，t)，1.10(3H，d)，1.52-1.40(2H，m)，3.89-3.83(1H，m)，7.65(2H，d)，8.30(1H，d)，8.57(2H，d)，8.65(1H，d)，9.91(1H，d)
				31	332	-	(300Mhz)1.30-1.25(2H，m)，2.11-2.05(1H，m)，3.05-2.99(1H，m)，7.33-7.17(5H，m)，7.67(2H，dd)，8.30(1H，d)，8.59(2H，dd)，8.69(1H，d)，9.91(1H，d)，13.01(1H，brs)
32	336	-	(300Mhz)3.44(1H，dd)，3.66(1H，dd)，4.76(1H，dd)，5.63(1H，brs)，7.41-7.22(5H，m)，7.63(2H，d)，8.32(1H，d)，8.55(2H，d)，8.62(1H，d)，10.29(1H，s)，12.80(1H，brs)
				33	336	-	(300Mhz)3.45(1H，dd)，3.66(1H，dd)，4.76(1H，dd)，5.62(1H，brs)，7.41-7.22(5H，m)，7.65(2H，d)，8.30(1H，d)，8.57(2H，d)，8.65(1H，d)，10.12(1H，s)，12.80(1H，brs)
34	348	-	(300Mhz)1.20(3H，d)，1.84-1.77(2H，m)，2.66-2.61(2H，m)，4.03-3.98(1H，m)，7.30-7.16(5H，m)，7.67(2H，dd)，8.29(1H，d)，8.58(2H，dd)，8.70(1H，d)，9.76(1H，d)，12.8(1H，brs)
				35	348	-	(300Mhz)1.20(3H，d)，1.84-1.77(2H，m)，2.66-2.60(2H，m)，4.05-3.96(1H，m)，7.30-7.14(5H，m)，7.68(2H，dd)，8.30(1H，d)，8.59(2H，d)，8.71(1H，d)，9.70(1H，d)，13.0(1H，brs)

Compound number III-	M+1(obs)	Rt(min)	1H-NMR
				36	270	-	(300Mhz)0.23-0.18(2H，m)，0.48-0.42(2H，m)，1.04-0.95(2H，m)，3.19(2H，d)，7.67(2H，dd)，8.28(1H，d)，8.59(2H，dd)，8.70(1H，d)，9.79(1H，t)，12.96(1H，brs)
37	310	-	(300Mhz)1.51-1.10(7H，m)，1.80-1.74(1H，m)，2.29-2.19(2H，m)，3.81-3.70(1H，m)，7.66(2H，d)，8.27(1H，d)，8.59(2H，d)，8.67(1H，d)，9.75(1H，d)
				38	400	-	(300Mhz)7.43-7.24(7H，m)，7.79-7.71(4H，m)，8.40(1H，d)，8.61(2H，d)，8.80(1H，d)，12.24(1H，s)，13.25(1H，brs)
39	350	-	(300Mhz)1.46(3H，d)，3.74(3H，s)，5.10(1H，quint.)，6.91(2H，d)，7.30(2H，d)，7.67(2H，d)，8.27(1H，d)，8.59(2H，d)，8.70(1H，d)，10.10(1H，d)
				40	327	-	(300Mhz)1.52-1.24(6H，m)，2.47-2.40(6H，m)，3.43(2H，t)，7.68(2H，d)，8.30(1H，d)，8.59(2H，dd)，8.70(1H，d)，9.81(1H，t)
41	336	-	(300Mhz)3.41-3.34(1H，m)，3.72-3.61(1H，m)，4.72-4.70(1H，dd)，5.63(1H，d)，7.41-7.22(5H，m)，7.65(2H，d)，8.30(1H，d)，8.57(2H，d)，8.65(1H，d)，10.11(1H，brs)
				42	377	7.2	3.04-3.14(4H，m)，3.70-3.79(4H，m)，6.98(2H，d)，7.59(2H，d)，7.71(2H，d)，8.37(1H，d)，8.61(2H，d)，11.91(1H，brs)，13.20(1H，brs)
43	374	7.2	1.10-1.90(10H，m)，2.40-2.56(1H，m)，7.22(2H，d)，7.62(2H，d)，7.72(2H，d)，8.39(1H，d)，8.61(2H，d)，8.80(1H，d)，12.10(1H，brs)
				44	375	8.8	1.48-1.68(6H，m)，3.05-3.15(4H，m)，6.93(2H，d)，7.56(2H，d)，7.72(2H，d)，8.36(1H，d)，8.61(2H，d)，8.80(1H，d)，11.90(1H，s)，13.20(1H，brs)
45	336	8.1	1.31(3H，t)，4.01(2H，q)，6.94(2H，d)，7.62(2H，d)，7.72(2H，d)，8.39(1H，d)，8.61(2H，d)，8.80(1H，d)，11.99，13.25(1H，2brs)

Compound number III-	M+1(obs)	Rt(min)	1H-NMR
				46	390	7.1	2.23(3H，s)，2.43-2.50(4H，m)，3.08-3.14(4H，m)，6.95(2H，d)，7.59(2H，d)，7.72(2H，d)，8.37(1H，d)，8.61(2H，d)，8.80(1H，d)，11.92(0.5H，s)
47	404	7.1	1.03(3H，t)，2.38(2H，q)，2.45-2.54(4H，m)，3.06-3.14(4H，m)，6.95(2H，d)，7.58(2H，d)，7.72(2H，d)，8.38(1H，d)，8.61(2H，d)，8.80(1H，d)，12.00(0.4H，s)
				48	306	6.3	3.39(3H，s)，7.10-7.39(5H，m)，7.46-7.60(2H，m)，7.80-8.02(2H，m)，8.48-8.56(2H，m)，12.10(0.1H，brs)
49	320	6.9	2.20(3H，s)，3.30(3H，s)，7.00-7.20(4H，m)，7.50-7.62(2H，m)，7.85-8.02(2H，m)，8.49-8.60(2H，m)，12.10(0.2H，brs)
				50	320	8.8	1.20(3H，t)，2.61(2H，q)，6.98(1H，brd)，7.25-7.32(1H，m)，7.51-7.60(2H，m)，7.72(2H，d)，8.39(1H，d)，8.61(2H，d)，8.81(1H，d)，12.02(1H，s)，13.26(0.8H，brs)
51	306	8.3	2.31(3H，s)，6.94(1H，d)，7.23-7.29(1H，m)，7.48-7.59(2H，m)，7.72(2H，d)，8.39(1H，d)，8.61(2H，d)，8.81(1H，d)，12.02(0.5H，s)
				52	391	6.7	1.40-1.57(2H，m)，1.76-1.87(2H，m)，2.75-2.86(2H，m)，3.43-3.68(3H，m)，4.70(1H，d)，6.95(2H，d)，7.56(2H，d)，7.73(2H，d)，8.37(1H，d)，8.61(2H，d)，8.80(1H，d)，11.90(1H，s)，13.20(0.6H，brs)
53	476	9.1	1.42(9H，s)，3.02-3.10(4H，m)，3.41-3.50(4H，m)，6.98(2H，d)，7.60(2H，d)，7.71(2H，d)，8.38(1H，d)，8.61(2H，d)，8.80(1H，d11.93(0.6H，s)
				54	376	6.2	2.81-2.97(4H，m)，3.00-3.12(4H，m)，6.89-6.99(2H，m)，7.52-7.62(2H，m)，7.65-7.75(2H，m)，8.38(1H，brs)，8.55-8.62(2H，m)，8.75(1H，brs)，12.15(0.6H，brs)

[0291]Example 13

[0292] N- (6-oxo-1, 6-dihydro- [3, 4' ] bipyridinyl-5-yl) -benzenesulfonamide IV-1

[0293] Amrinone (100mg, 0.53mmol) was suspended in pyridine (2mL) and benzenesulfonyl chloride (75. mu.L, 0.59mmol) was added dropwise at 0 ℃. The reaction mixture was stirred for 2 hours. Pyridine was removed in vacuo. MeOH was added to the crude mixture, and the solid was filtered, rinsing with more MeOH to give the title compound as a pale yellow solid (100mg, 57% yield).

MS(ES⁺)m/e＝328.¹H NMR(DMSO-d₆)δH7.51(2H，dd)，7.54-7.58(2H，m)，7.61-7.65(1H，m)，7.75(2H，dd)，7.90(2H，dd)，8.56(2H，dd)，9.78(1H，brs)，12.33(1H，brs).

Example 14: ITK inhibition assay：

[0294]Compounds were screened for their ability to inhibit Itk using a radioactive phosphate binding assay. The assay was carried out at 100mM HEPES (pH7.5), 10mM MgCl₂25mM NaCl, 0.01% BSA in a mixture with 1mM DTT. The final substrate concentration was 15. mu.M [ gamma-³³P]ATP(400mCi ³³P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 2. mu.M peptide (SAM68 protein D332-443). The measurement was carried out at 25 ℃ in the presence of 30 nMOtk. Assay stock buffer solutions were prepared containing all the above reagents, with the exception of ATP and related test compounds. 50 μ l of stock solution was placed in 96-well plates, followed by addition of 1.5 μ l of DMSO stock solution containing serial dilutions of test compound (usually starting at a final concentration of 15 μ M, 2-fold serial dilutions), in duplicate (final DMSO concentration 1.5%). The plate was preincubated at 25 ℃ for 10 minutes, and 50. mu.l of [ gamma-³³P]ATP initiated the reaction (final concentration 15. mu.M).

[0295] After 10 min the reaction was stopped by adding 50. mu.l of TCA/ATP mixture (20% TCA, 0.4mM ATP). Unifilter GF/C96 well plates (Perkin Elmer Life Sciences, Cat No.6005174) were pretreated with 50. mu.l MilliQ water and the entire reaction mixture (150. mu.l) was added. Plates were washed with 200. mu.l Milli Q water, followed by 200ml of TCA/ATP mix (5% TCA, 1mM ATP). This washing cycle was repeated 2 additional times. After drying, 30 μ l Optiphase 'SuperMix' Liquid scintillation cocktail reagent (PerkinElmer) was added to the wells, followed by scintillation counting (1450 MicRobeta Liquid scintillation counter, Wallac).

[0296]IC was calculated from nonlinear regression analysis of initial rate data using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA)₅₀And (4) data.

[0297]The assay was carried out at 20mM MOPS (pH7.0), 10mM MgCl₂0.1% BSA in a mixture with 1mM DTT. The final substrate concentration was 7.5. mu.M [ gamma-³³P]ATP(400mCi³³P ATP/mmol ATP, Amersham Pharmacia Biotech/Sigma Chemicals) and 3. mu.M peptide (SAM68 protein D332-443). The assay was performed at 25 ℃ in the presence of 50nM Itk. Assay stock buffer solutions were prepared containing all the above reagents, with the exception of ATP and related test compounds. 50 μ l of stock solution was placed in 96-well plates, followed by addition of 2 μ l of DMSO stock solution containing serial dilutions of test compound (usually starting at a final concentration of 50 μ M, 2-fold serial dilutions), in duplicate (final DMSO concentration 2%). The plate was preincubated at 25 ℃ for 10 minutes, and 50. mu.l of [ gamma-³³P]ATP initiated the reaction (final concentration 7.5. mu.M).

[0298]After 10 min, 100mL of 0.2M phosphoric acid + 0.01% Tween 20 was added to stop the reaction. Multiscreen phosphocellulose 96-well filter plates (Millipore, Cat No. maphnob50) were pretreated with 100 μ L0.2M phosphoric acid + 0.01% tween 20, then 170mL of the stop assay mixture was added. Plates were washed with 4 × 200 μ L0.2M phosphoric acid + 0.01% tween 20. After drying, 30 μ L of Optiphase 'SuperMix' liquid scintillation cocktail reagent (Perkin Elmer) was added to the wells followed by scintillation counting (1450 MicR)^obetaLiquid Scintillation Counter，Wallac)。

[0299] Ki (app) data was calculated from nonlinear regression analysis of initial rate data using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

[0300] In general, the compounds of the present invention are effective in terms of inhibition of ITK. Preferred compounds show a Ki of less than 0.1. mu.M in a radioactive binding assay (I-68, I-71, I-74, I-77, I-81, II-14, II-17, II-20, II-22, II-23, II-28, II-29, II-30, II-31, II-35, II-40, II-46, II-51, II-58, II-63, II-64, II-65, II-66, II-77, II-78, II-79, II-80, II-81, II-97, II-107, II-112, II-114, II-115, II-126, II-129, II-130, II-131, II-134, II-135, II-136, II-138, II-139, II-142, II-143, II-145, II-146, II-147, II-148, II-153, II-155, II-156, II-157, II-158, II-159, II-160, II-162, II-163, II-164, II-165, II-166, II-167, II-168, II-169, II-170, II-171, II-172, II-177, II-178, II-179, II-181, II-182, III-42, III-44, III-46, III-47, III-52, III-54). Preferred compounds show Ki's in the radioactive binding assay between 0.1. mu.M and 1. mu.M (I-5, I-10, I-11, I-20, I-21, I-22, I-27, I-45, I-46, I-47, I-69, I-72, I-73, I-75, I-82, I-83, I-84, I-85, II-4, II-7, II-15, II-21, II-32, II-34, II-38, II-39, II-41, II-43, II-45, II-47, II-52, II-56, II-57, II-59, II-60, II-61, II-62, II-69, II-70, II-71, II-75, II-76, II-83, II-85, II-87, II-95, II-98, II-99, II-100, II-101, II-104, II-105, II-108, II-120, II-121, II-123, II-124, II-132, II-133, II-137, II-140, II-144, II-149, II-150, II-151, II-152, II-154, II-161, II-174, II-175, II-176, III-4, III-5, III-7, III-8, III-11, III-16, III-43, III-45).

Example 15: ITK inhibition assay (UV)：

[0301]Compounds were screened for ability to inhibit Itk using a standard coupled enzyme assay (Foxeta)l.，PR^otein Sci.，(1998)7，2249)。

[0302]The assay was carried out at 20mM MOPS (pH7.0), 10mM MgCl₂0.1% BSA, 1mM DTT, 2.5mM phosphoenolpyruvate, 300. mu.M NADH, 30. mu.g/ml pyruvate kinase in admixture with 10. mu.g/ml lactate dehydrogenase. The final substrate concentrations in the assay were 100. mu.M ATP (Sigma Chemicals) and 3. mu.M peptide (biotinylated SAM 68. DELTA. 332-443). The assay was performed at 25 ℃ in the presence of 100nM Itk.

[0303]Assay stock buffer solutions were prepared containing all the above reagents, with the exception of ATP and related test compounds. 60 μ l of stock solution was placed in each well of a 96-well plate, followed by the addition of 2 μ l DMSO (usually starting at a final concentration of 15 μ M) containing serial dilutions of the test compound. The plates were preincubated at 25 ℃ for 10 minutes and 5. mu.l ATP was added to initiate the reaction. The initial reaction rate was determined for 10 minutes using a Molecular Devices SpectraMax Plus plate reader. IC was calculated from nonlinear regression analysis using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA)₅₀And Ki data.

[0304] In general, the compounds of the present invention are effective in terms of inhibition of ITK. Preferred compounds show Ki's of less than 0.1. mu.M in coupled enzyme assays (I-70, I-76, I-78, I-79, I-80). Preferred compounds show Ki's between 0.1. mu.M and 1. mu.M in a coupled enzyme assay (I-5, I-10, I-11, I-69, I-82, I-83, I-84, II-4, II-7, II-41).

Example 16: assay for BTK inhibition：

[0305]Compounds were screened for their ability to inhibit Btk using the radioactive phosphate binding assay in Vertex Pharmaceuticals. The assay was carried out at 20mM MOPS (pH7.0), 10mM MgCl₂0.1% BSA in a mixture with 1mM DTT. The final substrate concentration was 50. mu.M [ gamma-³³P]ATP(200mCi ³³P ATP/mmol ATP，Amersham PharmaciaBiotech，Amersham，UK/Sigma CChemicals) and 2 μ M peptide (SAM 68D 332-443). The assay was performed in the presence of 25nM Btk at 25 ℃. Assay stock buffer solutions were prepared containing all the above reagents, except peptides and related test compounds. 75 μ l of stock solution was placed in 96-well plates, followed by addition of 2 μ l of DMSO stock solution (usually starting at a final concentration of 15 μ M) containing serial dilutions of the test compound in duplicate (final DMSO concentration 2%). The plates were preincubated at 25 ℃ for 15 minutes and 25. mu.l peptide was added to initiate the reaction (final concentration 2. mu.M). Prior to priming with peptide, 100mL of 0.2M phosphate + 0.01% tween was added to control wells containing assay stock buffer and DMSO, and background counts were determined.

[0306]After 10 min, 100mL of 0.2M phosphoric acid + 0.01% Tween was added to stop the reaction. Multiscreen phosphocellulose 96-well filter plates (Millipore, Cat No. maphn0b50) were pretreated with 100 μ L of 0.2M phosphoric acid + 0.01% tween 20, and then 170mL of a stop assay mixture was added. Plates were washed with 4X 200. mu.L of 0.2M phosphoric acid + 0.01% Tween 20. After drying, 30 μ L of Optiphase 'SuperMix' liquid scintillation cocktail reagent (Perkin Elmer) was added to the wells followed by scintillation counting (1450 MicR)^obetaLiquid Scintillation Counter，Wallac)。

[0307] After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

[0308] In general, the compounds of the present invention, including the compounds of table 1, are effective for inhibition of Btk. Preferred compounds show Ki's higher than 0.5. mu.M in the radioactive binding assay (II-43, II-61, II-114, II-149). Preferred compounds show Ki's of less than 0.5 μ M in a radioactive binding assay (II-51, II-58, II-61, II-63, II-77, II-78, II-80, II-112).

Example 17: BTK inhibition assay (AlphaScreen ™)^TM)：

[0309]In Vertex Pharmaceuticals utilization of AlphaScreen^TMCompounds are screened for their ability to inhibit Btk. The assay was carried out at 20mM MOPS (pH7.0), 10mM MgCl₂0.1% BSA in a mixture with 1mM DTT. The final substrate concentrations in the assay were 50. mu.M ATP (Sigma Chemicals) and 2. mu.M peptide (biotinylated SAM 68D 332-443). The assay was performed in the presence of 25nM Btk at 25 ℃. Assay stock buffer solutions were prepared containing all the above reagents, except peptides and related test compounds. 37.5 μ l of stock solution was placed in each well of a 96-well plate, followed by addition of 1 μ l DMSO containing serial dilutions of test compounds (usually starting at a final concentration of 15 μ M), in duplicate (final DMSO concentration 2%). The plates were preincubated at 25 ℃ for 15 minutes and the reaction was initiated by the addition of 12.5. mu.l peptide (final concentration 2. mu.M). Prior to priming with biotin-SAM 68, 5 μ l of 500mM EDTA was added to control wells containing assay stock buffer and DMSO, and background counts were determined.

[0310]After 30 minutes, the 225-fold reaction mixture was diluted to MOPS buffer (20mM MOPS (pH7.0), 1mM DTT, 10mM MgCl) containing 50mM EDTA₂0.1% BSA) to give a final concentration of 9 nM.

[0311]AlphaScreen was prepared according to the manufacturer's instructions^TMReagent (AlphaScreen)^TMPhosphotyrosine (P-Tyr-100) assay kit, Perkinelmer catalog number 6760620C). Under soft light, 20. mu.l AlphaScreen^TMReagents were placed in each well of a white half-zone 96-well plate (Corning Inc. -COSTAR 3693) containing 30. mu.l of the stopped diluted kinase reaction. The plates were incubated in the dark for 60 minutes and then read on a Fusion Alpha plate reader (PerkinElmer).

[0312] After removing the average background value for all data points, ki (app) data was calculated from nonlinear regression analysis using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA).

Example 18: RLK inhibition assay：

[0313]Compounds were screened for their ability to inhibit Rlk using a standard coupled enzyme assay (Foxet al., PR)^oProtein Sci., (1998)7, 2249). The assay was carried out at 20mM MOPS (pH7.0), 10mM MgCl₂0.1% BSA in a mixture with 1mM DTT. The final substrate concentrations in the assay were 100. mu.M ATP (Sigma Chemicals) and 10. mu.M peptide (Poly Glu: Tyr 4: 1). The assay was performed at 30 ℃ in the presence of 40nM Rlk. The final concentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 300. mu.M NADH, 30. mu.g/ml pyruvate kinase and 10. mu.M/ml lactate dehydrogenase.

[0314]Assay stock buffer solutions were prepared containing all the above reagents, with the exception of ATP and related test compounds. 60 μ l of stock solution was placed in each well of a 96-well plate, followed by the addition of 2 μ l DMSO (usually starting at a final concentration of 7.5 μ M) containing serial dilutions of the test compound. The plates were preincubated at 30 ℃ for 10 minutes and 5. mu.l ATP was added to initiate the reaction. The initial reaction rate was determined for 10 minutes using a Molecular Devices SpectraMax Plus plate reader. IC was calculated from nonlinear regression analysis using the Prism Software package (GraphPad Prism version 3.0cx for Macintosh, GraphPad Software, San Diego California, USA)₅₀And Ki data.

[0315] In general, the compounds of the present invention are effective in terms of the inhibitory effect of Rlk. Preferred compounds show a Ki of above 1 μ M in a coupled enzyme assay (I-5, I-11, I-71, I-74, II-7, II-15, II-17, II-38, II-41, II-46, II-47, II-65, II-75, II-83, II-85, II-87, II-114, II-115, II-143, II-148, II-149, II-159, II-160, II-163, II-164, II-166, II-168, II-171, II-178, II-179, III-4, III-5). Preferred compounds show Ki's of less than 1 μ M in a coupled enzyme assay (II-14, II-28, II-29, II-30, II-31, II-35, II-40, II-77, II-78, II-79, II-80, II-81, II-112).

[0316] While we have described some embodiments of this invention, it is apparent that our basic examples can be modified to provide other embodiments that employ the compounds and methods of this invention. It will therefore be appreciated that the scope of the invention is defined by the claims rather than the specific embodiments represented by the examples above.

Claims (55)

1. A compound of formula I:

formula I

Or a pharmaceutically acceptable salt thereof, wherein

Each R³And R⁴Independently H, halogen or optionally halogen, C_1-2Aliphatic radical, OCH₃、NO₂、NH₂、CN、NHCH₃、SCH₃Or N (CH)₂Substituted C_1-4An aliphatic group;

R²is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; r²Optionally J is^RSubstitution;

each X¹And X²Independently is-C (O) -, -NR-or-SO₂-, wherein X¹Or X²One is-NR-, X¹Or X²is-C (O) -or-SO₂-；

R is H, unsubstituted C_1-6An aliphatic group;

R¹is-T-Q;

t is a bond or C_1-6An aliphatic radical in which up to three methylene units of the chain are optionally and independently replaced by G or G', wherein G is-NR⁵-、-O-、-S-、-SO-、SO₂-, -CS-or-CO-; g is cyclopropyl, C ≡ C or C ═ C; t is optionally J^TSubstitution;

q is independently hydrogen, C_1-6An aliphatic group, a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; q is optionally J^QSubstitution;

R⁵is optionally substituted R, C_6-10Aryl radical, C_3-10A cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl; or two R⁵The groups, together with the atoms to which they are attached, form an optionally substituted 3-7 membered monocyclic or 8-14 membered bicyclic ring;

j on an unsaturated carbon atom of an aryl or heteroaryl group^R、J^TAnd J^QThe substituents are selected from halogen; -R^o(ii) a Is optionally substituted by R^oSubstituted C_1-6Alkyl, wherein up to three methylene units of the chain are optionally and independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-, -CO-, cyclopropyl, C ≡ C or C ═ C is replaced by a chemically stable arrangement; -OCF₃；-SCF₂；C_1-4A haloalkyl group; -CH₂-a halogen; is optionally substituted by R^oSubstituted C_6-10An aryl group; is optionally substituted by R^oSubstituted 5-12 membered heteroaryl; is optionally substituted by R^oA substituted 3-12 membered heterocyclic ring; is optionally substituted by R^oSubstituted-o (ph); is optionally substituted by R^osubstituted-CH ═ CH (ph); is optionally substituted by R^osubstituted-CH ≡ CH (ph); is optionally substituted by R^osubstituted-C_1-6Alkyl- (3-12 membered heterocyclyl); is optionally substituted by R^osubstituted-C_1-6Alkyl radical- (C)_6-10Aryl groups); is optionally substituted by R^osubstituted-C_1-6Alkyl- (5-10 membered heteroaryl); is optionally substituted by R^oSubstituted C_3-10A cycloaliphatic group; is optionally substituted by R^osubstituted-C_1-6Alkyl radical- (C)_3-10A cycloaliphatic group); is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -OR^o(ii) a Is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -N (R)^o)₂(ii) a Is optionally substituted by R^oSubstituted- (C)_1-6Alkyl) -SR^o；-NO₂；-CN；-OR^o；-SR^o；-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)₂；-P(O)₂R^o；-PO(R^o)₂；-OPO(R^o)₂(ii) a And- (CH)₂)_0-2NHC(O)R^o；

Each R^oIndependently selected from hydrogen, NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group), halogenated C_1-4Aliphatic radical, optionally substituted C_1-6An aliphatic group (wherein up to 2 methylene units are optionally replaced by O, N or S), an optionally substituted 5-8 membered heterocyclic group, an unsubstituted 5-6 membered heteroaryl group, an unsubstituted 3-6 membered cycloaliphatic group, an unsubstituted phenyl group, an unsubstituted-O (Ph), an unsubstituted-CH₂(Ph), unsubstituted-CH₂(5-7 membered heterocyclic group) or unsubstituted-CH₂(5-6 membered heteroaryl); or R independently occurs twice on the same substituent or different substituents, although as defined above^oAnd each R^oThe atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R^oon an aliphatic radical or from two R^oThe optional substituents on the ring formed by the radicals 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) and halogeno C_1-4An aliphatic radical, in which R^oEach of the above C_1-4Aliphatic groups are unsubstituted;

j on aliphatic, heteroaliphatic or non-aromatic heterocyclic saturated carbon^R、J^TAnd J^QThe substituents are selected fromFrom those listed above for aryl or heteroaryl unsaturated carbons, and additionally including the following groups: o, S, NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl) ═ NNHSO₂(alkyl), - (NOH) and- (NR)^*Wherein each R is^*Independently selected from hydrogen or optionally substituted C₁-C₆An aliphatic group;

j on non-aromatic heterocyclic or heteroaryl ring nitrogen^R、J^TAnd J^QThe substituent is selected from-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⁺¹)₂、-C(＝NH)-N(R⁺)₂and-NR⁺SO₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6An aliphatic group, an optionally substituted phenyl group, an optionally substituted-O (Ph), an optionally substituted-CH₂(Ph); optionally substituted- (CH₂)₂(Ph); optionally substituted-CH ═ CH (ph); or unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or R independently occurring twice on the same substituent or different substituents, although as defined above⁺And each R⁺The atoms to which the groups are bonded together form an optionally substituted 3-12 membered saturated, partially unsaturated or fully unsaturated monocyclic or bicyclic ring having 0-4 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 radical)₂Halogen, C_1-4Aliphatic radical, -OH, -O (C)_1-4Aliphatic radical), -NO₂、-CN、-CO₂H、-CO₂(C_1-4Aliphatic group), -O (halogeno-C)_1-4Aliphatic group) and halo (C)_1-4Aliphatic radical), wherein R⁺Each of the above C_1-4Aliphatic groups are unsubstituted;

provided that it is

If R is²Is 4-pyridyl or 3-pyridyl, R³Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not CH (CH)₃)OC(＝O)CH₃、CH₂OC(＝O)CH₃Or CH₂C(＝O)CH₃；

b)R¹Is not C_1-6Alkyl or O (C)_1-6Alkyl groups);

if R is²Is 4-pyridyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not methyl, imidazole, OCH₃Or H;

b) when T is-CH₂When Q is not 3-OH-phenyl, 4-pyridyl, 3-NO₂-phenyl, OH, -O (C ═ O) CH₃or-C (═ O) CH₃；

c) When T is-CH (CH)₃) When Q is not-OC (═ O) CH₃；

d) When T is-CH₂CH₂-when Q is not 2-pyridyl or-COOH;

e) when T is CH (CH)₃) When OC (O) -, Q is not CH₃；

If R is²Is 4-pyridyl, R³Is H, R⁴Is not H, X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not CH₃；

b)R¹Is not CH (CH)₃)OC(＝O)CH₃；

If R is²Is 2, 4-pyrimidinyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not methyl, NHCH₃or-NHC (═ O) NH₂；

If R is²Is 4-pyridyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-SO₂-, then

a) When T is a bond, Q is not optionally substituted C_6-10Aryl or C_5-10A heteroaryl group;

if R is²Is 4-thiazolyl, R³Is H, R⁴Is CH₃，X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is-CH₂CH₂When Q is not N (CH)₃)₂；

If R is²Is unsubstituted phenyl, R³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then

If T is C₁An aliphatic radical in which 1 methylene unit of the chain is replaced by G; g is-NR⁵-；R⁵Is H; then Q is not 2, 6-di-isopropylphenyl;

if R is²Is unsubstituted phenyl, R³Is H, R⁴Is CH₃，X¹is-C (O) -, X²is-NR-, R is H, then

a) When T is a bond, Q is not CH₃Or CH₂CH₃；

b) When T is-CH₂CH₂When Q is not unsubstituted phenyl or N (CH)₂CH₃)₂；

c) When T is-CH₂CH₂CH₂When Q is not N (CH)₂CH₃)₂；

d)R¹Is not NH₂；

If R is²Is unsubstituted phenyl, R³Is H, R⁴Is CH₃，X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is-O-CH₂-when Q is not unsubstituted phenyl;

if R is²Is 4-OCH₃Phenyl radical, R³Is H, R⁴Is CH₃，X¹is-NR-, R is H, X²is-C (O) -, then

a) When T is a bond, Q is not CH₃；

If R is²Is provided with 2 nitrogens6-membered heteroaryl, R³Is H, methyl or ethyl, R⁴Is methyl or ethyl, X¹is-NR-, R is H, X²is-C (O) -, then

a)R¹Is not CH₃；

If X¹is-C (O) -, X²is-NR-, R is H, then R¹Is not H or methyl;

if R is²Is thatR³And R⁴Is H, X¹is-NR-, R is H, X²is-C (O) -, then R¹Is not CH₃；

If R is²Is unsubstituted phenyl, R³And R⁴Is H, X¹is-C (O) -, X²is-NR-, R is H, then R¹Is not provided with

2. The compound according to claim 1, wherein T is C_1-3Aliphatic radical, optionally interrupted by zero or one G group, where G is selected from O, NR⁵And S.

3. The compound according to claim 1, wherein T is-C_1-2An aliphatic radical-G-wherein G is O or NR⁵G is bonded to Q in a chemically stable arrangement.

4. The compound according to claim 1, wherein T is C_1-3An aliphatic group, optionally interrupted by zero G groups.

5. The compound according to claim 1, wherein T is C_1-3Aliphatic groups, optionally interrupted by zero or one G' group.

6. According to claim 1A compound wherein T is-CH₂-。

7. A compound according to claim 1, wherein T is a bond.

8. The compound according to any one of claims 1-7, wherein each R is³And R⁴Independently is H.

9. A compound according to claim 8, wherein R³And R⁴Are all H.

10. The compound according to any one of claims 1-9, wherein R²Is a 5-8 membered monocyclic ring, optionally substituted by up to five J^RAnd (4) substituting the group.

11. A compound according to claim 10, wherein R²Is C_3-8Cycloaliphatic radical, optionally substituted by up to five J^RAnd (4) substituting the group.

12. A compound according to claim 11, wherein R²Is C_3-8Cycloalkyl, optionally substituted by up to five J^RAnd (4) substituting the group.

13. A compound according to claim 11, wherein R²Is C_3-8Cycloalkenyl, optionally substituted by up to five J^RAnd (4) substituting the group.

14. A compound according to claim 11, wherein R²Is cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cycloheptenyl, optionally substituted by up to five J^RAnd (4) substituting the group.

15. A compound according to claim 10, wherein R²Is a 5-6 membered aryl or heteroaryl group, optionally substituted by up to five J^RAnd (4) substituting the group.

16. A compound according to claim 15, wherein R²Is a 5-6 membered heteroaryl, optionally substituted by up to five J^RAnd (4) substituting the group.

17. A compound according to claim 16, wherein R²Is a 6 membered heteroaryl having 1 or 2 nitrogen atoms; r²Optionally up to five J^RAnd (4) substituting the group.

18. A compound according to claim 17, wherein R²Is a pyridine ring, optionally substituted by up to five J^RAnd (4) substituting the group.

19. A compound according to claim 18, wherein R²Is 2-pyridyl, optionally substituted by up to five J^RAnd (4) substituting the group.

20. A compound according to claim 18, wherein R²Is a 3-pyridyl group, optionally substituted by up to five J^RAnd (4) substituting the group.

21. A compound according to claim 18, wherein R²Is 4-pyridyl, optionally substituted by up to five J^RAnd (4) substituting the group.

22. A compound according to claim 17, wherein R²Is a pyrimidine ring, optionally substituted by up to five J^RAnd (4) substituting the group.

23. A compound according to claim 22, wherein R²Is 2, 4-pyrimidinyl, optionally substituted by up to five J^RAnd (4) substituting the group.

24. A compound according to claim 16, wherein R²Is a 5 membered heteroaryl ring, optionally substituted by up to five J^RAnd (4) substituting the group.

25. A compound according to claim 24, wherein R²Is a thiophene ring, optionally substituted by up to five J^RAnd (4) substituting the group.

26. A compound according to claim 24, wherein R²Is a pyrazole ring, optionally substituted by up to five J^RAnd (4) substituting the group.

27. A compound according to claim 15, wherein R²Is phenyl, optionally substituted by up to five J^RAnd (4) substituting the group.

28. The compound according to any one of claims 1-27, wherein each J is^RSelected from oxo or ═ NOH.

29. The compound according to any one of claims 1-27, wherein each J is^RIs selected from C_1-6Alkyl radical, C_6-10Aryl radical, -C_1-6alkyl-C_6-10Aryl radical, C_1-4Haloalkyl, -OR^o、-N(R^o)₂、-SR^o、NO₂CN, 3-12 membered heterocyclic group, - (C)_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂、-(C_1-6Alkyl) -SR^o、-C(O)OR^o、-NR^oCOR^o、-COR^o、-CON(R^o)₂、-SO₂R^o、-SO₂N(R^o)₂Or C_1-6Alkyl, wherein up to three methylene units of the chain are independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-or-CO-is replaced by a chemically stable arrangement; each J^RIndependently and optionally by R^oAnd (4) substitution.

30. The compound according to claim 29, wherein each J is^RIndependently and optionally by R^oSubstituted, selected from-OR^o、-N(R^o)₂、-SR^o、-(C_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂Or- (C)_1-6Alkyl) -SR^o。

31. The compound according to claim 29, wherein each J is^RIs independently selected from the group consisting of an optionally substituted 5-8 membered heterocyclic group, an optionally substituted-NR (C)_1-4Alkyl) N (R)^o)₂Optionally substituted-NR (C)_1-4Alkyl) OR^o、-N(R^o)₂Or an optionally substituted-NH (5-6 membered heterocyclyl).

32. The compound according to claim 31, wherein each J is^RIndependently selected from optionally substituted-NH (5-6 membered heterocyclyl).

33. A compound according to claim 32, wherein said 5-6 membered heterocyclyl contains 1-2 nitrogen atoms.

34. A compound according to claim 33, wherein the 5-6 membered heterocyclyl is selected from pyrrolidine, piperidine or piperazine.

35. The compound according to any one of claims 1-30, wherein each X is¹And X²Independently is-C (O) -or-NR-, wherein X¹Or X²One is-NR-, X¹Or X²is-C (O) -.

36. A compound according to claim 35, wherein X¹Is C (O), X²Is NR.

37. A compound according to claim 35, wherein X¹Is NR, X²Is C (O).

38. The compound according to any one of claims 1-37, wherein Q is a 3-8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

39. The compound according to claim 38, wherein Q is C_6-10Aryl radical, C_3-10A cycloaliphatic group, a 5-14 membered heteroaryl group, or a 5-14 membered heterocyclic group.

40. A compound according to claim 39, wherein Q is C_6-10Aryl or 5-14 membered heteroaryl.

41. The compound according to claim 40, wherein Q is 5-6 membered aryl or heteroaryl.

42. A compound according to claim 41, wherein Q is phenyl.

43. The compound according to any one of claims 1-42, wherein Q is replaced by up to 3J^QIs substituted by radicals in which each J^QSelected from CN, C_1-6Alkyl radical, C_1-4Haloalkyl, -OR^o、-N(R^o)₂、-SR^o、-(C_1-6Alkyl) -OR^o、-(C_1-6Alkyl) -N (R)^o)₂、-(C_1-6Alkyl) -SR^o、C_6-10Aryl radical, -C_1-6alkyl-C_6-10Aryl radical, C_3-10Cycloaliphatic radical, -C_1-6Alkyl radical- (C)_3-10Cycloaliphatic radical), C_3-10Heterocyclyl radical, -C_1-6Alkyl radical- (C)_3-10Heterocyclyl), -C (O) OR^o、-NR^oCOR^o、-COR^o、-CON(R^o)₂、-SO₂R^o、-SO₂N(R^o)₂Or C_1-6Alkyl, wherein up to three methylene units are optionally and independently replaced by-NR^o-、-O-、-S-、-SO-、SO₂-, -CO-, cyclopropyl, C ≡ C or C ═ C is replaced by a chemically stable arrangement; each J^QOptionally and independently by R^oAnd (4) substitution.

44. The compound according to claim 43, wherein each J^Qis-SO₂N(R^o)₂、-SO₂R^o、-NR^oC(O)OR^o、-C≡C-R^o、-C＝C-R^oPhenyl, -O-Ph, -O-CH₂Ph、C_5-6Heteroaryl group, C_3-7Heterocyclyl or C_3-7A cycloaliphatic group.

45. The compound according to claim 43, wherein each J^QIs CN, C_1-6Alkyl, -CF₃、-OCF₃、-OR^o、-N(R^o)₂、-SR^o、-CH₂-halogen, -SCF₂、-(C_1-6Alkyl) -N (R)^o)₂、C₆Aryl radical, C_5-6Heteroaryl, -C (O) OR^o、-NR^oCOR^o、-COR^oor-CON (R)^o)₂。

46. The compound according to any one of claims 38-45, wherein R^oSelected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, tert-butyl, OH, halogen, -CH₂-pyrrolidine, COCH₃、-(C_1-4Alkyl radical)_0-1-O(C_1-4Alkyl), - (C)_1-4Alkyl radical)_0-1-O(C_1-4Alkyl) OH, - (C)_1-4Alkyl radical)_0-1-NH(C_1-4Alkyl), - (C)_1-4Alkyl radical)_0-1-N(C_1-4Alkyl radical)₂Or- (C)_1-4Alkyl radical)_0-1-NH₂。

47. A compound selected from the group consisting of:

48. a compound selected from the group consisting of I-82 to I-85, II-88, II-89, II-90, II-91, II-92 to II-182, III-11 to III-54, IV-1.

49. A pharmaceutical composition comprising a compound according to any one of claims 1 to 48 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

50. Inhibition:

(a) a patient; or

(b) Biological sample

A method of Tec family (e.g., Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in a subject, the method comprising administering to the subject or contacting the biological sample with a compound of claim 1.

51. The method of claim 50, wherein the method comprises inhibiting Itk kinase activity.

52. A method of treating or lessening the severity of a disease or condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease, comprising administering to a patient in need thereof a compound according to any one of claims 1-48.

53. The method of claim 52, wherein the disease or condition is asthma, acute rhinitis, allergy, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer's lung, fibrotic lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Lett's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopic dermatitis, contact dermatitis with other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigus, epidermolysis bullosa, urticaria, vascular dermatitis, vasculitis, erythroderma, cutaneous eosinophilia, uveitis, alopecia, vernal conjunctivitis clusteritis, celiac disease, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, sjogren's syndrome, systemic sclerosis, and leiomyelitis, Proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, crohn's disease, ulcerative colitis, food-related allergies, multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, hyper IgE syndrome, leprosy nodular leprosy, sexil syndrome, and idiopathic thrombocytopenic purpura, post-angioplasty restenosis, tumors, atherosclerosis, systemic lupus erythematosus, allograft rejection, including, without limitation, acute and chronic allograft rejection, e.g., secondary to post-transplantation of the kidney, heart, liver, lung, bone marrow, skin, and cornea; and chronic graft versus host disease.

54. A compound of formula 22:

wherein:

R¹⁰is an amino protecting group;

R¹¹is H or C_1-6Alkyl, or R¹⁰And R¹¹Together with the nitrogen atom to which they are bonded, form an amine protecting group;

R¹²is a hydroxy protecting group; and

R²as defined herein.

55. A process for preparing a compound of formula I comprising reacting a compound of formula 22 with a compound R²-X, wherein X is a suitable leaving group, to give a compound of formula 23:

wherein:

R¹⁰is an amino protecting group;

R¹¹is H or C_1-6Alkyl, or R¹⁰And R¹¹Together with the nitrogen atom to which they are bonded, form an amine protecting group;

R¹²is a hydroxy protecting group; and

R²as defined herein.