HK1192227B

HK1192227B - Thiazolopyrimidine compounds

Info

Publication number: HK1192227B
Application number: HK14105455.1A
Authority: HK
Inventors: Johannes Cornelius Hermann; Lee Edwin LOWRIE JR.; Matthew C. Lucas; Kin-Chun Thomas Luk; Fernando Padilla; Jutta Wanner; Wenwei XIE; Xiaohu Zhang
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2011-03-28
Filing date: 2012-03-26
Publication date: 2017-07-28

Description

Thiazolopyrimidine compounds

Technical Field

Protein kinases constitute one of the largest families of human enzymes and regulate many different signaling processes by adding phosphate groups to proteins; in particular, tyrosine kinases phosphorylate proteins on the alcohol portion of tyrosine residues. The tyrosine kinase family includes members that control cell growth, migration, and differentiation. Abnormal kinase activity has been implicated in a number of human diseases including cancer, autoimmune and inflammatory diseases. Since protein kinases belong to key regulators of cell signaling, they provide the goal of regulating cellular function with small molecule inhibitors of kinase activity and are therefore good drug design targets. In addition to the treatment of kinase-mediated disease processes, selective and potent inhibitors of kinase activity may also be useful in studying cellular signaling processes and in identifying other therapeutically significant cellular targets.

SYK (spleen tyrosine kinase) is a non-receptor tyrosine kinase that is important for B cell activation via BCR signaling. SYK becomes activated upon binding to phosphorylated BCR and thus initiates early signaling events following BCR activation. SYK deficient mice show early blocks of B cell development. Therefore, inhibition of SYK enzymatic activity in cells has been suggested for the treatment of autoimmune diseases through its role in autoantibody production.

In addition to its role in BCR signaling and B-cell activation, SYK also plays a key role in FcRI-mediated mast cell degranulation and eosinophil activation. Thus, SYK is involved in allergic disorders including asthma, is bound by its SH2 domain to the phosphorylated γ chain of Fc γ RI, and is essential for downstream signaling. SYK deficient mast cells exhibit defective degranulation, arachidonic acid and cytokine secretion. Pharmacological agents that inhibit SYK activity in mast cells are also shown. Treatment with SYK antisense oligonucleotides inhibited antigen-induced infiltration of eosinophils and neutrophils in an asthma animal model. SYK-deficient eosinophils also show impaired activation in response to FcR stimulation. Therefore, small molecule inhibitors of SYK would be useful in the treatment of allergy-induced inflammatory diseases including asthma.

In view of the wide variety of conditions that are expected to benefit from treatment involving modulation of the SYK pathway, it is apparent that novel compounds that modulate the SYK pathway and methods of using these compounds will provide substantial therapeutic benefit to a wide variety of patients. Provided herein are novel compounds that are useful for treating disorders directed to the SYK pathway or that inhibit SYK kinase, and that are therapeutically effective in treating autoimmune and inflammatory diseases.

The present application provides compounds of formula I or pharmaceutically acceptable salts thereof

I

Wherein:

R¹is phenyl, optionally substituted by one or more lower alkyl, lower haloalkyl, hydroxy lower alkyl, lower alkoxy, lower alkylsulfonyl, halogen, nitro, amino, aminoalkyl, amido, cyano, oxo or R^1’Substitution;

R^1’is heterocycloalkyl or spiroheterocycloalkyl, each of which is optionally substituted by one or more R^1”Substitution;

R^1”is hydroxy, halogen,Lower alkyl, lower alkoxy or lower haloalkyl;

b is phenyl, pyridyl, pyrrolidinyl or piperidinyl;

x is OH, lower alkoxy, NHC (= O) Y, C (= O) NH₂、C(=O)NHY、C(=O)X’、C(=O)Y、CH₂NHY、CH₂CH₂Y、CF=CHY、CH=CHY、CH₂OH、C(=O)NHCH₂CH₂N(CH₃)₂Or C (= O) NHCH₂CH₂Y；

X' is OH or lower alkoxy;

y is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each of which is optionally substituted by one or more Y³Substitution;

Y³is hydroxy, lower alkyl, lower alkoxy, halogen, oxo, lower haloalkyl, hydroxy lower alkyl, amino, acylamino, C (= O) NH (CH)₃)、C(=O)OH、C(=O)OY⁴Or heteroaryl, optionally substituted with one or more lower alkyl, oxo or SH;

Y⁴is a lower alkyl group.

The present application provides a method of treating an inflammatory or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-12.

Definition of

The phrase "an" or "an" entity, as used herein, refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. Thus, the terms "a" (or "an)", "one or more" and "at least one" may be used interchangeably herein.

The phrase "as defined above" refers to the broadest definition of each group as provided in the summary of the invention or the broadest claims. In all other embodiments provided below, substituents that may be present in each embodiment and are not explicitly defined remain with the broadest definition provided in the summary of the invention.

As used in this specification, the terms "comprises" and "comprising," whether in transitional phrases or in the main body of the claims, should be construed to have an open-ended meaning. That is, the term should be construed as synonymous with the phrase "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a compound or composition means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

As used herein, unless specifically indicated otherwise, the use of the word "or" is in the "inclusive" sense of "and/or" and not in the "exclusive" sense of "or/and.

The term "independently" as used herein means that the variables are used in either case regardless of the presence or absence of variables having the same or different definitions within the same compound. Thus, in a compound where R "occurs twice and is defined as" independently carbon or nitrogen, "both R" can be carbon, both R "can be nitrogen, or one R" can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formula depicting or describing compounds employed or claimed in the present invention, its definition on each occurrence is independent of its definition at each other occurrence. Furthermore, combinations of substituents and/or variables are permissible only if such compounds result in stable compounds.

The symbol "at the bond end" or "cross-linking" refers to the point of attachment of a functional group or other chemical moiety to the remainder of the molecule of which it is a part, respectively. Thus, for example:

MeC(=O)OR⁴wherein

A bond drawn into a ring system (as opposed to being attached at a distinct vertex) means that the bond can be attached to any suitable ring atom.

The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the optionally substituted moiety may incorporate a hydrogen atom or a substituent.

The phrase "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds. If a substituent is designated as "bond" or "absent," the atoms attached to that substituent are directly attached.

The term "about" as used herein means approximately, near, roughly, or about. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. Generally, the term "about" as used herein changes a numerical value to the extent that the difference is between above and below the stated value by 20%.

Certain compounds may exhibit tautomerism. Tautomeric compounds may exist in two or more species that can interconvert. Tautomers of proton transfer result from the migration of a covalently bound hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers generally produce mixtures whose chemical and physical properties are consistent with mixtures of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in the case of many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. Common tautomers of proton transfer include keto/enol (-C (= O) -CH-and-C (-OH) = CH-), amide/imide (-C (= O) -NH-and-C (-OH) = N-) and amidine (-C (= NR) -NH-and-C (-NHR) = N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings, and the present invention includes all tautomeric forms of the compounds.

Technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined. Reference is made herein to various methods and materials known to those skilled in the art. Standard references listing general principles of pharmacology include the pharmacologic basises of therapeutics, 10 th edition, mcgrawhills companies inc, new york (2001), both Goodman and Gilman. Any suitable materials and/or methods known to those skilled in the art may be used in the practice of the present invention. However, preferred materials and methods are described. Materials, reagents, etc. referred to in the following description and examples are available from commercial sources unless otherwise indicated.

The definitions described herein may be appended to form chemically relevant combinations, such as "heteroalkylaryl," "haloalkylheteroaryl," "arylalkyl heterocyclyl," "alkylcarbonyl," "alkoxyalkyl," and the like. When the term "alkyl" is used as a suffix following another term, such as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one to two substituents selected from the group of the other specified nomenclature. Thus, for example, "phenylalkyl" refers to an alkyl group having 1 to 2 phenyl substituents, and thus includes benzyl, phenylethyl and biphenyl. "alkylaminoalkyl" is an alkyl group having 1 to 2 alkylamino substituents. "hydroxyalkyl" includes 2-hydroxyethyl, 2-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 2, 3-dihydroxybutyl, 2- (hydroxymethyl), 3-hydroxypropyl and the like. Thus, as used herein, the term "hydroxyalkyl" is used to define a subset of heteroalkyl groups defined below. The term- (ar) alkyl refers to unsubstituted alkyl or aralkyl groups. The term (hetero) aryl or (hetero) aryl refers to aryl or heteroaryl.

The term "spirocycloalkyl" as used herein refers to a spiro cycloalkyl group such as, for example, spiro [3.3] heptane. The term spiroheterocycloalkyl as used herein refers to a spirocyclic heterocycloalkyl group such as, for example, 2, 6-diazaspiro [3.3] heptane.

The term "acyl" as used herein denotes a group of formula-C (= O) R, wherein R is hydrogen or lower alkyl as defined herein. The term "alkylcarbonyl" as used herein denotes a group of formula-C (= O) R, wherein R is alkyl as defined herein. Term C_1-6Acyl means a radical-C (= O) R, which contains 6 carbon atoms. The term "arylcarbonyl" as used herein denotes a group of formula C (= O) R, wherein R is aryl; the term "benzoyl" as used herein is "arylcarbonyl" wherein R is phenyl.

The term "ester" as used herein denotes a group of formula-C (= O) OR, wherein R is lower alkyl as defined herein.

The term "alkyl" as used herein denotes an unbranched or branched saturated monovalent hydrocarbon residue containing from 1 to 10 carbon atoms. The term "lower alkyl" denotes a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms. "C" as used herein_1-10Alkyl "refers to an alkyl group consisting of 1 to 10 carbons. Examples of alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term "alkyl" is used as a suffix following another term, as in "phenylalkyl" or "hydroxyalkyl", it is intended to indicate an alkyl group, as defined above, substituted with one to two substituents selected from the group of the additional specified nomenclature. Thus, for example, "phenylalkyl" denotes the group R 'R "-, where R' is phenyl and R" is alkylene as defined herein, with the understanding that the attachment point of the phenylalkyl moiety will be on the alkylene. Examples of arylalkyl groups include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The term "arylalkyl" or "aralkyl" is similarly construed, except that R' is aryl. The terms "(hetero) arylalkyl" or "(hetero) aralkyl" are similarly construed, except that R' is optionally aryl or heteroaryl.

The term "haloalkyl" or "halo-lower alkyl" or "lower haloalkyl" refers to a straight or branched chain hydrocarbon residue containing 1 to 6 carbon atoms, wherein one or more carbon atoms are substituted with one or more halogen atoms.

The term "alkylene (or alkylenyl)" as used herein denotes a divalent saturated straight-chain hydrocarbon group of 1 to 10 carbon atoms (e.g., (CH)₂)_n) Or a branched saturated divalent hydrocarbon radical of 2 to 10 carbon atoms (e.g. -CHMe-or-CH)₂CH(i-Pr)CH₂-) unless otherwise indicated. Except in the case of methylene, the open valences of the alkylene groups are not attached to the same atom. Examples of alkylene groups include, but are not limited to: methylene, ethylene, propylene, 2-methyl-propylene, 1-dimethyl-ethylene, butylene, 2-ethylbutylene.

The term "alkoxy" as used herein denotes-O-alkyl, wherein alkyl is as defined above, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, including isomers thereof. "lower alkoxy" as used herein denotes alkoxy having a "lower alkyl" group as defined above. "C" as used herein_1-10Alkoxy "means an-O-alkyl group wherein alkyl is C_1-10。

The term "PCy₃"refers to a phosphine trisubstituted with three cyclic moieties.

The term "haloalkoxy" or "halo-lower alkoxy" or "lower haloalkoxy" refers to lower alkoxy wherein one or more carbon atoms are substituted with one or more halogen atoms.

The term "hydroxyalkyl" as used herein denotes an alkyl group as defined herein wherein 1 to 3 hydrogen atoms on different carbon atoms are replaced by a hydroxyl group.

The terms "alkylsulfonyl" and "arylsulfonyl" as used herein refer to the formula-S (= O)₂R, wherein R is independently alkyl or aryl, and alkyl and aryl are as defined herein. The term "heteroalkylsulfonyl" as used herein denotes the formula-S (= O)₂The group of R, wherein R is "heteroalkyl" as defined herein.

The terms "alkylsulfonylamino" and "arylsulfonylamino" as used herein refer to the formula-NR' S (= O)₂R, wherein R is independently alkyl or aryl, R' is hydrogen or C_1-3Alkyl, and alkyl and aryl are as defined herein.

The term "cycloalkyl" as used herein refers to a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. "C" as used herein_3-7Cycloalkyl "refers to a cycloalkyl group consisting of 3 to 7 carbons in a carbocyclic ring.

The term carboxy-alkyl as used herein refers to an alkyl moiety in which one hydrogen atom has been replaced by a carboxy group, wherein it is understood that the point of attachment of the heteroalkyl group is through a carbon atom. The term "carboxy (or carboxyl)" means-CO₂And (4) a H part.

The term "heteroaryl" or "heteroaromatic" as used herein refers to a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic or partially unsaturated ring, each ring containing 4 to 8 atoms, to which is bonded one or more N, O or S heteroatoms, the remaining ring atoms being carbon, wherein it is understood that the attachment point of the heteroaryl group will be on the aromatic or partially unsaturated ring. As is well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counterparts (counterparts). Therefore, forFor the purposes of the present invention, heteroaryl groups need only have some degree of aromatic character. Examples of heteroaryl moieties include monocyclic aromatic heterocycles having 5 to 6 ring atoms and 1 to 3 heteroatoms, including, but not limited to, pyridyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl, imidazolyl, trifluoromethyl, and the like,Azolyl, 4, 5-dihydro-Azolyl, 5, 6-dihydro-4H- [1,3]Azolyl radical, isoOxazole, thiazole, isothiazole, triazoline, thiadiazole andbisoxazolines (oxadixolines) which may be optionally substituted by 1 or more, preferably 1 or 2, substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl and dialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino and arylcarbonylamino. Examples of bicyclic moieties include, but are not limited to, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzoAzole, benzisohOxazole, benzothiazole, naphthyridinyl, 5,6, 7, 8-tetrahydro- [1, 6]Naphthyridinyl groupAnd benzisothiazoles. The bicyclic moiety may be optionally substituted on either ring, but the point of attachment is on the ring containing the heteroatom.

The term "heterocyclyl", "heterocycloalkyl" or "heterocycle" as used herein denotes a monovalent saturated cyclic group consisting of one or more rings, preferably 1 to 2 rings (including spiro ring systems), 3 to 8 atoms per ring, to which one or more ring heteroatoms (selected from N, O or S (O))_0-2) And which may be optionally independently substituted with one or more, preferably 1 or 2, substituents selected from hydroxy, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halogen, lower haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino and ionic forms thereof, unless otherwise indicated. Examples of heterocyclyl groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl,oxazolidinyl, thiazolidinyl, isooxazolidinylOxazolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and imidazolinyl groups and ionic forms thereof. Examples may also be bicyclic, such as, for example, 3, 8-diaza-bicyclo [3.2.1]Octane, 2, 5-diaza-bicyclo [2.2.2]Octane or octahydro-pyrazino [2, 1-c][1，4]And (3) an oxazine.

SYK inhibitors

In some embodiments, the present application provides a compound of formula I or a pharmaceutically acceptable salt thereof

I

Wherein:

R^1”is hydroxy, halogen, lower alkyl, lower alkoxy or lower haloalkyl;

b is phenyl, pyrrolidinyl or piperidinyl;

x is OH, NHC (= O) Y, C (= O) NH₂、C(=O)NHY、C(=O)X’、C(=O)Y、CH₂NHY、CH₂CH₂Y、CF=CHY、CH=CHY、CH₂OH、C(=O)NHCH₂CH₂N(CH₃)₂Or C (= O) NHCH₂CH₂Y；

X' is OH or lower alkoxy;

Y³is hydroxy, lower alkyl, lower alkoxy, halogen, oxo, lower haloalkyl, hydroxy lower alkyl, amino, amido, C (= O) OH or C (= O) OY⁴；

Y⁴Is a lower alkyl group.

The present application provides compounds of formula I as described above, wherein B is phenyl.

The present application also provides compounds of formula I as described above, wherein B is pyrrolidinyl.

The present application also provides compounds of formula I as described above, wherein B is piperidinyl.

The present application provides compounds of formula I, wherein X is NHC (= O) Y, C (= O) NH₂、C(=O)NHY、C(=O)X’、C(=O)Y、C(=O)NHCH₂CH₂N(CH₃)₂Or C (= O) NHCH₂CH₂Y。

The present application provides compounds of formula I, wherein X is NHC (= O) Y, C (= O) NHY, CH₂NHY or CH₂OH。

The present application provides compounds of formula I, wherein X is NH and Y is C = O.

The present application provides compounds of formula I, wherein B is pyrrolidinyl, X is NH, and Y is C = O.

The present application provides compounds of formula I, wherein B is piperidinyl, X is NH, and Y is C = O.

The present application provides compounds of formula I, wherein X is C = O and Y is NH.

The present application provides compounds of formula I, wherein B is phenyl, X is C = O, and Y is NH.

The present application provides compounds of formula I, wherein R¹Is 3, 4-dimethoxy-phenyl.

The present application provides compounds of formula I wherein Y is phenyl, pyridyl or indazolyl, optionally substituted with one or more Y³And (4) substitution.

The present application provides compounds of formula I wherein Y is phenyl, optionally substituted with one or more Y³And (4) substitution.

The present application provides compounds of formula I wherein Y is heteroaryl, optionally substituted with one or more Y³And (4) substitution.

The present application provides compounds of formula I wherein Y is heterocycloalkyl, optionally substituted with one or more Y³And (4) substitution.

The application provides compounds of formula I, wherein Y³Is hydroxy, lower alkoxy, C (= O) OH or C (= O) OY 4.

The present application provides a compound selected from the group consisting of:

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzoic acid;

[1,4] diazepan-1-yl- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -phenyl } -methanone;

3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (4- (methylcarbamoyl) phenyl) benzamide;

4- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzoylamino } -benzoic acid;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidin-3-ylcarbamoyl) benzoic acid;

4- ({1- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -piperidine-3-carbonyl } -amino) -benzoic acid;

n- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) -2-oxoindoline-6-carboxamide;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-hydroxybenzoic acid;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-methoxybenzoic acid;

n- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) -1H-indazole-6-carboxamide;

n- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) pyrazine-2-carboxamide;

6-amino-N- {1- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -pyrrolidin-3-yl } -nicotinamide;

n- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazole-5-carboxamide;

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]-N- [4- (5-mercapto- [1,3, 4]]Oxadiazol-2-yl) -phenyl]-a benzamide;

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzoylamino) -2-methoxybenzoic acid;

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]-N- [4- (5-oxo-4, 5-dihydro- [1,2, 4)]Oxadiazol-3-yl) -phenyl]-a benzamide;

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -N- (1H-indazol-5-yl) -benzamide;

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -N- (1H-indazol-6-yl) -benzamide;

4- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -N- (2-pyridin-4-yl-ethyl) -benzamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2- (pyridin-4-yl) ethyl) piperidine-4-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) piperidine-4-carboxamide;

4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) benzamide;

4- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -N- [2- (1-methyl-2-oxo-1, 2-dihydro-pyridin-4-yl) -ethyl ] -benzamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2- (pyridin-4-yl) ethyl) piperidine-3-carboxamide;

3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzoic acid methyl ester;

3- [7- (3-methanesulfonyl-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzoic acid;

3- {7- [3- (2-methoxymethyl-pyrrolidin-1-yl) -phenylamino ] -thiazolo [5,4-d ] pyrimidin-5-yl } -benzoic acid;

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzylamino) benzoic acid tert-butyl ester;

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzylamino) benzoic acid;

4- ((E) -2- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -phenyl } -2-fluoro-vinyl) -benzoic acid;

(E) -4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) styryl) benzoic acid;

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) phenethyl) benzoic acid;

3- {7- [ (1R,5S) -3- (8-oxa-3-aza-bicyclo [3.2.1] oct-3-yl) -phenylamino ] -thiazolo [5,4-d ] pyrimidin-5-yl } -benzoic acid;

n- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) -1H-indazole-5-carboxamide;

(S) -N- (3- (2-methylpyrrolidin-1-yl) phenyl) -5- (3- ((piperidin-4-ylamino) methyl) phenyl) thiazolo [5,4-d ] pyrimidin-7-amine;

n5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-yl) pyridine-2, 5-dicarboxamide;

methyl 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) picolinate;

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) picolinic acid;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2-oxoindolin-5-yl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (1H-indazol-5-yl) piperidine-3-carboxamide;

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidine-3-carboxamido) picolinic acid;

4- ({1- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -piperidine-3-carbonyl } -amino) -2-methoxy-benzoic acid;

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-oxo-4, 5-dihydro-1, 2, 4-)Oxadiazol-3-yl) phenyl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (1H-indazol-6-yl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (1-oxoisoindolin-5-yl) piperidine-3-carboxamide;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidine-3-carboxamido) -2-hydroxybenzoic acid;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (5-oxopyrrolidin-3-yl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (pyrazin-2-yl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (1, 3-dioxoisoindolin-5-yl) piperidine-3-carboxamide;

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-mercapto-1, 3, 4-)Oxadiazol-2-yl) phenyl) piperidine-3-carboxamide;

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (4- (5-mercapto-4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) piperidine-3-carboxamide;

3- {7- [3- (2-oxa-6-aza-spiro [3.3] hept-6-yl) -phenylamino ] -thiazolo [5,4-d ] pyrimidin-5-yl } -benzoic acid;

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidine-3-carboxamido) benzoic acid;

4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5,4-d ] pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid;

3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzoic acid methyl ester;

3- [7- (3-trifluoromethyl-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzoic acid;

3- [7- (3,4, 5-trimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzamide;

1- (7- (3- ((S) -2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidin-3-ol;

4- {7- [ 3-methoxy-5- ((S) -2-methyl-pyrrolidin-1-yl) -phenylamino ] -thiazolo [5,4-d ] pyrimidin-5-yl } -benzamide;

(S) -5- (6-methoxypyridin-3-yl) -N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d ] pyrimidin-7-amine;

4- {7- [3- ((S) -2-methyl-pyrrolidin-1-yl) -phenylamino ] -thiazolo [5,4-d ] pyrimidin-5-yl } -benzamide;

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -N- [4- (2, 4-dioxo-thiazolidin-5-yl) -phenyl ] -benzamide;

4- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzamide;

(S) -N- (2- (dimethylamino) ethyl) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) benzamide;

4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) -N- (2- (dimethylamino) ethyl) benzamide;

{3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -phenyl } -methanol; and

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] pyrimidin-5-yl ] -benzamide.

The present application provides a method of treating an inflammatory or autoimmune disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides the above method further comprising administering an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.

The present application provides a method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides a method of treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides a method of treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides methods of treating immune disorders including lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, organ transplant complications, xenotransplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, and leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides a method of treating an inflammatory disorder comprising administering to a patient in need thereof a therapeutically effective amount of an anti-inflammatory compound in combination with a compound of formula I.

The present application provides a method of treating an immune disorder comprising administering to a patient in need thereof a therapeutically effective amount of an immunosuppressive compound in combination with a compound of formula I.

The present application provides pharmaceutical compositions comprising a compound of formula I in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

The present application provides the above pharmaceutical composition further comprising an additional therapeutic agent selected from the group consisting of chemotherapeutic or anti-proliferative agents, anti-inflammatory agents, immunomodulatory or immunosuppressive agents, neurotrophic factors, agents for treating cardiovascular disease, agents for treating diabetes, and agents for treating immunodeficiency disorders.

The present application provides the use of a compound of formula I for the manufacture of a medicament for the treatment of disorders associated with Syk.

The application provides the use of a compound of formula I for the manufacture of a medicament for the treatment of rheumatoid arthritis.

A compound, method or composition as described herein.

Compound (I)

Examples of representative compounds encompassed by the present invention and within the scope of the present invention are provided in the following tables. The following examples and preparations are provided to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Generally, the nomenclature used in this application is based on AUTONOMTMv.4.0, the BeilsteinInstitute computerized system used to generate IUPAC systematic nomenclature or Structure = Name, the NameApplication is carried out. If there is a discrepancy between a drawn structure and the name given to the structure, the drawn structure is taken as the standard. Further, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

Table I describes examples of pyridone compounds according to general formula I.

Table I.

Synthesis of

Flow chart

The compounds disclosed herein can be synthesized using general schemes I-III:

description of the flow charts

I

In the above-mentioned flow charts, R¹May be aryl, optionally substituted by one or more lower alkyl, hydroxy lower alkyl, lower alkoxy, halogen, nitro, amino, aminoalkyl, acylamino, cyano, oxo or halo-lower alkyl, W may be CH or N, N may be 0 or 1, m may be 1 or 2, X may be NH, CH, C₂C = O, CH or CF, Y may be O, N, C or C = O, R²May be H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and R³May be H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. Detailed representative reaction schemes are shown in schemes IV and V below.

Pharmaceutical compositions and administration

The compounds of the present invention may be formulated into a variety of oral administration dosage forms and carriers. The form for oral administration can be tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups or suspensions. The compounds of the present invention are effective when administered by other routes of administration, including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include penetration enhancers), buccal, nasal, inhalation, and suppository administration, among others. The preferred mode of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient.

The compounds of the present invention and their pharmaceutically acceptable salts may be formulated in pharmaceutical compositions and unit dosage forms with one or more conventional excipients, carriers or diluents. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or substances, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range of use. The pharmaceutical compositions may be used in solid (e.g., tablets or filled capsules), semi-solid, powder, sustained release formulations or liquid (e.g., solutions, suspensions, emulsions, elixirs or filled capsules) for oral administration; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Typical formulations will contain from about 5% to about 95% active compound (w/w). The term "formulation" or "dosage form" is intended to include both solid and liquid formulations of the active compound, and those skilled in the art will appreciate that the active ingredient may be present in different formulations depending on the target organ or tissue and the desired dosage and pharmacokinetic parameters.

The term "excipient" as used herein refers to a compound used in the preparation of pharmaceutical compositions, which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and which include veterinary and human pharmaceutically acceptable excipients. The compounds of the present invention may be administered alone, but will generally be administered in admixture with one or more suitable pharmaceutical excipients, diluents or carriers selected with regard to the intended route of administration and standard pharmaceutical practice.

By "pharmaceutically acceptable" it is meant that it is useful in the preparation of pharmaceutical compositions that are generally safe, non-toxic and neither biologically nor otherwise undesirable, and that include veterinary as well as human pharmaceutical uses.

The "pharmaceutically acceptable salt" form of the active ingredient may also initially impart desirable pharmacokinetic properties to the active ingredient that are not present in the non-salt form, and may even positively affect the pharmacodynamics of the active ingredient with respect to its in vivo therapeutic activity. The phrase "pharmaceutically acceptable salt" of a compound refers to a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. The salt comprises: (1) formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) or with organic acids (e.g., acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, dodecylsulfuric acid, and the like), Gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.); or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, alkaline earth ion, or aluminum ion) or is co-present with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like).

Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is usually a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is usually mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include, without limitation, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. In addition to the active ingredients, solid form preparations may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

Liquid preparations are also suitable for oral administration and include emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted, prior to use, to liquid form preparations. Emulsions may be prepared in solution, for example in aqueous propylene glycol, or they may contain emulsifying agents, for example lecithin, sorbitan monooleate or acacia. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions may be prepared by dispersing the finely divided active component in water containing viscous material, for example natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

The compounds of the invention may be formulated for parenteral administration (e.g. by injection, e.g. bolus injection or continuous infusion) and they may be in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, as solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and which may contain formulatory agents such as preservatives, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use, by aseptic isolation of sterile solid or by lyophilization from solution.

The compounds of the invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. For example, ointments and creams may be formulated with an aqueous or oily base to which suitable thickening and/or gelling agents are added. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include: lozenges comprising the active agent in a flavored base (usually sucrose and acacia or tragacanth); pastilles comprising the active ingredient in an inert base (e.g. gelatin and glycerin or sucrose and acacia); and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration as suppositories. The low melting wax (e.g., a mixture of fatty acid glycerides and cocoa butter) is first melted and the active ingredient is dispersed uniformly, such as by stirring. The molten homogeneous mixture is then poured into a mold of conventional size, allowed to cool and solidify.

The compounds of the invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers in addition to the active ingredient are suitable as is known in the art.

The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions can be applied directly to the nose by conventional means, for example with a dropper, pipette or nebulizer. The formulations may be provided in single or multiple dose forms. In the latter case of a dropper or pipette, this may be achieved by the patient administering a suitable, predetermined volume of solution or suspension. In the case of a nebulizer, this can be achieved, for example, by a metered nebulization spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, and include intranasal administration. The compounds typically have a small particle size, for example, on the order of 5 microns or less. The particle size may be obtained by methods known in the art, for example by micronisation. The active ingredient is provided in pressurized packs with a suitable propellant, e.g. a chlorofluorocarbon (CFC), such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or carbon dioxide or other suitable gas. The aerosol may also suitably contain a surfactant, for example lecithin. The dosage of the drug can be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nose. The powder composition may be in unit dosage form, e.g. in capsules or cartridges such as gelatin or blister packs, from which the powder may be administered by means of an inhaler.

When desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated into transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a solid support that adheres to the skin. The compound of interest can also be combined with a penetration enhancer such as azone (1-dodecylaza-cycloheptan-2-one). The sustained release delivery system is inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in a lipid soluble film (e.g., silicone rubber) or a biodegradable polymer (e.g., polylactic acid).

Suitable formulations with pharmaceutical carriers, diluents and excipients are described in Remington, the science and practice of pharmacy1995, mack publishing company, 19 th edition, Easton, pa, edited by e.w. The skilled formulation scientist, given the benefit of this disclosure, will be able to modify the formulation to provide a variety of formulations for specific routes of administration without destabilizing or otherwise compromising the therapeutic activity of the compositions of the present invention.

For example, modifications of the compounds of the invention to make them more stable in water or other vehicles can be readily accomplished by minor modifications (salt formation, esterification, etc.), which are within the ordinary skill in the art. The route of administration and dosage regimen of a particular compound can be modified in order to control the pharmacokinetics of the compound of the present invention and thereby maximize the beneficial effects in the patient, and is also within the ordinary skill in the art.

The term "therapeutically effective amount" as used herein refers to the amount required to reduce the symptoms of a disease in an individual. The dosage is adjusted to the individual requirements in each particular case. The dosage may vary within wide limits depending on a variety of factors such as the severity of the disease being treated, the age and general health of the patient, other drugs being used while the patient is being treated, the route and form of administration, and the preferences and experience of the attending physician. For oral administration, daily dosages between about 0.01 to about 1000mg/kg body weight per day should be suitable for monotherapy and/or combination therapy. Preferred daily dosages are between about 0.1 to about 500mg/kg body weight, more preferably between 0.1 to about 100mg/kg body weight per day, and most preferably between 1.0 to about 10mg/kg body weight per day. Thus, for administration to a 70kg human, the dosage range will be about 7mg to 0.7g per day. The daily dose may be administered in a single dose or in divided doses, typically between 1 and 5 doses per day. Typically, treatment is initiated at smaller doses than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is achieved for the individual patient. The ordinarily skilled artisan in treating the diseases described herein will be able to determine, without undue experimentation and relying on his or her personal knowledge, experience, and disclosure of the present application, a therapeutically effective amount of a compound of the invention for a given disease and patient.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation, the package containing a discrete quantity of the preparation, for example, packeted tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form may itself be a capsule, tablet, cachet, or lozenge, or it may be the appropriate number of any of these in packaged form.

Preparation

Pharmaceutical formulations delivered by various routes were formulated as shown in the table below. The "active ingredient" or "active compound" used in the tables refers to one or more compounds of formula I.

Compositions for oral administration

Composition (I)	%wt./wt.
		Active ingredient	20.0%
Lactose	79.5%
		Magnesium stearate	0.5%

Mixing the ingredients and dispensing in capsules, each capsule containing about 100 mg; one capsule approximates the total daily dose.

Compositions for oral administration

Composition (I)	%wt./wt.
		Active ingredient	20.0%
Magnesium stearate	0.5%
		Croscarmellose sodium	2.0%
Lactose	76.5%
		PVP (polyvinylpyrrolidone)	1.0%

The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20mg of the active compound) with a suitable tablet press.

Compositions for oral administration

Composition (I)	Measurement of
		Active compound	1.0g
Fumaric acid	0.5g
		Sodium chloride	2.0g
P-hydroxybenzoic acid methyl ester	0.15g
		Propyl p-hydroxybenzoate	0.05g
Granular sugar	25.5g
		Sorbitol (70% solution)	12.85g
Veegum K(Vanderbilt Co.)	1.0g
		Flavouring agent	0.035mL
Coloring agent	0.5mg
		Distilled water	Proper amount to 100mL

These ingredients are mixed to form a suspension for oral administration.

Parenteral formulations

Composition (I)	%wt./wt.
		Active ingredient	0.25g
Sodium chloride	Proper amount of the drug to be isotonic
		Water for injection	100mL

The active ingredient is dissolved in a portion of the water for injection. Sufficient sodium chloride is then added with stirring to make the solution isotonic. The solution was made up to weight with the remaining water for injection, filtered through a 0.2 micron membrane filter, and packaged under sterile conditions.

Suppository formulation

Composition (I)	%wt./wt.
		Active ingredient	1.0%
Polyethylene glycol 1000	74.5%
		Polyethylene glycol 4000	24.5%

The ingredients were melted and mixed together on a steam bath and poured into a mold containing a total weight of 2.5 g.

Topical formulations

Composition (I)	Keke (Chinese character of 'Keke')
		Active compound	0.2-2
Span60	2
		Tween60	2
Mineral oil	5
		Vaseline	10
P-hydroxybenzoic acid methyl ester	0.15
		Propyl p-hydroxybenzoate	0.05
BHA (butylated hydroxyanisole)	0.01
		Water (W)	Proper amount to 100

All ingredients except water were combined and heated to about 60 ℃ with stirring. Sufficient water at about 60 c is then added with vigorous stirring to emulsify these ingredients, followed by the addition of a suitable amount of water to about 100 g.

Nasal spray

Several aqueous suspensions containing about 0.025-0.5% active compound were formulated as nasal sprays. The formulation optionally contains inactive ingredients such as microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust the pH. The nasal spray may be delivered by a nasal spray metering pump, typically delivering about 50-100 microliters of formulation per actuation. A typical dosing regimen is to spray 2-4 times every 4-12 hours.

Indications and treatment methods

The compounds described herein are kinase inhibitors, in particular SYK inhibitors. These inhibitors may be used to treat one or more diseases responsive to kinase inhibition in a mammal, including diseases responsive to inhibition of SYK and/or inhibition of B-cell proliferation. Without wishing to be bound by any particular theory, it is believed that the interaction of the compounds of the present invention with SYK results in the inhibition of SYK activity and thus in the pharmaceutical use of these compounds. Accordingly, the present invention includes a method of treating a mammal, e.g., a human, having a disease responsive to inhibition of SYK activity and/or inhibition of B-cell proliferation, comprising administering to the mammal having such a disease an effective amount of at least one chemical entity provided herein. Effective concentrations can be determined experimentally, for example by analyzing the blood concentration of the compound, or theoretically by calculating bioavailability. Other kinases that may be affected in addition to SYK include, but are not limited to, other tyrosine kinases and serine/threonine kinases.

Kinases play an important role in signaling pathways that control basic cellular processes such as proliferation, differentiation and death (apoptosis). Abnormal kinase activity has been implicated in a wide range of diseases including various cancers, autoimmune and/or inflammatory diseases and acute inflammatory responses. The multifaceted role of kinases in key cellular signaling pathways provides an important opportunity to identify new drugs that target kinases and signaling pathways.

The present application provides a method of treating an inflammatory or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

The present application provides a method of treating asthma-like comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I.

Examples

Abbreviations

Commonly used abbreviations include: acetyl (Ac), azo-bis-isobutyronitrile (AIBN), atmospheric pressure (Atm), 9-borabicyclo [3.3.1]Nonane (9-BBN or BBN), 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), tert-butoxycarbonyl (Boc), di-tert-butyl pyrocarbonate or Boc anhydride (Boc)₂O), benzyl (Bn), butyl (Bu), chemical abstracts accession number (CASRN), benzyloxycarbonyl (CBZ or Z), Carbonyldiimidazole (CDI), 1, 4-diazabicyclo [2.2.2]Octane (DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone (dba), 1, 5-diazabicyclo [4.3.0]Non-5-ene (DBN), 1, 8-diazabicyclo [5.4.0]Undec-7-ene (DBU), N ' -Dicyclohexylcarbodiimide (DCC), 1, 2-Dichloroethane (DCE), Dichloromethane (DCM), 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), diisobutylaluminum hydride (DIBAL or DIBAL-H), Diisopropylethylamine (DIPEA), N-Dimethylacetamide (DMA), 4-N, N-Dimethylaminopyridine (DMAP), N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1 ' -bis- (diphenylphosphino) ethane (dppe), 1 ' -bis- (diphenylphosphino) ferrocene (dppf), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) ) 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), ethyl (Et), ethyl acetate(EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acid Ethyl Ester (EEDQ), diethyl ether (Et)₂O), Ethyl isopropyl ether (EtOiPr), O- (7-azabenzotriazol-1-yl) -N, N, N 'N' -tetramethyluronium hexafluorophosphate acetic acid (HATU), acetic acid (HOAc), 1-N-hydroxybenzotriazole (HOBt), High Pressure Liquid Chromatography (HPLC), Isopropanol (IPA), isopropyl magnesium chloride (iPrMgCl), Hexamethyldisilazane (HMDS), Liquid Chromatography Mass Spectrometry (LCMS), lithium hexamethyldisilazane (LiHMDS), m-chloroperoxybenzoic acid (m-CPBA), methanol (MeOH), melting point (mp), MeSO₂- (methylsulfonyl or Ms), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), mass spectrometry (Ms), methyl tert-butyl ether (MTBE), methyltetrahydrofuran (MeTHF), N-bromosuccinimide (NBS), N-butyllithium (nBuLi), N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine (NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC), dichloro- ((bis-diphenylphosphino) ferrocene) palladium (II) (Pd (dppf) Cl₂) Palladium (II) acetate (Pd (OAc)₂) Tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃) Pyridine Dichromate (PDC), phenyl (Ph), propyl (Pr), isopropyl (i-Pr), pounds per square inch (psi), pyridine (pyr), 1,2, 3,4, 5-pentaphenyl-1' - (di-tert-butylphosphino) ferrocene (Q-Phos), room temperature (ambient temperature, RT or RT), sec-butyllithium (sBuLi), tert-butyldimethylsilyl or t-BuMe2Si (TBDMS), tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et), and the like₃N), 2, 6, 6-tetramethylpiperidine 1-oxyl (TEMPO), trifluoromethanesulfonic or CF₃SO₂- (Tf), trifluoroacetic acid (TFA), 1 ' -bis-2, 2, 6, 6-tetramethylheptane-2, 6-dione (TMHD), O-benzotriazol-1-yl-N, N, N ', N ' -tetramethyluronium tetrafluoroborate (TBTU), Thin Layer Chromatography (TLC), Tetrahydrofuran (THF), trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂-or tosyl (Ts) and N-urethane-N-carboxy anhydride (UNCA). The usual nomenclature (including the prefixes n, i-, sec-, t-, and neo) has its conventional meaning when used with alkyl moieties (j.rigaudy and d.p.klesney, Nomencla)ureinOrganicChemistry，IUPAC1979PergamonPress，Oxford)。

General conditions

All temperatures include melting point (i.e., MP) in degrees celsius (° c), unless otherwise stated. It will be appreciated that the reaction which produces the indicated and/or desired product need not necessarily result directly from the combination of the two reagents initially added, i.e., one or more intermediates produced may be present in the mixture which ultimately results in the formation of the indicated and/or desired product. The following abbreviations may be used in the preparation examples and examples. All names were generated using Autonom and ChemDraw.

The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They are not to be considered as limiting the scope of the invention, but merely as being exemplary and representative thereof.

Preparation examples

Preparation example 1

(5-chloro-thiazolo [5, 4-d)]Pyrimidin-7-yl) - (3, 4-dimethoxy-phenyl) -amines

Reacting 5, 7-dichloro-thiazolo [5,4-d ]]A mixture of pyrimidine (0.925g, 4.49mmol), 3, 4-dimethoxy-phenylamine (0.89g, 5.83mmol) and DIEA (0.86g, 6.73mmol) in 12mL of LDMSO was stirred at room temperature for 2 h. The mixture was poured into 50mL of water and filtered; the resulting solid was washed with water (50mL) to give the crude product, which was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate as eluent) to give (5-chloro-thiazolo [5,4-d ]]Pyrimidin-7-yl) - (3, 4-dimethoxy-phenyl) -amine (0.92g, 63.8%) as a solid. LC-MS: 323.1[ M + H]⁺，t_R=1.56 minutes.

Preparation example 2

3-[7-(3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]-benzoic acid methyl ester

The method comprises the following steps:

(5-chloro-thiazolo [5,4-d ] stirred at room temperature]Pyrimidin-7-yl) - (3, 4-dimethoxy-phenyl) -amine (0.90g, 2.79mmol) and 3- (4, 4,5, 5-tetramethyl- [1,3, 2]Dioxaborolan-2-yl) -benzoic acid methyl ester (0.95g, 3.62mmol) in 100mL1, 4-bisAdding Na into the solution in the alkane₂CO₃(0.93g, 8.8mmol) and 5mL of water. The mixture was then degassed with nitrogen for 15 minutes. One-time addition of Pd (PPh)₃)₄(0.32g, 0.279mmol) and the reaction mixture was stirred at 100 ℃ under nitrogen for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, CH)₂Cl₂Methanol =100:1) to give 3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]Methyl benzoate (0.95g, 81%) as yellow solid. LC-MS: 423.1[ M + H]⁺，t_R=1.68 minutes.

Example 1

3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]-benzoic acid

The method comprises the following steps:

stirring of 3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl]-methyl benzoate (0.85g,2mmol) in 20mL of THF and 20mL of methanol was added a solution of NaOH (0.08g, 20mmol) in 2mL of water. The reaction was then stirred at this temperature for 16 hours. The solvent was evaporated and the residue was suspended in 50ml thf and then treated with 6n hcl to pH =3. The solvent was evaporated and then dissolved in 30ml of THF and filtered. The filtrate was evaporated to give 3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]Benzoic acid (0.8g, 97.5%) as a yellow solid.¹HNMR(300MHz，DMSO):13.15(s，1H)，10.18(s，1H)，9.38(s，1H)，8.98(s，1H)，8.61(d，1H，J=8.1Hz)，8.06(d，1H，J=7.5Hz)，7.84(d，1H，J=2.4Hz)，7.64(t，1H，J=7.8Hz)，7.42(dd，1H，J1=8.7Hz，J₂=2.1Hz)，6.98(d，1H，J=8.7Hz)，3.82(s，3H)，3.77(s，3H)。LC-MS：409[M+H]⁺，839[2M+Na]⁺，t_R=1.74 minutes. HPLC: 98.38% at 214nm, 97.29% at 254nm, t_R=3.44 minutes.

Example 2

[1，4]Diazepan-1-yl- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d] Pyrimidin-5-yl]-phenyl } -methanone

Step 1

4- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]-benzoyl Radical } - [1,4]-diazepan-1-carboxylic acid tert-butyl ester

The method comprises the following steps:

stirring of 3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl]DIEA (30mg, 0.23mmol) was added to a solution of benzoic acid (95mg, 0.23mmol) in 10mL THF. Then 1, 4-diazepan-1-carboxylic acid tert-butyl ester (60mg, 0.3mmol), BOP-Cl (76mg, 0.3mmol) were addedAnd DIEA (59mg, 0.46mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, methanol: CH)₂Cl₂=1:100) to give 4- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5, 4-d)]Pyrimidin-5-yl]-benzoyl } - [1,4]-diazepan-1-carboxylic acid tert-butyl ester (130mg, 95.7%) as a yellow solid. LC-MS: 591.2[ M + H]⁺，t_R=1.81 min

Step 2

The method comprises the following steps:

4- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] stirring at room temperature]Pyrimidin-5-yl]-benzoyl } - [1,4]Diazepan-1-carboxylic acid tert-butyl ester (130mg, 0.22mmol) at 10mLCH₂Cl₂To the solution of (1) CF is slowly added₃COOH (4mL) the mixture was then stirred at room temperature for 16 h the solvent was evaporated and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were initial 20% acetonitrile/80% water (0.1% TFAV/V) then done in a linear fashion after 9 min to 45% acetonitrile/55% water (0.1% TFAV/V)), then 1MHCl (0.5mL) was added and stirred then the solvent was removed under reduced pressure to give [1, 4mL ], [1]Diazepan-1-yl- {3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d]Pyrimidin-5-yl]Phenyl } -methanone as HCl salt (35mg, 30.2%) as yellow solid.¹HNMR(300MHz，DMSO):10.18(s，1H)，9.38(s，1H)，9.05(brs，2H)，8.46-8.44(m，2H)，7.86(s，1H)，7.60-7.59(m，2H)，7.42(dd，1H，J₁=8.7Hz，J₂=2.7Hz)，6.99(d，1H，J=8.7Hz)，3.85(brs，2H)，3.80(s，3H)，3.77(s，3H)，3.44(brs，2H)，3.30(brs，2H)，3.20(brs，2H)，2.02-1.96(m，2H)。LC-MS：491.2[M+H]⁺，t_R=1.51 minutes. HPLC: 99.24%, at 214nm, 98.23%, at 254nm, t_R=4.65 minutes.

Example 3

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (methylamino) Formyl) phenyl) benzamide

The method comprises the following steps:

to 3- [7- (3, 4-dimethoxy-phenylamino) -thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl]-benzoic acid (170mg, 0.41mmol) in 10mL of DMF was added 4-amino-N-methyl-benzamide (81mg, 0.54mmol), HATU (205mg, 0.54mmol) and DIEA (79mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 16 h]Pyrimidin-5-yl) -N- (4- (methylcarbamoyl) phenyl) benzamide (66mg, 29.7%) as a yellow solid.¹HNMR(300MHz，DMSO):10.66(s，1H)，10.21(s，1H)，9.39(s，1H)，8.93(s，1H)，8.59(d，1H，J=7.2Hz)，8.38-8.37(m，1H)，8.05(d，1H，J=8.7Hz)，7.89-7.82(m，6H)，7.71-7.68(m，12H)，7.54-7.50(m，1H)，6.97(d，1H，J=8.7Hz)，3.78(s，3H)，3.72(s，3H)，2.78(d，1H，J=3.9Hz)。LC-MS：541.1[M+H]⁺，t_R=1.72 minutes. HPLC: 96.60%, at 214nm,97.75% at 254nm, t_R=6.68 minutes.

Example 4

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoylamino) benzene Formic acid

Step 1

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoylamino) benzene (iv) Carboxylic acid tert-butyl ester

The method comprises the following steps:

reacting 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]A mixture of pyrimidin-5-yl) benzoic acid (130mg, 0.32mmol), tert-butyl methyl 4-aminobenzoate (185mg, 0.96mmol), EDC (122mg, 0.64mmol) and DMAP (78mg, 0.64mmol) in 10mL DMF was stirred at room temperature for 2 hours. Excess DMF was removed under reduced pressure and the residue was dissolved in 100mL ethyl acetate, washed with brine (10mL) and dried over anhydrous sodium sulfate. The crude residue was purified by silica gel chromatography (200 mesh, 300 mesh, eluting with ethyl acetate) to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoylamino) benzoic acid tert-butyl ester (130mg, 70%) as a white solid.¹HNMR(300MHz，DMSO):10.76(s，1H)，10.18(s，1H)，9.41(s，1H)，8.97(s，1H)，8.62(d，1H，J=8.1Hz)，8.10(d，1H，J=7.8Hz)，7.95(s，4H)，7.85(s，1H)，7.71(t，1H，J=7.7Hz)，7.54(dd，1H，J₁=9.0Hz，J₂=2.4Hz)，6.99(d，1H，J=9.0Hz)，3.81(s，3H)，3.75(s，3H)，1.57(s，3H)。LC-MS：584[M+H]⁺，t_R=1.78 minutes. HPLC: 98.03%, at 214nm, 98.38%, at 254nm, t_R=7.05 min.

Step 2

The method comprises the following steps:

tert-butyl-4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] in 10mL of CCM was treated by dropwise addition of TFA (2mL)]Pyrimidin-5-yl) benzoylamino) benzoate (45mg, 0.077 mmol). The resulting yellow solution was stirred at ambient temperature overnight. Excess solvent was removed under reduced pressure, the residue triturated with n-hexane, decanted, and dried to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoylamino) benzoic acid (27mg, 66.4%).¹HNMR(300MHz，DMSO):12.80(brs，1H)，10.76(s，1H)，10.19(s，1H)，9.41(s，1H)，8.96(s，1H)，8.62(d，1H，J=7.8Hz)，8.09(d，1H，J=7.8Hz)，7.97(s，4H)，7.84(s，1H)，7.71(t，1H，J=7.7Hz)，7.54(dd，1H，J₁=8.7Hz，J₂=2.1Hz)，6.99(d，1H，J=8.7Hz)，3.81(s，3H)，3.74(s，3H)。LC-MS：528[M+H]⁺，t_R=1.54 minutes. HPLC: 96.02%, at 214nm, 95.94%, at 254nm, t_R=6.62 minutes.

Example 5

Step 1

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino (iv) Carboxylic acid tert-butyl ester

The method comprises the following steps:

(5-chloro-thiazolo [5,4-d ] stirred at room temperature under nitrogen]Pyrimidin-7-yl) - (3, 4-dimethoxy-phenyl) -amine (150mg, 0.46mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (130mg, 0.69mmol), X-Phos (115mg, 0.24mmol) and Cs₂CO₃(580mg, 1.78mmol) in 60mL dry EriAdding Pd into the solution in the alkane at one time₂(dba)₃(60mg, 0.065 mmol). The reaction mixture was then degassed with nitrogen for 15 minutes. The final mixture was stirred at 95 ℃ under nitrogen for 24 hours. The solvent was evaporated and the crude product was purified by silica gel chromatography (silica gel 200-300 mesh, petroleum ether: ethyl acetate =1:2) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (191mg, 87.8%) as a solid. LC-MS: 473.2[ M + H]⁺，t_R=1.56 minutes.

Step 2

5- (3-Aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amines Hydrochloride salt

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (191mg, 0.40mmol) in 50mL saturated HCl in bisIn an alkane) was stirred at room temperature for 24 hours. Evaporating the solvent under reduced pressure to obtain 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine hydrochloride (165mg, 100%) as a solid. It was used in the next step without further purification. LC-MS: 373.1[ M + H]⁺，t_R=1.15 min.

Step 3

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) benzoic acid methyl ester

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A solution of pyrimidin-7-amine hydrochloride (165mg, 0.4mmol), 4- (methoxycarbonyl) benzoic acid (94mg, 0.52mmol), HATU (197mg, 0.52mmol) and DIEA (154.8mg, 1.2mmol) in 10mL of DMF was stirred at room temperature for 2 h. A small amount of the desired product was detected according to LCMS analysis. EDCI.HCl (76.4mg, 0.42mmol) and DMAP (49mg, 0.4mmol) were then added in one portion and the solution was stirred at room temperature for an additional 4 days. The solvent was evaporated in vacuo at 80 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, dichloromethane: methanol =20:1) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid methyl ester (190mg, 87.8%) as a yellow solid. LC-MS: 535.1[ M + H]⁺，t_R=1.48 minutes.

Step 4

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) benzoic acid

The method comprises the following steps:

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid methyl ester (190mg, 0.255mmol) and LiOH₂A solution of O (149mg, 3.55mmol) in 2mL of water, 10mL of methanol and 15mL of THF was stirred at room temperature for 2 hours, the solution was acidified to pH =2 with 2N Cl and the solvent evaporated and the residue dissolved in 50mL of THF, filtered to remove the salts, the filtrate evaporated and the residue purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 25% acetonitrile/75% water (0.1% TFAV/V) and then proceeding in a linear fashion to 45% acetonitrile/55% water (0.1% TFAV/V) after 9 minutes to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ])]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid (86mg, 46.5%) as a solid.¹HNMR(300MHz，DMSO):9.63(s，1H)，8.36-8.79(m，2H)，8.02-7.88(m，5H)，7.60-7.50(m，1H)，6.93(d，1H，J=8.7Hz)，4.61-4.59(m，1H)，3.95-3.66(m，10H)，2.28-2.10(m，2H)。LC-MS：521[M+H]⁺；518.8[M-H]^-，t_R=1.36 min. HPLC: 99.85% at 214nm, 99.84% at 254nm, t_R=4.67 minutes.

Example 6

Step 1

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylaminomethyl Tert-butyl ester

The method comprises the following steps:

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5,4-d ] is stirred at room temperature under nitrogen]Pyrimidin-5-yl) piperidin-3-ylcarbamic acid tert-butyl ester (140mg, 0.433mmol), piperidin-3-ylcarbamic acid tert-butyl ester (130mg, 0.649mmol), X-Phos (115mg, 0.24mmol), and Cs₂CO₃(580mg, 1.78mmol) in 60mL dry EriAdding Pd into the solution in the alkane at one time₂(dba)₃(60mg, 0.065 mmol). The reaction mixture was then degassed with nitrogen for 15 minutes. Thereafter, the mixture was stirred at 95 ℃ under nitrogen for 24 hours. The solvent was evaporated, and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, petroleum ether: ethyl acetate =1:2) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidin-3-ylcarbamic acid tert-butyl ester (195mg, 92.8%) as a solid. LC-MS: 487.1[ M + H]⁺，t_R=1.67 minutes.

Step 2

5- (3-Aminopiperidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidine-7-amine salts Acid salts

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylcarbamic acid tert-butyl ester (195mg, 0.4mmol) in 85mL saturated HCl in bisIn an alkane) was stirred at room temperature for 24 hours. Evaporation of the solvent at 40 ℃ under reduced pressure gave 5- (3-aminopiperidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine hydrochloride (200mg, crude) as a yellow solid. It was used in the next step without further purification. LC-MS: 387.0[ M + H ]]⁺，t_R=1.19 minutes.

Step 3

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylamino Formyl) benzoic acid methyl ester

The method comprises the following steps:

reacting 5- (3-aminopiperidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A solution of pyrimidin-7-amine hydrochloride (200mg, 0.47mmol), 4- (methoxycarbonyl) benzoic acid (111mg, 0.61mmol), HATU (231mg, 0.61mmol) and DIEA (182mg, 1.41mmol) in 10mL of DMF was stirred at room temperature for 2 h. Only a small amount of the desired product was detected by LCMS analysis. EDCI.HCl (90mg, 0.47mmol) and DMAP (57mg, 0.47mmol) were added in one portion and the solution was stirred at room temperature for an additional 4 days. The solvent was evaporated in vacuo at 80 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, dichloromethane: methanol =20:1) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylcarbamoyl) benzoic acid methyl ester (250mg, 96.1%) as a solid. LC-MS: 549.2[ M + H]⁺，t_R=1.56 minutes.

Step 4

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylamino Formyl) benzoic acid

The method comprises the following steps:

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylcarbamoyl) benzoic acid methyl ester (250mg, 0.45mmol) and LiOH₂A solution of O (191mg, 4.5mmol) in 2mL water, 12mL methanol and 30mL thf is stirred at room temperature for 1 hour the solvent is evaporated and the residue is suspended in 30mL thf then treated with 2NHCl to pH =2 the solvent is evaporated and the residue is dissolved in 50mL thf, filtered to remove the salts the filtrate is evaporated and the crude product is purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min;wavelength: 214nm and 254 nm; the gradient conditions were: starting with 28% acetonitrile/72% water (0.1% TFAV/V) and then proceeding in a linear fashion after 9 minutes to 50% acetonitrile/50% water (0.1% TFAV/V)) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidin-3-ylcarbamoyl) benzoic acid (45mg, 18.4%) as a solid.¹HNMR(300MHz，DMSO):13.20(brs，1H)，9.63(s，1H)，8.85(s，1H)，8.04-7.95(m，4H)，7.63(s，1H)，7.41-7.32(m，2H)，6.88-6.85(m，1H)，5.34-5.31(m，1H)，4.71-4.52(m，2H)，3.70(s，3H)，3.67(s，3H)，3.04-2.97(m，2H)，2.04-1.96(m，4H)。LC-MS：535[M+H]⁺；532.9[M-H]^-，t_R=1.43 minutes. HPLC: 99.26%, at 214nm, 99.79%, at 254nm, t_R=5.37 minutes.

Example 7

Step 1

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxylic acid methyl ester

The method comprises the following steps:

to (5-chloro-thiazolo [5, 4-d)]Pyrimidin-7-yl) - (3, 4-dimethoxy-phenyl) -amine (80mg, 0.25mmol) in 10mL of bisTo the solution in alkane was added piperidine-3-carboxylic acid methyl ester (107mg, 0.75mmol), Cs₂CO₃(163mg, 0.50mmol), X-Phos (47.6mg, 0.1 mmol). Degassing under nitrogen for 3 times, and adding Pd₂(dba)₃(28mg, 0.05 mmol). The resulting mixture was degassed 1 additional time and stirred at reflux overnight. Removing excess di under reduced pressureAlkane, and the residue was purified by silica gel chromatography (200-300 mesh, petroleum ether: ethyl acetate =1:1) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxylic acid methyl ester (60mg, 56%) as an oil that solidified upon standing overnight.¹HNMR(300MHz，CDCl₃):8.41(s，1H)，7.77(s，1H)，7.64(s，1H)，7.08(d，1H，J=9.0Hz)，6.88(d，1H，J=8.7Hz)，4.92-4.87(m，1H)，4.68-4.64(m，1H)，3.93(s，3H)，3.91(s，3H)，3.71(s，3H)，3.30-3.22(m，1H)，3.10-3.09(m，1H)，2.60-2.59(m，1H)，2.11-2.06(m，1H)，1.85-1.60(m，3H)。LC-MS：430.1[M+H]⁺，452.1[M+Na]⁺，t_R=1.63 minutes.

Step 2

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxylic acid

The method comprises the following steps:

stirring of 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]To a solution of methyl pyrimidin-5-yl) piperidine-3-carboxylate (0.06g, 0.139mmol) in 5mL THF and 5mL methanol was added a solution of NaOH (0.056g, 1.39mmol) in 1mL water. After addition, the reaction was stirred at this temperature for 24 hours. The solvent was evaporated and the residue was suspended in 10ml thf and then treated with HCl to pH =2. The solvent was evaporated and then dissolved in 30ml of THF and filtered. The filtrate was evaporated to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) piperidine-3-carboxylic acid (0.057g, 98%) as a solid. LC-MS: 416.1[ M + H]⁺，t_R=1.57 min.

Step 3

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides Yl) benzoic acid tert-butyl ester

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) piperidine-3-carboxylic acid (57mg, 0.137mmol), tert-butyl-4-aminobenzoate (34.4mg, 0.178mmol), HATU (67.6mg, 0.178mmol) and DIEA (53mg, 0.411mmol) in 10mL DMF was stirred at room temperature for 72 h. The solvent was evaporated, and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, ethyl acetate: petroleum ether =1:1) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) benzoic acid tert-butyl ester (75mg, 92%) as a solid. LC-MS: 591.2[ M + H]⁺，t_R=1.77 minutes.

Step 4

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides Yl) benzoic acid

Method of producing a composite material

Stirring 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) piperidine-3-carboxamido) benzoic acid tert-butyl ester (75mg, 0.127mmol) in 5mL CDM was added dropwise TFA (2mL) then the reaction mixture was stirred at room temperature for 24 h the solvent was evaporated at 40 ℃ under reduced pressure and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 30% acetonitrile/70% water (0.1% TFAV/V) and then proceeding in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V) after 9 min to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4] thiazolo [5, 4-TFAV/V) ]-d]Pyrimidin-5-yl) piperidine-3-carboxamido) benzoic acid (25mg, 36.8%) as a white solid.¹HNMR(300MHz，CD₃OD):8.71(s，1H)，7.99-7.96(m，2H)，7.68-7.65(m，2H)，7.51(s，1H)，7.27-7.23(m，1H)，6.86(d，1H，J=8.4Hz)，3.79(s，3H)，3.70(s，3H)，2.67(brs，3H)，2.19-1.87(m，6H)。LC-MS：535[M+H]⁺；533[M-H]^-，t_R=1.47 min. HPLC: 96.74% at 214nm, 97.85% at 254nm, t_R=5.46 minutes.

Example 8

N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- 2-oxoindoline-6-carboxamides

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A mixture of pyrimidin-7-amine hydrochloride (82mg, 0.2mmol), 2-oxoindoline-6-carboxylic acid (36mg, 0.2mmol), EDCI (76mg, 0.4mmol) and N-methylimidazole (50mg, 0.6mmol) in 5mL of EDCM was stirred at room temperature for 16 h. The mixture was washed with (4 mL). With Na₂SO₄The organic layer was dried, filtered and concentrated, and the residue was purified by preparative TLC (silica gel, 20cm × 20cm, isolated with EtOAc, eluting with DCM: MeOH =1:20, v/v) to give N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) -2-oxoindoline-6-carboxamide (25mg, 23.5%).¹HNMR(300MHz，DMSO):10.52(s，1H)，9.56(s，1H)，8.81(s，1H)，8.61(d，1H，J=6.3Hz)，7.90(brs，1H)，7.48-7.46(m，2H)，7.28-7.25(m，2H)，6.93-6.90(m，1H)，4.54(brs，1H)，3.77-3.34(m，11H)，2.50-2.34(m，1H)，2.07-1.99(m，2H)。LC-MS：532[M+H]⁺，530[M-H]^-，t_R=1.35 min. HPLC: 97.39%, at 214nm, 97.05%, at 254nm, t_R=4.54 minutes.

Example 9

Step 1

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) -2-hydroxybenzoic acid methyl ester

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A mixture of pyrimidin-7-amine hydrochloride (164mg, 0.4mmol), 3-hydroxy-4- (methoxycarbonyl) benzoic acid (78mg, 0.4mmol), EDCI (153mg, 0.8mmol) and N-methylimidazole (100mg, 1.2mmol) in 5mL of EDCM was stirred at room temperature for 16 h. The mixture was washed with water (4 mL). With Na₂SO₄The organic layer was dried. After filtration and concentration, the residue was purified by column chromatography (silica gel, 100% DCM to DCM: MeOH =50:1) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-hydroxybenzoic acid methyl ester (100mg, yield 45%). LC-MS: 551[ M + H ]]⁺，t_R=1.61 min.

Step 2

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) -2-hydroxybenzoic acid

The method comprises the following steps:

stirring 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-hydroxybenzoic acid methyl ester in a solution of 5mL of THF and 5mL of methanol was added 1N NaOH solution (5 mL.) after addition, the reaction was stirred at that temperature for 16 hours, the solvent was evaporated and the residue was diluted with water and adjusted to pH =2 with HCl (aq.) the suspension was filtered and dried the crude product was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were initial 20% acetonitrile/80% water (0.1% TFAV/V) and then done in a linear fashion after 9 minutes to 45% acetonitrile/55% water (0.1% TFAV/V)) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] - [5,4-d ]]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-hydroxybenzoic acid (15mg, 14% over two steps).¹HNMR(300MHz，DMSO):9.72(s，1H)，8.85(s，1H)，8.76(d，1H，J=6.0Hz)，7.86(s，1H)，7.84(s，1H)，7.43-7.37(m，3H)，6.92(d，1H，J=8.4Hz)，4.56(brs，1H)，3.77-3.73(m，11H)，2.27-2.23(m，1H)，2.09-2.07(m，1H)。LC-MS：537[M+H]⁺，t_R=1.37 minutes. HPLC: 99.62%, at 214nm, 99.22%, at 254nm, t_R=3.53 min.

Example 10

Step 1

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) -2-methoxybenzoic acid methyl ester

The method comprises the following steps:

to 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-hydroxybenzoic acid methyl ester (100mg, 0.18mmol) inTo the mixture in 2mL DMF were added MeI (38mg, 0.27mmol) and K₂CO₃(37mg, 0.27mmol), the mixture was then stirred for 16 h, the mixture was poured into water and extracted with EtOAc (3 × 5mL), the organic layer was washed with 0.1N Cl (5mL) and brine, Na₂SO₄The organic layer was dried. After filtration and concentration, crude 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d) is obtained]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-methoxybenzoic acid methyl ester and was used in the next step without further purification (80mg, 78%). LC-MS: 565[ M + H]⁺，t_R=1.48 minutes.

Step 2

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) -2-methoxybenzoic acid

The method comprises the following steps:

stirring 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-methoxybenzoic acid methyl ester (80mg, 0.14mmol) in a solution of 5mL THF and 5mL methanol was added 1N NaOH solution (5 mL.) after addition, the reaction was stirred at that temperature for 16 hours, the solvent was evaporated, and the residue was diluted with water and adjusted to pH =2 with HCl (aq.) the suspension was filtered and dried the crude product was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were 20% acetonitrile/80% water (0.1% TFAV/V) initially and then carried out in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V) after 9 min to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] V ] was obtained]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) -2-methoxybenzoic acid (30mg, 39%) as a white solid.¹HNMR(300MHz，DMSO):9.66(s，1H)，8.83(s，1H)，8.74-8.72(m，1H)，7.88(brs，1H)，7.66(d，1H，J=7.8Hz)，7.50-7.46(m，3H)，6.91(d，1H，J=8.7Hz)，4.59(brs，1H)，3.87(s，4H)，3.76-3.72(m，8H)，2.27(brs，1H)，2.09(brs，1H)。LC-MS：550.8[M+H]⁺，t_R=1.38 minutes. HPLC: 98.09%, at 214nm, 96.40%, at 254nm, t_R=4.64 minutes.

Example 11

N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- 1H-indazole-6-carboxamides

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A mixture of pyrimidin-7-amine hydrochloride (100mg, 0.245mmol), 1H-indazole-6-carboxylic acid (40mg, 0.245mmol), EDCI (97mg, 0.49mmol), and N-methylimidazole (60mg, 0.735mmol) in 10mL of EDCM was stirred at room temperature for 16H. The mixture was washed with water (5 mL). With Na₂SO₄The organic layer was dried, filtered and concentrated, and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 25% acetonitrile/75% water (0.1% TFAV/V) and then carried out in a linear fashion to 50% acetonitrile/50% water (0.1% TFAV/V) after 9 minutes) to give N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) pyrrolidin-3-yl) -1H-indazole-6-carboxamide (45mg, 36%) as a white solid.¹HNMR(300MHz，DMSO):9.69(s，1H)，8.84(s，1H)，8.74(d，1H，J=6.3Hz)，8.14(s，1H)，8.06(s，1H)，7.89(s，1H)，7.81(d，1H，J=8.4Hz)，7.63-7.44(m，2H)，6.92(d，1H，J=9.0Hz)，4.62-4.25(m，2H)，3.96-3.66(m，10H)，2.35-2.11(m，3H)。LC-MS：516.9[M+H]⁺，t_R=1.38 minA clock. HPLC: 100% at 214nm, 100% at 254nm, t_R=5.76 min.

Example 12

N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) Pyrazine-2-carboxamides

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A mixture of pyrimidin-7-amine hydrochloride (40mg, 0.1mmol), pyrazine-2-carboxylic acid (14mg, 0.11mmol), EDCI (38mg, 0.2mmol) and N-methylimidazole (25mg, 0.3mmol) in 3mL CDM was stirred at room temperature for 15 h. The mixture was washed with water (5 mL). With Na₂SO₄The organic layer was dried, filtered and concentrated, and the residue was purified by preparative TLC (silica gel, 20cm × 20cm, isolated with EtOAc, eluting with DCM: MeOH =1:20, v/v) to give N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) pyrazine-2-carboxamide (35mg, 73%) as a white solid.¹HNMR(300MHz，DMSO):9.56(s，1H)，9.18(s，1H)，9.12(d，1H，J=7.8Hz)，8.86(d，1H，J=2.4Hz)，8.80(s，1H)，8.71(s，1H)，7.85(s，1H)，7.50-7.27(m，1H)，6.90(d，1H，J=8.4Hz)，4.64-4.62(m，1H)，3.75-3.64(m，10H)，2.27-2.16(m，2H)。LC-MS：479[M+H]⁺，477[M-H]^-，t_R=1.39 minutes. HPLC: 97.06%, at 214nm, 96.92%, at 254nm, t_R=4.63 minutes.

Example 13

6-amino-N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrroles Alk-3-yl) nicotinamide

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]A mixture of pyrimidin-7-amine hydrochloride (100mg, 0.245mmol), 6-aminonicotinic acid (40mg, 0.27mmol), EDCI (97mg, 0.49mmol) and N-methylimidazole (60mg, 0.735mmol) in 5mL of EDCM was stirred at room temperature for 16 h. The mixture was washed with water (5 mL). With Na₂SO₄The organic layer was dried. After filtration and concentration, the residue was purified by silica gel column chromatography using CH₂Cl₂And methanol (100:1 → 15:1) to obtain 6-amino-N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) nicotinamide (40mg, 33%).¹HNMR(300MHz，DMSO):9.57(s，1H)，8.81(s，1H)，8.475-8.46(m，1H)，8.27-8.25(m，2H)，7.60-7.25(m，2H)，6.92(d，1H，J=8.7Hz)，6.47-6.39(m，3H)，4.54-4.52(m，1H)，3.76-3.58(m，10H)，2.34-2.04(m，2H)。LC-MS：247[M/2+H]⁺，493[M+H]⁺，491[M-H]^-，t_R=1.22 minutes. HPLC: 95.20%, at 214nm, 95.06%, at 254nm, t_R=5.64 minutes.

Example 14

N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- 2-oxo-2, 3-dihydro-1H-benzo [ d ] yl]Imidazole-5-carboxamides

The method comprises the following steps:

reacting 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-diMethoxyphenyl) thiazolo [5,4-d]Pyrimidine-7-amine hydrochloride (100mg, 0.245mmol), 2-oxo-2, 3-dihydro-1H-benzo [ d]A mixture of imidazole-5-carboxylic acid (48mg, 0.27mmol), EDCI (97mg, 0.49mmol) and N-methylimidazole (60mg, 0.735mmol) in 10mL of EDCM was stirred at room temperature for 16 h. The mixture was washed with water (5 mL). With Na₂SO₄The organic layer was dried. After filtration and concentration, the residue was purified by silica gel column chromatography using CH₂Cl₂And methanol (100:1 to 20:1, V/V) to obtain N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) -2-oxo-2, 3-dihydro-1H-benzo [ d]Imidazole-5-carboxamide (25mg, 19%) as a white solid.¹HNMR(300MHz，DMSO):9.57(s，1H)，8.81(s，1H)，8.475-8.46(m，1H)，8.27-8.25(m，2H)，7.60-7.25(m，2H)，6.92(d，1H，J=8.7Hz)，6.47-6.39(m，3H)，4.54-4.52(m，1H)，3.76-3.58(m，10H)，2.27-2.05(m，2H)。LC-MS：247[M/2+H]⁺，493[M+H]⁺，491[M-H]^-，t_R=1.22 minutes. HPLC: 95.20%, at 214nm, 95.06%, at 254nm, t_R=5.64 minutes.

Example 15

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-mercapto) -acetic acid -1，3，4- Oxadiazol-2-yl) phenyl) benzamides

The method comprises the following steps:

reacting 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoic acid (100mg, 0.245mmol), 5- (4-aminophenyl) -1,3,4-A mixture of diazole-2-thiol (53mg, 0.27mmol), EDCI (94mg, 0.49mmol) and DMAP (90mg, 0.735mmol) in 5mL DMF was stirred at room temperature for 40 h, the mixture was poured into water and extracted with EtOAc (3 × 10mL), the aqueous layer was allowed to stand overnight and then filtered to give 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (4- (5-mercapto-1, 3, 4-)Oxadiazol-2-yl) phenyl) benzamide (28mg, 19.5%) as a white solid. 10.67(s, 1H), 10.20(s, 1H), 9.41(s, 1H), 8.96(s, 1H), 9.61(d, 1H, J =7.8Hz), 8.10(d, 1H, J =8.1Hz), 7.96-7.93(m, 3H), 7.83-7.68(m, 4H), 7.55(d, 1H, J =6.6Hz), 6.99(d, 1H, J ═ 9.0Hz), 3.81(s, 3H), 3.74(s, 3H). LC-MS: 584[ M + H ]]⁺，582[M-H]^-，t_R=1.61 min. HPLC: 96.43%, at 214nm, 96.83%, at 254nm, t_R=4.60 minutes.

Example 16

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoylamides 2-methoxybenzoic acid radical

Step 1

2-methoxy-4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide Yl) benzoic acid methyl ester

The method comprises the following steps:

3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (600mg, 2.4mmol), methyl 4-amino-2-methoxybenzoate (362 m)A mixture of g, 2mmol), EDCI (764mg, 4mmol) and DMAP (488mg, 4mmol) in 10mL DMF was stirred at room temperature for 38 h the mixture was poured into water and extracted with EtOAc (3 × 15mL), the organic layer was washed with brine and Na₂SO₄And (5) drying. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with (petroleum ether: EtOAc =4:1), to give methyl 2-methoxy-4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoylamino) benzoate (180mg, 22%) as a solid.¹HNMR(300MHz，CD₃OD):8.31(s，1H)，8.05-8.01(m，1H)，7.97-7.94(m，1H)，7.81(d，1H，J=8.7Hz)，7.71(d，1H，J=1.8Hz)，7.53(d，1H，J=7.5Hz)，7.37(dd，1H，J₁=8.7Hz，J₂=2.1Hz)，3.91(s，3H)，3.85(s，3H)。

Step 2

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoylamides 2-Methoxybenzoic acid methyl ester

The method comprises the following steps:

to the mixture under nitrogen and with stirring was added 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (155mg, 0.48mmol) and methyl 2-methoxy-4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoylamino) benzoate (180mg, 0.44mmol) in 10mL1, 4-bisTo a solution of alkane and 1mL of water was added Na₂CO₃(140mg, 1.32mmol) followed by the addition of Pd (PPh)₃)₄(26 mg). The mixture was refluxed under nitrogen for 15 hours. After cooling, the solvent was evaporated by rotary evaporation. The residue was purified by silica gel column chromatography, eluting with (petroleum ether: EtOAc =1:1), to give 4- (3- (7- (3, 4-dimethoxyphenylamino) amino) Thiazolo [5,4-d]Pyrimidin-5-yl) benzoylamino) -2-methoxybenzoic acid methyl ester (160mg, 64%) as a solid. LC-MS: 572[ M + H]⁺，t_R=1.62 minutes.

Step 3

The method comprises the following steps:

stirring 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) benzoylamino) -2-methoxybenzoic acid methyl ester (100mg, 0.175mmol) in a solution of 20mL of THF and 5mL of methanol was added 1N NaOH solution (2 mL.) after addition, the reaction was stirred at that temperature for 16 hours the solvent was evaporated and the residue was diluted with water and adjusted to pH =2 with HCl (aq.) the mixture was concentrated by rotary evaporation the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were initial 20% acetonitrile/80% water (0.1% TFAV/V) and then after 9 minutes proceeded in a linear fashion to 70% acetonitrile/30% water (0.1% TFAV/V)) to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] -methanol]Pyrimidin-5-yl) benzoylamino) -2-methoxybenzoic acid (30mg, 31%).¹HNMR(300MHz，DMSO):10.70(s，1H)，10.21(s，1H)，9.41(s，1H)，8.96(s，1H)，8.62(d，1H，J=7.5Hz)，8.09(d，1H，J=7.8Hz)，7.84(s，1H)，7.77-7.70(m，3H)，7.54(d，1H，J=8.4Hz)，6.99(d，1H，J=9.0Hz)，3.84(s，3H)，3.81(s，3H)，3.74(s，3H)。LC-MS：558[M+H]⁺，t_R=1.54 minutes. HPLC: 100% at 214nm, 100% at 254nm, t_R=6.02 min.

Example 17

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-oxo) -4, 5-dihydro-1, 2,4- Oxadiazol-3-yl) phenyl) benzamides

The method comprises the following steps:

to the 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoic acid (40mg, 0.1mmol) and 3- (4-aminophenyl) -1,2,4-To a mixture of diazol-5 (4H) -one hydrochloride (22mg, 0.1mmol) in 3ml dccm was added EDCI (58mg, 0.3mmol) followed by N-methylimidazole (25mg, 0.3 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc to give 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (4- (5-oxo-4, 5-dihydro-1, 2, 4-)Oxadiazol-3-yl) phenyl) benzamide (15mg, 26%) was a white solid.¹HNMR(300MHz，DMSO):10.82(s，1H)，10.22(s，1H)，9.43(s，1H)，8.98(s，1H)，8.64(d，1H，J=8.1Hz)，8.12-8.02(m，3H)，7.87-7.54(m，5H)，7.01(d，1H，J=9.0Hz)，3.82(s，3H)，3.76(s，3H)。LC-MS：568[M+H]⁺，t_R=1.54 min, HPLC: 97.16%, at 214nm, 96.94%, at 254nm, t_R=2.86 minutes.

Example 18

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1H-indazol-5-yl) Benzamide derivatives

The method comprises the following steps:

to the 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]To a mixture of pyrimidin-5-yl) benzoic acid (82mg, 0.2mmol) and 1H-indazol-5-amine (27mg, 0.2mmol) in 5ml dccm was added EDCI (80mg, 0.6mmol) followed by N-methylimidazole (50mg, 0.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc to give 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (1H-indazol-5-yl) benzamide (20mg, 19%) as a white solid.¹HNMR(300MHz，DMSO):13.01(s，1H)，10.46(s，1H)，10.14(s，1H)，9.42(s，1H)，8.99(s，1H)，8.62(d，1H，J=7.8Hz)，8.29(s，1H)，8.13-8.10(m，2H)，7.88(s，1H)，7.74-7.69(m，2H)，7.58-7.55(m，2H)，7.01(d，1H，J=8.7Hz)，3.84(s，3H)，3.75(s，3H)。LC-MS：524[M+H]⁺，t_R=1.50 minutes. HPLC: 95.85%, at 214nm, 95.63%, at 254nm, t_R=4.60 minutes.

Example 19

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1H-indazol-6-yl) Benzamide derivatives

The method comprises the following steps:

to the 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzathinesTo a mixture of acid (82mg, 0.2mmol) and 1H-indazol-6-amine (27mg, 0.2mmol) in 5mL DCM was added EDCI (80mg, 0.6mmol) followed by N-methylimidazole (50mg, 0.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica eluting with EtOAc to give 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (1H-indazol-6-yl) benzamide (30mg, 28%) as a white solid.¹HNMR(300MHz，DMSO):12.96(s，1H)，10.57(s，1H)，10.15(s，1H)，9.42(s，1H)，8.99(s，1H)，8.63(d，1H，J=8.1Hz)，8.33(s，1H)，8.12(d，1H，J=7.8Hz)，8.03(s，1H)，7.87(s，1H)，7.76-7.70(m，2H)，7.57(dd，1H，J1=8.7Hz，J₂=2.4Hz)，7.45(dd，1H，J₁=8.7Hz，J₂=1.5Hz)，7.01(d，1H，J=9.0Hz)，3.84(s，3H)，3.74(s，3H)。LC-MS：524[M+H]⁺，t_R=1.52 minutes. HPLC: 97.61%, at 214nm, 97.19%, at 254nm, t_R=4.75 minutes.

Example 20

4- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) Ethyl) benzamide

Step 1

N- (2- (pyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) Benzamide derivatives

The method comprises the following steps:

to a solution of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (150mg, 0.60mmol) in 30mL DCM was added 2- (pyridin-4-yl) ethylamine (110mg, 0.9mmol), HATU (274mg, 0.72mmol) and DIEA (232mg, 1.80mmol) at room temperature. Then theThe reaction mixture was stirred at room temperature overnight. With saturated NaHCO₃(2 × 20mL), brine (20mL), then dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude N- (2- (pyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (250mg) which was used without further purification LC-MS: 353[ M + H ]. RTM]⁺，t_R=1.22 minutes.

Step 2

The method comprises the following steps:

stirring 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d at room temperature]Pyrimidin-7-amine (100mg, 0.31mmol) and N- (2- (pyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (140mg, 0.4mmol) in 25mL1, 4-bisAdding Na into the solution in the alkane₂CO₃(64mg, 0.6mmol) and 3mL of water. The mixture was then degassed with nitrogen for 15 minutes. One-time addition of Pd (PPh)₃)₄(20mg, 0.017mmol) and the reaction mixture was heated at reflux under nitrogen for 16 h. The solvent was evaporated and the residue was purified by silica gel chromatography (200 mesh 300, eluted with EtOAc) to give 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) ethyl) benzamide (50mg, 31%) as a yellow solid.¹HNMR(300MHz，DMSO):10.15(s，1H)，9.37(s，1H)，8.68(t，1H，J=5.3Hz)，8.46-8.42(m，4H)，7.94-7.91(m，2H)，7.81(d，1H，J=2.7Hz)，7.52-7.47(m，1H)，7.27-7.26(m，2H)，7.00(d，1H，J=8.7Hz)，4.02(s，3H)，4.00(s，3H)，3.58-3.52(m，2H)，2.89(t，2H，J=7.0Hz)。LC-MS：513[M+H]⁺，511[M-H]^-，t_R=1.32 minutes. HPLC: 97.72%, at 214nm, 96.31%, at 254nm, t_R=4.19 minutes.

Example 21

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) Ethyl) piperidine-4-carboxamide

Step 1

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-4-carboxylic acid methyl ester

Method of producing a composite material

Reacting 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (200mg, 0.62mmol), piperidine-4-carboxylic acid methyl ester (177mg, 1.24mmol), Cs₂CO₃(404mg，1.24mmol)、X-Phos(20mg，0.042mmol)、Pd(dba)₂(20mg, 0.035mmol) in 30mL ofMixtures in alkanes at 100 ℃ in N₂Stirred under atmosphere for 18 hours. Removing excess di under reduced pressureAlkane and the residue was purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate =3: 1) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-4-carboxylic acid methyl ester (150mg, 56%) as a yellow solid. LC-MS: 430[ M + H ]]⁺，t_R=1.63 minutes.

Step 2

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-4-carboxylic acid

The method comprises the following steps:

stirring of 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) piperidine-4-carboxylic acid methyl ester (150mg, 0.35mmol) in 7.5mL1, 4-bisAlkane and 7.5mLH₂To the solution in O was added NaOH (140mg, 3.5 mmol). The reaction was then stirred at 60 ℃ for 3 hours. The solvent was evaporated and the residue was suspended in 50mLH₂O, then treated with 1NHCl to pH =5. A white solid appeared, which was then filtered and dried to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-4-carboxylic acid (130mg, 90%) as a yellow solid.

Step 3

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) piperidine-4-carboxylic acid (50mg, 0.12mmol), 2- (pyridin-4-yl) ethylamine (22mg, 0.18mmol), EDCI (69mg, 0.36mmol) and 1-methyl-1H-imidazole (50mg, 0.60mmol) in 25mL DCM was stirred at room temperature for 16H. Excess DCM was removed under reduced pressure and H was used₂The residue was washed with O (30mL) and EtOAc (20mL) and dried under reduced pressure to give 1- (7- (3, 4-)Dimethoxyphenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) ethyl) piperidine-4-carboxamide (30mg, 48%) as a yellow solid.¹HNMR(300MHz，CD₃OD):8.62(s，1H)，8.44-8.42(m，2H)，7.61(d，1H，J=2.4Hz)，7.31-7.18(m，3H)，6.95(d，1H，J=8.7Hz)，4.82-4.77(m，2H)，3.86(s，3H)，3.84(s，3H)，3.47(t，2H，J=6.9Hz)，2.95-2.92(m，2H)，2.86(t，2H，J=6.9Hz)，2.44(brs，1H)，1.74-1.62(m，4H)。LC-MS：520[M+H]⁺，260[M/2+H]⁺，518[M-H]^-，t_R=1.29 min. HPLC: 97.06%, at 214nm, 97.32%, at 254nm, t_R=3.47 min.

Example 22

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (2-oxo) -1, 2-dihydropyridin-4-yl) ethyl) piperidine-4-carboxamide

Step 1

2-methoxy-4-methylpyridine

The method comprises the following steps:

2-chloro-4-methylpyridine (20g, 0.156mol) and NaOCH₃A mixture of (9.3g, 0.172mol) in DMSO (200mL) was stirred at 100 ℃ for 4 hours. This solution was added to H₂O, then extracted with ethyl acetate (50mL × 2) over H₂The organic layer was washed with O (300mL), brine (300mL), and dried and concentrated to give 2-methoxy-4-methylpyridine (9g, 46%). LC-MS: 124[ M + H ]]⁺，t_R=1.21 min.

Step 2

3- (2-methoxypyridin-4-yl) propionic acid

The method comprises the following steps:

sodium amide (4g, 103mmol) and 2-methoxy-4-methylpyridine (9g, 73mmol) in liquid ammonia (150mL) were stirred at-50 ℃ for 30 minutes, the dark orange mixture was cautiously treated with sodium 2-chloroacetate (9g, 78mmol), after 1.5 hours, a second portion of sodium 2-chloroacetate (8g, 69mmol) was added, after a total reaction time of 3.5 hours, the reaction mixture was treated with ammonium chloride (13g, 245mmol), ammonia was evaporated, and the solid residue was treated with water (200mL), and extracted with DCM (50mL × 3), the aqueous layer was acidified to pH =1 with concentrated hydrochloric acid, then extracted with ethyl acetate (3 × 50mL), the aqueous layer was basified to pH4.5 with 40% w/v aqueous sodium hydroxide solution, then cooled to 0-5 ℃, and stirred at this temperature for 2 hours, the mixture was filtered under reduced pressure, and washed with water (5mL), and dried, yielding 3- (2-methoxy-pyridine-4-methylpyridine-propionic acid (3 g, 24H) as a white cake [ LC ] + LC: [ 3.5% ] solid:%]⁺，t_R=1.10 minutes.

Step 3

2- (2-methoxypyridin-4-yl) ethylamine hydrochloride

The method comprises the following steps:

3- (2-methoxypyridin-4-yl) propionic acid (2.5g, 18.3mmol) was added to concentrated H₂SO₄(10mL) and stirred at 70 ℃. When the solution became clear, sodium azide (1.8g, 27.6mmol) was added slowly over 2 hours. The mixture was stirred at 70 ℃ for 2 hours, then at room temperature for 16 hours, and then poured onto ice. With saturated NaHCO₃The solution was basified and extracted with DCM (3 × 100mL) over anhydrous Na₂SO₄The combined organic layers were dried and evaporated under reduced pressure to leave an oilThe retentate dissolves in anhydrous EtOH and will be in IIHCl in an alkane was added to the solution. Evaporation of the solvent under reduced pressure gave 2- (2-methoxypyridin-4-yl) ethylamine hydrochloride (1.3g, 50%) as a yellow solid. LC-MS: 153[ M + H ]]⁺，t_R=0.36 min.

Step 4

4- (2-aminoethyl) pyridin-2 (1H) -one hydrobromide

The method comprises the following steps:

a solution of 2- (2-methoxypyridin-4-yl) ethylamine hydrochloride (0.8g, 4.23mmol) was dissolved in 45% HBr (7mL) and HOAc (7 mL). The mixture was heated to reflux for 4 hours and then the solvent was removed under reduced pressure. The residue was washed with THF (20mL) and dried to give 4- (2-aminoethyl) pyridin-2 (1H) -one hydrobromide (0.8g86%) as a gray solid. LC-MS: 139[ M + H ] +, tR =0.28 min.

Step 5

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) piperidine-4-carboxylic acid (70mg, 0.22mmol), 4- (2-aminoethyl) pyridin-2 (1H) -one hydrobromide (70mg, 0.32mmol), EDC (170mg, 0.89mmol) and 1-methyl-1H-imidazole (108mg, 1.32mmol) in 20mL LPCM at room temperatureStir overnight. Excess DCM was removed under reduced pressure and the residue was taken up with H₂O (30mL) and EtOAc (20mL) were triturated together then dried under reduced pressure to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) -N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) piperidine-4-carboxamide (25mg, 40%) as a yellow solid.¹HNMR(300MHz，CD₃OD):8.62(s，1H)，7.61(d，1H，J=2.4Hz)，7.35(d，1H，J=7.2Hz)，7.20(dd，1H，J₁=8.7Hz，J₂=2.4Hz)，6.95(d，1H，J=8.7Hz)，6.36-6.32(m，2H)，4.83-4.79(m，2H)，3.86(s，3H)，3.84(s，3H)，3.44(t，2H，J=6.8Hz)，3.00-2.92(m，2H)，2.70(t，2H，J=6.8Hz)，2.45(brs，1H)，1.80-1.64(m，4H)。LC-MS：536[M+H]⁺，534[M-H]^-，t_R=1.38 minutes. HPLC: 95.70%, at 214nm, 96.10%, at 254nm, t_R=3.65 minutes.

Example 23

4- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (2-oxo) -1, 2-dihydropyridin-4-yl) ethyl) benzamide

Step 1

N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxan Boroacropentan-2-yl) benzamides

The method comprises the following steps:

a mixture of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (100mg, 0.4mmol), 4- (2-aminoethyl) pyridin-2 (1H) -one hydrobromide (96mg, 0.44mmol), HATU (182mg, 0.48mmol) and DIEA (155mg, 1.20mmol) in 30mL LPCM was stirred at room temperature overnight. With saturated NaHCO₃(2×30mL), brine (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (160mg) and was used without further purification. LC-MS: 369[ M + H]⁺，t_R=1.35 min.

Step 2

The method comprises the following steps:

in N₂Under the atmosphere, 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (100mg, 0.31mmol), N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (140mg, 0.38mmol), Pd (PPh)₃)₄(20mg, 0.017mmol) was added to 20mL1, 4-bisIn an alkane. Na in 3mL of water was added₂CO₃(100mg, 0.94mmol) and the mixture was then stirred at reflux for 18 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1), to give 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) benzamide (15mg, 9%) as a yellow solid.¹HNMR(300MHz，DMSO):11.34(s，1H)，10.15(s，1H)，9.38(s，1H)，8.67-8.65(m，1H)，8.45(s，1H)，8.43(s，1H)，7.95-7.81(m，3H)，7.51-7.47(m，1H)，7.26(d，1H，J=6.6Hz)，7.01(d，1H，J=8.7Hz)，6.15(s，1H)，6.08(d，1H，J=6.6Hz)，3.83(s，3H)，3.78(s，3H)，3.50-3.48(m，2H)，2.72-2.65(m，2H)。LC-MS：528.9[M+H]⁺，t_R=1.35 min. HPLC: 98.40%, at 214nm, 99.86%, at 254nm, t_R=5.18 min.

Example 24

4- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (1-methyl-2-) Oxo-1, 2-dihydropyridin-4-yl) ethyl) benzamide

Step 1

2- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) isoindoline-1, 3-dione

The method comprises the following steps:

a mixture of 4- (2-aminoethyl) pyridin-2 (1H) -one hydrobromide (400mg, 1.83mmol), isobenzofuran-1, 3-dione (271mg, 1.83mmol) and DIEA (472mg, 3.66mmol) in 30mL xylene was stirred at 140 ℃ for 6H. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with DCM/MeOH (30/1) to give 2- (2- (2-oxo-1, 2-dihydropyridin-4-yl) ethyl) isoindoline-1, 3-dione (370mg, 76%) as a white solid. LC-MS: 269[ M + H]⁺，t_R=1.23 min.

Step 2

2- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) isoindoline-1, 3-dione

The method comprises the following steps:

2- (2- (2-oxo-1, 2-dihydro)Pyridin-4-yl) ethyl) isoindoline-1, 3-dione (300mg, 1.1mmol), CH₃I (1.0g, 7mmol) and K₂CO₃(700mg, 5mmol) of the mixture in 30mL of CCM and 10mL of DMF was stirred at room temperature for 3 days. Add 30 mLDCM. By H₂O (3 × 30mL) washed the mixture, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give 2- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) isoindoline-1, 3-dione (230mg, 73%) as a white solid]⁺，t_R=1.29 min.

Step 3

4- (2-aminoethyl) -1-methylpyridin-2 (1H) -one hydrochloride

The method comprises the following steps:

2- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) isoindoline-1, 3-dione (230mg, 0.8mmol) in concentrated HCl (25mL) was stirred at 95 ℃ for 18 h. Addition of H₂O (20mL), then extracted with ethyl acetate (3 × 30mL) the aqueous layer was concentrated under reduced pressure to give 4- (2-aminoethyl) -1-methylpyridin-2 (1H) -one hydrochloride (130mg, 85%). LC-MS: 153[ M + H ] -hydrochloride]⁺，t_R=0.42 min.

Step 4

N- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2- Dioxaborolan-2-yl) benzamides

The method comprises the following steps:

4- (2-aminoethyl) -1-methylpyridin-2 (1H) -one hydrochloride (76mg, 0.4mmol), 4- (4, 4,5, 5-tetramethyl-A mixture of 1,3, 2-dioxaborolan-2-yl) benzoic acid (100mg, 0.4mmol), HATU (190mg, 0.5mmol) and DIEA (260mg, 2mmol) in 25mL DCM and 5mL DCMF was stirred at room temperature overnight. With saturated NaHCO₃(2 × 20mL), brine (2 × 20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude N- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (230mg) and used in the next step without further purification LC-MS: 383[ M + H]⁺，t_R=1.41 minutes.

Step 5

The method comprises the following steps:

in N₂5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d ] in 3mL of water under an atmosphere]Pyrimidin-7-amine (150mg, 0.47mmol), N- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) -4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (220mg, crude), Pd (PPh)₃)₄(40mg, 0.035mmol) and Na₂CO₃(100mg, 0.94mmol) 30mL1, 4-bisIn an alkane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with DCM/MeOH (20/1, v/v) to give 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (2- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) ethyl) benzamide (30mg, 12%) as a yellow solid.¹HNMR(300MHz，CD₃OD):9.13(s，1H)，8.52-8.50(m，2H)，7.89-7.80(m，3H)，7.58(d，1H，J=6.9Hz)，7.40(dd，1H，J₁=8.4Hz，J₂=2.4Hz)，7.03(d，1H，J=8.7Hz)，6.46(s，1H)，6.38(dd，1H，J₁=6.6Hz，J₂=1.8Hz)，3.94(s，3H)，3.88(s，3H)，3.66(t，2H，J=7.0Hz)，3.54(s，3H)，2.84(t，2H，J=7.0Hz)。LC-MS：543[M+H]⁺，541[M-H]^-，t_R=1.37 minutes. HPLC: 100% at 214nm, 100% at 254nm, t_R=5.36 min.

Example 25

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) Ethyl) piperidine-3-carboxamide

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) piperidine-3-carboxylic acid (50mg, 0.12mmol), 2- (pyridin-4-yl) ethylamine (50mg, 0.41mmol), EDC (50mg, 0.26mmol) and 1-methyl-1H-imidazole (50mg, 0.61mmol) in 25mL DCM was stirred at room temperature overnight. Excess DCM was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (pyridin-4-yl) ethyl) piperidine-3-carboxamide (25mg, 39%) as a yellow solid.¹HNMR(300MHz，DMSO):9.64(s，1H)，8.85(s，1H)，8.46-8.44(m，2H)，8.02-8.01(m，1H)，7.71-7.69(m，1H)，7.33-7.21(m，3H)，6.92(d，1H，J=9.0Hz)，4.64-4.63(m，2H)，3.75(s，3H)，3.73(s，3H)，3.35-3.30(m，2H)，2.98-2.91(m，2H)，2.77-2.75(m，2H)，2.51(brs，1H)，1.82-1.42(m，4H)。LC-MS：520[M+H]⁺，260[M/2+H]⁺，518[M-H]^-，t_R=1.29 minA clock. HPLC: 97.55%, at 214nm, 97.72%, at 254nm, t_R=3.51 minutes.

Example 26

3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid

Step 1

5-chloro-N- (3- (methylsulfonyl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]A mixture of pyrimidine (200mg, 0.97mmol), 3- (methylsulfonyl) aniline (182mg, 1.07mmol) and DIEA (375g, 2.91mmol) in 20mL of DMSO was stirred at room temperature overnight. The mixture was poured into 150mL of water and filtered, the resulting solid was washed with petroleum ether and dried to give the crude product which was purified by silica gel chromatography (silica gel 200-300 mesh) eluting with ethyl acetate to give 5-chloro-N- (3- (methylsulfonyl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (220mg, 66%) as a yellow solid. LC-MS: 341[ M + H]⁺，3621[M+Na]⁺，t_R=1.48 minutes.

Step 2

3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester

The method comprises the following steps:

in N₂5-chloro-N- (3- (methylsulfonyl) phenyl) thiazolo [5, 4] in 5mL of water under an atmosphere-d]Pyrimidin-7-amine (200mg, 0.59mmol), methyl 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (183mg, 0.7mmol), Pd (PPh)₃)₄(30mg, 0.026mmol) and Na₂CO₃(127mg, 1.2mmol) 5mL of water and 50mL of 1, 4-bisIn a solvent mixture of alkanes. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give 3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid methyl ester (150mg, 58%) as a yellow solid.¹HNMR(300MHz，DMSO):10.76(s，1H)，9.45(s，1H)，8.99-8.98(m，1H)，8.93(s，1H)，8.73(d，1H，J=7.8Hz)，8.21-8.18(m，1H)，8.09(d，1H，J=7.8Hz)，7.69-7.65(m，3H)，3.91(s，3H)，3.26(s，3H)。LC-MS：441[M+H]⁺，903[2M+Na]⁺，439[M-H]^-，t_R=1.61 min. HPLC: 98.78%, at 214nm, 97.72%, at 254nm, t_R=8.14 minutes.

Example 27

The method comprises the following steps:

will be at 3mL1, 4-bisAlkane and 3mLH₂3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5,4-d ] in O]Pyrimidin-5-yl) benzoic acid methyl ester (130mg, 0.29mmol) and NaOH (130mg, 3.25mmol) were stirred at room temperature for 3 hours, then treated with concentrated HCl to pH =3-4-removal of solvent under reduced pressure and purification of the residue by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 40% acetonitrile/60% water (0.1% TFAV/V) and then linear progression to 55% acetonitrile/45% water (0.1% TFAV/V) after 9 min) to give 3- (7- (3- (methylsulfonyl) phenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoic acid (50mg, 40%) as a yellow solid.¹HNMR(300MHz，DMSO):13.18(brs，1H)，10.76(s，1H)，9.45(s，1H)，8.99-8.95(m，2H)，8.72(dt，1H，J₁=7.8Hz，J₂=1.5Hz)，8.22-8.18(m，1H)，8.08(dt，1H，J₁=8.1Hz，J₂=1.4Hz)，7.69-7.61(m，3H),3.24(s，3H)。LC-MS：427[M+H]⁺，t_R=1.48 minutes. HPLC: 98.42%, at 214nm, 99.23%, at 254nm, t_R=5.75 minutes.

Example 28

3- (7- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) Benzoic acid hydrochloride

Step 1

2- (methoxymethyl) -1- (3-nitrophenyl) pyrrolidine

The method comprises the following steps:

in N₂Under the atmosphere, 1-bromo-3-nitrobenzene (300mg, 1.48mmol), 2- (methoxymethyl) pyrrolidine (187mg, 1.63mmol), Cs₂CO₃(800mg，2.45mmol)、X-Phos(50mg，0.1mmol)、Pd(dba)₂(50mg, 0.087mmol) in 50mL of ErbBThe mixture in the alkane was stirred at reflux overnight. Removing by reduced pressureAmount twoAlkane, and the residue was purified by silica gel chromatography, eluting with a mixture of petroleum ether and ethyl acetate (5:1) to give 2- (methoxymethyl) -1- (3-nitrophenyl) pyrrolidine (250mg, 72%) as a yellow solid. LC-MS: 237[ M + H ]]⁺，t_R=1.71 min.

Step 2

3- (2- (methoxymethyl) pyrrolidin-1-yl) aniline

The method comprises the following steps:

a mixture of 2- (methoxymethyl) -1- (3-nitrophenyl) pyrrolidine (200mg, 0.85mmol), Pd/C (50mg, 10%) in 50mM My OH at room temperature in H₂Stirred under atmosphere for 18 hours. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give crude 3- (2- (methoxymethyl) pyrrolidin-1-yl) aniline (170mg) as an oil. LC-MS: 207[ M + H]⁺，t_R=1.15 min.

Step 3

5-chloro-N- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]A mixture of pyrimidine (170mg, 0.83mmol), 3- (2- (methoxymethyl) pyrrolidin-1-yl) aniline (170mg, 0.83mmol) and DIEA (214g, 1.66mmol) in 15mL of DMMSO was stirred at room temperature overnight, 100mL of water was added, the mixture was extracted with ethyl acetate (3 × 30mL), the organic was washed with water (2 × 30mL) and brine (30mL)Concentrating the layer under reduced pressure to obtain 5-chloro-N- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (200mg, 64%) as a yellow solid. LC-MS: 376[ M + H]⁺，t_R=1.75 minutes.

Step 4

3- (7- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) Benzoic acid methyl ester

The method comprises the following steps:

in N₂To 5-chloro-N- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenyl) thiazolo [5,4-d ] in 5mL of water under an atmosphere]Pyrimidin-7-amine (200mg, 0.53mmol), methyl 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (153mg, 0.58mmol), Pd (PPh)₃)₄(40mg, 0.035mmol) and Na₂CO₃(112mg, 1.06mmol) 30mL1, 4-bisIn an alkane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (3:1) to give 3- (7- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid methyl ester (150mg, 59%) as a yellow solid.¹HNMR(300MHz，CDCl₃):9.13(s，1H)，8.82(s，1H)，8.68(d，1H，J=7.8Hz)，8.14(d，1H，J=7.8Hz)，8.06(s，1H)，7.54(t，1H，J=7.8Hz)，7.35(s，1H)，7.28(t，1H，J=7.2Hz)，7.16(d，1H，J=7.8Hz)，6.49(d，1H，J=7.5Hz)，3.96(brs，4H)，3.57-3.50(brs，2H)，3.32(s，3H)，3.25-3.19(m，2H)，2.11-2.02(m，5H)。LC-MS：476[M+H]⁺，t_R=1.93 minutes. HPLC: 98.15%, at 214nm, 97.85%, at 254nm, t_R=5.24 min.

Step 5

The method comprises the following steps:

will be at 3mL1, 4-bisAlkane and 3mLH₂3- (7- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenylamino) thiazolo [5,4-d in O]Pyrimidin-5-yl) benzoic acid methyl ester (100mg, 0.21mmol) and NaOH (100mg, 2.5mmol) were stirred at room temperature for 3 hours, then treated with concentrated HCl to pH =3-4 the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 50% acetonitrile/50% water (0.1% TFAV/V) and then proceeding in a linear fashion to 80% acetonitrile/20% water (0.1% TFAV/V) after 9 minutes) to give 3- (7- (3- (2- (methoxymethyl) pyrrolidin-1-yl) phenylamino) thiazolo [5,4-d ]/V ]]Pyrimidin-5-yl) benzoic acid hydrochloride (30mg, 31%) as a yellow solid.¹HNMR(300MHz，DMSO):10.28(s，1H)，9.41(s，1H)，8.98(s，1H)，6.62(d，1H，J=7.5Hz)，8.08(d，1H，J=7.5Hz)，7.66-7.62(m，2H)，7.47(brs，1H)，7.28(brs，1H)，3.95(brs，1H)，3.54-3.51(m，2H)，3.32-3.27(m，2H)，3.19(s，3H)，2.03-1.19(m，4H)。LC-MS：462[M+H]⁺，t_R=1.66 minutes. HPLC: 96.12%, at 214nm, 96.76%, at 254nm, t_R=6.84 minutes.

Example 29

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl)Benzylamino) benzathines Acid hydrochloride

Step 1

4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylamino) benzoic acid tert-butyl ester Butyl ester

The method comprises the following steps:

a mixture of 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (100mg, 0.43mmol), tert-butyl 4-aminobenzoate (83mg, 0.43mmol), NaHB (OAc)₃A mixture of (273g, 1.29mmol) and AcOH (2 drops) in 30mL of LPCM was stirred at room temperature overnight. With saturated NaHCO₃The mixture was washed (30mL), water (2 × 30mL), and brine (30mL), over Na₂SO₄Dried and concentrated under reduced pressure to give crude tert-butyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylamino) benzoate (130mg) as a black oil. LC-MS: 410[ M + H]⁺，t_R=1.92 minutes.

Step 2

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzylamino) benzyl Tert-butyl ester

The method comprises the following steps:

in N₂To 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d ] in 5mL of water under an atmosphere]Pyrimidin-7-amine (100mg, 0.31mmol), tert-butyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylamino) benzoate (150mg, crude), Pd (PPh)₃)₄(30mg, 0.026mmol) and Na₂CO₃(150mg, 1.41mmol) 30mL1, 4-bisIn an alkane. The mixture was stirred at reflux for 18 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography, eluting with petroleum ether and ethyl acetate (5:1) to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzylamino) benzoic acid tert-butyl ester (72mg, 41%) as a yellow solid.¹HNMR(300MHz，DMSO):8.87(s，1H)，8.54-8.47(m，2H)，7.86-7.82(m，3H)，7.49-7.28(m，2H)，7.27-7.23(m，1H)，6.94(d，1H，J=8.7Hz)，6.65-6.62(m，2H)，4.49(s，2H)，4.16(s，3H)，4.13(s，3H)。LC-MS：570[M+H]⁺，t_R=1.83 minutes. HPLC: 98.31%, at 214nm, 98.91%, at 254nm, t_R=8.06 min.

Example 30

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzylamino) benzyl Acid hydrochloride

The method comprises the following steps:

stirring 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) benzylamino) benzoic acid tert-butyl ester (45mg, 0.08mmol) at 10mLCH₂Cl₂Adding CF into the solution₃COOH (4mL) the mixture was then stirred at room temperature for 16 h the solvent was evaporated and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 20% acetonitrile/80% water (0.1% TFAV/V) and then proceeding in a linear fashion to 50% acetonitrile/50% water (0.1% TFAV/V) after 9 min) to give the corresponding trifluoroethyleneAn acid salt. The salt was suspended in MeOH (10mL) and concentrated HCl (0.5mL) was added dropwise and the mixture stirred for 10 min. The mixture was then concentrated under reduced pressure to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzylamino) benzoic acid hydrochloride (25mg, 57%) as a yellow solid.¹HNMR(300MHz，DMSO):10.05(s，1H)，9.36(s，1H)，8.43(s，1H)，8.36(brs，1H)，7.81(s，1H)，7.67-7.48(m，5H)，7.00(d，1H，J=8.7Hz)，6.65(d，1H，J=9.0Hz)，4.44(s，2H)，3.82(s，3H)，3.78(s，3H)。LC-MS：514[M+H]⁺，t_R=1.53 min. HPLC: 96.98%, at 214nm, 96.99%, at 254nm, t_R=4.45 minutes.

Example 31

(Z) -4- (2- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenyl) -2- Fluorovinyl) benzoic acid

Step 1

(3-bromophenyl) (hydroxy) methylphosphonic acid diethyl ester

The method comprises the following steps:

a mixture of 3-bromobenzaldehyde (22.2g, 0.12mol) and diethyl phosphonate (13.8g, 0.1mol) was reacted at 100 ℃ and 110 ℃ under N₂Stirred under atmosphere for 15 hours. The mixture was purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate =10-0: 1) to give diethyl (3-bromophenyl) (hydroxy) methylphosphonate (22g, 68%) as a colorless oil. LC-MS: 323[ M + H]⁺，347[M+Na]⁺，669[2M+Na]⁺，t_R=1.41 minutes.

Step 2

(3-bromophenyl) fluoromethylphosphonic acid diethyl ester

The method comprises the following steps:

at-78 ℃ in N₂A solution of diethyl (3-bromophenyl) (hydroxy) methylphosphonate (5g, 15mmol) in 40mL LPCM was added dropwise to a solution of DAST (2.9g, 18mmol) in 20mL LPCM under an atmosphere via syringe. The mixture was warmed to room temperature and stirred for an additional 2 hours, then carefully quenched by pouring into a solution of EtOH (50mL) and pyridine (3 mL). The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate =3:1-1: 1) to give diethyl (3-bromophenyl) fluoromethylphosphonate (4.7g, 94%) as a colorless oil. LC-MS: 327[ M + H]⁺，349[M+Na]⁺，673[2M+Na]⁺，t_R=1.62 minutes.

Step 3

(Z) -4- (2- (3-bromophenyl) -2-fluorovinyl) benzoic acid methyl ester

The method comprises the following steps:

at-78 ℃ in N₂A solution of diethyl (3-bromophenyl) fluoromethylphosphonate (2.1g, 6.5mmol) in 50mL THF was added dropwise to a solution of LDA (5mL, 10mmol) in THF under an atmosphere via syringe. After 30 minutes at this temperature, methyl 4-formylbenzoate (1.1g, 6.5mmol) in 50ml of THF was added dropwise via syringe, then stirred at this temperature for 30 minutes, then warmed to room temperature over 4 hours, and stirred overnight. The mixture is poured into H₂O (300mL) was then extracted with ethyl acetate (3 × 100 mL.) the combined organic layers were concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate =50:1) to give methyl (Z) -4- (2- (3-bromophenyl) -2-fluorovinyl) benzoate (0).73g, 33.6%) as a yellow solid.

Step 4

(Z) -4- (2-fluoro-2- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) ethane Alkenyl) benzoic acid methyl ester

The method comprises the following steps:

methyl (Z) -4- (2- (3-bromophenyl) -2-fluorovinyl) benzoate (700mg, 2.1mmol), bis (pinacolato) diboron (600mg, 2.4mmol), Pd (dppf) Cl₂A mixture of (150mg, 0.2mmol) and KOAc (620mg, 6.3mmol) in 30mL of LDMSO was at 80 deg.C under N₂Stir under atmosphere overnight. To the mixture was added 200mL of ethyl acetate, washed with water, and washed with anhydrous Na₂SO₄Dried and concentrated under reduced pressure to give methyl (Z) -4- (2-fluoro-2- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) vinyl) benzoate (500mg, crude) as an oil which was used in the next step without further purification.

Step 5

(Z) -4- (2- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenyl) -2- Fluorovinyl) benzoic acid methyl ester

The method comprises the following steps:

stirring 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d at room temperature]Pyrimidin-7-amine (100mg, 0.31mmol) and methyl (Z) -4- (2-fluoro-2- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) vinyl) benzoate (150mg, 0.39mmol) in 25mL1, 4-bisAdding Na into the solution in the alkane₂CO₃(64mg, 0.6mmol) and 3mL of water. The mixture was then degassed with nitrogen for 15 minutes. One-time addition of Pd (PPh)₃)₄(20mg, 0.017mmol) and the reaction mixture is stirred under nitrogen at reflux for 18 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (200 mesh, 300 mesh, eluting with a mixture of petroleum ether and ethyl acetate =1:1) to give (Z) -4- (2- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenyl) -2-fluorovinyl) benzoic acid methyl ester (70mg, 42%) as a yellow solid. 543[ M + H ]]⁺，t_R=1.88 min.

Step 6

The method comprises the following steps:

(Z) -4- (2- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d) stirred at room temperature]Pyrimidin-5-yl) phenyl) -2-fluorovinyl) benzoic acid methyl ester (50mg, 0.09mmol) in 3mL1, 4-bisAlkane and 3mLH₂NaOH (140mg, 3.5mmol) was added to the solution in O then the reaction was stirred at room temperature overnight, then treated with concentrated HCl to pH =3-4 the solvent was removed under reduced pressure and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 40% acetonitrile/60% water (0.1% TFAV/V) and then proceeding in a linear fashion after 9 minutes to 55% acetonitrile/45% water (0.1% TFAV/V)) to give (Z) -4- (2- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d-)]Pyrimidin-5-yl) phenyl) -2-Fluorovinyl) benzoic acid (25mg, 51%) as a yellow solid.¹HNMR (300MHz in DMSO):12.94(brs, 1H, can be D)₂O exchange), 10.18(s, 1H, may be D₂O exchange), 9.40(s, 1H), 8.54-8.49(m, 2H), 7.82-7.74(m, 3H), 7.41-7.31(m, 5H), 6.90-6.78(m, 2H), 3.80(s, 6H). LC-MS: 529[ M + H]⁺，527[M-H]^-，t_R=1.71 min. HPLC: 96.85%, at 214nm, 95.49%, at 254nm, t_R=5.08 min.

Example 32

(E) -4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) styryl groups Benzoic acid

Step 1

(4- (methoxycarbonyl) benzyl) triphenylphosphine Bromide compound

The method comprises the following steps:

methyl 4- (bromomethyl) benzoate (5g, 22mmol) and PPh₃A mixture of (5.77g, 22mmol) in 150mL of toluene was stirred at 120 ℃ for 5 hours. The mixture was cooled to room temperature, filtered and dried to give (4- (methoxycarbonyl) benzyl) triphenylphosphineBromide (8.8g, 82%) as a white solid.¹HNMR(300MHz，DMSO):7.92-7.63(m，17H)，7.11-7.08(m，2H)，5.32-5.26(m，2H)，3.32(s，3H)。

Step 2

(E)-4-(3-(4，4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) styryl) benzyl Acid methyl ester

The method comprises the following steps:

at-78 ℃ in N₂(4- (methoxycarbonyl) benzyl) triphenylphosphine in an atmosphere by syringeA solution of bromide (2.9g, 6mmol) in 50mL THF was added dropwise to a solution of LDA (5mL, 10mmol) in THF. After 30 minutes at this temperature, 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzaldehyde (1.4g, 6mmol) in 50ml of THF was added dropwise via syringe, then stirred at this temperature for 30 minutes, then warmed to room temperature over 4 hours, and stirred overnight. The mixture is poured into H₂O (300mL), then extracted with ethyl acetate (3 × 100mL), the combined organic layers were concentrated and purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate =50:1) to give (E) -methyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) styryl) benzoate (0.9g, 41%) as a colorless oil LC-MS: 365[ M + H]⁺，t_R=1.98 min.

Step 3

(E) -4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) styryl groups Benzoic acid methyl ester

The method comprises the following steps:

stirring 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d at room temperature]Pyrimidin-7-amine (150mg, 0.46mmol)) And methyl (E) -4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) styryl) benzoate (200mg, 0.55mmol) in 25mL1, 4-bisAdding Na into the solution in the alkane₂CO₃(100mg, 0.94mmol) and 3mL of water. The mixture was then degassed with nitrogen for 15 minutes. One-time addition of Pd (PPh)₃)₄(40mg, 0.035mmol) and the reaction mixture was stirred under nitrogen at reflux for 18 h. The solvent was evaporated and the residue was purified by silica gel chromatography (200 mesh, 300 mesh, eluting with a mixture of petroleum ether and ethyl acetate =1:1) to give (E) -4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) styryl) benzoic acid methyl ester (90mg, 37%) as a yellow solid. LC-MS: 525[ M + H ]]⁺，t_R=1.89 minutes.

Step 4

The method comprises the following steps:

(E) -4- (3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d) with stirring at room temperature]Pyrimidin-5-yl) styryl) benzoic acid methyl ester (90mg, 0.17mmol) in 3mL1, 4-bisAlkane and 3mLH₂To the solution in O was added NaOH (140mg, 3.5 mmol). The reaction was then stirred at room temperature overnight and then treated with concentrated HCl to pH = 3-4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give (E) -4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) styryl) benzoic acid (33mg, 38%) as a yellow solid.¹HNMR(300MHz，DMSO):12.95(brs，1H)，10.09(s，1H)，9.38(s，1H)，8.37-8.30(m，2H)，7.82-7.78(m，3H)，7.47-7.32(m，5H)，6.92-6.78(m，3H)，3.81(s，3H)，3.80(s，3H)。LC-MS：511[M+H]⁺，509[M-H]^-，t_R=1.71 min. HPLC: 99.30% at 214nm, 99.65% at 254nm, t_R=4.98 min.

Example 33

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenethyl) benzoic acid

Step 1

4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) benzoic acid methyl ester

The method comprises the following steps:

methyl (E) -4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) styryl) benzoate (200mg, 0.55mmol) and PtO₂(50mg, 0.22mmol) in 30 mM My NaOH at room temperature in H₂Stirred under atmosphere for 18 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (200 mesh, 300 mesh, eluting with a mixture of petroleum ether and ethyl acetate =50:1) to give methyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) benzoate (90mg, 50%) as a colorless oil.

Step 2

4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenethyl) benzoic acid Methyl ester

The method comprises the following steps:

stirring 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d at room temperature]Pyrimidin-7-amine (88mg, 0.27mmol) and methyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenethyl) benzoate (100mg, 0.27mmol) in 25mL1, 4-bisAdding Na into the solution in the alkane₂CO₃(100mg, 0.94mmol) and 3mL of water. The mixture was then degassed with nitrogen for 15 minutes. One-time addition of Pd (PPh)₃)₄(20mg, 0.017mmol) and the reaction mixture is stirred under nitrogen at reflux for 18 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (200 mesh, 300 mesh, elution with a mixture of petroleum ether and ethyl acetate =1:1) to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenethyl) benzoic acid methyl ester (80mg, 56%) as a yellow solid. LC-MS: 527[ M + H]⁺，t_R=1.87 min.

Step 3

The method comprises the following steps:

stirring 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Pyrimidin-5-yl) phenethyl) benzoic acid methyl ester (70mg, 0.13mmol) in 3mL1, 4-bisAlkane and 3mLH₂To the solution in O was added NaOH (140mg, 3.5 mmol). The reaction was then stirred at room temperature overnight and then treated with concentrated HClUntil pH = 3-4. Removing the solvent under reduced pressure and reacting the residue with H₂O (3 × 10mL) and ethyl acetate (3 × 10mL) were triturated together and then dried to give 4- (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) phenethyl) benzoic acid (35mg, 51%) as a yellow solid.¹HNMR(300MHz，DMSO):10.13(s，1H)，9.39(s，1H)，8.32-8.24(m，2H)，7.89-7.84(m，3H)，7.52-7.40(m，5H)，7.03(d，1H，J=8.7Hz)，3.84(s，3H)，3.79(s，3H)，3.37(brs，4H)。LC-MS：513[M+H]⁺，t_R=1.67 minutes. HPLC: 97.30%, at 214nm, 97.09%, at 254nm, t_R=5.16 minutes.

Example 34

3- (7- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenylamino) thiazolo [5，4-d]Pyrimidin-5-yl) benzoic acid

Step 1

(1R,5S) -3- (3-Nitrophenyl) -8-oxa-3-azabicyclo [3.2.1]Octane

The method comprises the following steps:

1-bromo-3-nitrobenzene (0.15g, 0.743mmol), (1R,5S) -8-oxa-3-azabicyclo [3.2.1]Octane hydrochloride (0.122g, 0.82mmol), Pd₂(dba)₃(0.043g, 0.074mmol), X-Phos (0.071g, 0.15mmol) and Cs₂CO₃(0.727g, 2.23mmol) in bisMixture in alkane (30mL) in N₂Heat to 100 ℃ for 16 hours under atmosphere. Then concentrated to dryness. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate: petroleum ether =1: 8) to give (1R,5S) -3- (3-nitrophenyl) -8-oxa-3-nitrogenHeterobicyclics [3.2.1]Octane (0.12g, 69%) as a brown solid. LC-MS: 235[ M + H ]]⁺，t_R=1.57 min.

Step 2

3- ((1R, 5S) -8-oxa-3-azabicyclo [3.2.1]Octan-3-yl) anilines

The method comprises the following steps:

to a stirred mixture of (1R,5S) -3- (3-nitrophenyl) -8-oxa-3-azabicyclo [3.2.1] at 25 deg.C]Octane (0.08g, 0.341mmol) and Zn (0.223g, 3.41mmol) in dioxaneAlkane (10mL) and H₂To a solution in O (2mL) was added concentrated HCl (0.34mL, 3.41mmol) dropwise for 2 hours. By adding solid NaHCO₃Adjusting to pH =8 filter and extract the filtrate with ethyl acetate (2 × 10mL) and concentrate the filtrate to dryness column chromatography purifies the residue (silica gel, 200-300 mesh, eluting with ethyl acetate: petroleum ether =1:2) to give 3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Octan-3-yl) aniline (0.061g, 88%) was a yellow oil. LC-MS: 205[ M + 1]]⁺，t_R=1.09 minutes.

Step 3

N- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenyl) -5-chlorothiazolo [5，4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 3- ((1R, 5S) -8-oxa-3-azabicyclo [3.2.1]Octyl-3-yl) aniline (0.061g, 0.3mmol), 5, 7-dichlorothiazolo [5,4-d]Pyrimidine (0.061g, 0)3mmol) and DIPEA (0.046g, 0.36mmol) in DMSO (10mL) were heated to 30 ℃ for 2 hours then diluted with water and extracted with ethyl acetate (3 × 10mL), the organic layer was dried and concentrated the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with MeOH: DCM =1:80) to give N- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenyl) -5-chlorothiazolo [5,4-d]Pyrimidin-7-amine (0.095g, 86%) as a yellow solid. LC-MS: 374[ M + H]⁺，t_R=1.66 minutes.

Step 4

3- (7- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenylamino) thiazolo [5，4-d]Pyrimidin-5-yl) benzoic acid methyl ester

The method comprises the following steps:

reacting N- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenyl) -5-chlorothiazolo [5,4-d]Pyrimidin-7-amine (0.095g, 0.254mmol), methyl 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (0.073g, 0.28mmol), Pd (PPh)₃)₄(0.015g, 0.013mmol) and Na₂CO₃(0.081g, 0.762mmol) in bisAlkane (20mL) and H₂Mixture in O (5mL) in N₂Heat to 100 ℃ for 16 hours under atmosphere. Then concentrated to dryness. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with ethyl acetate: petroleum ether =1:2) to give 3- (7- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester (0.094g, 78%) as a yellow solid. LC-MS: 474[ M + H]⁺，t_R=1.84 minutes.

Step 5

The method comprises the following steps:

reacting 3- (7- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester (0.094g, 0.2mmol) and NaOH (0.079g, 2.0mmol) in bisAlkane (10mL) and H₂The mixture in O (5mL) was stirred at 30 ℃ for 2h concentrated, the residue was diluted with water, washed with ether (2 × 5mL) and the aqueous layer was adjusted to pH =4 by addition of concentrated HCl, then the solid formed was filtered and purified by recrystallization (15mL, MeOH: EtOAc: ether =5:20:100, v/v/v) to give 3- (7- (3- ((1R, 5S) -8-oxa-3-azabicyclo [ 3.2.1)]Oct-3-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid (0.042g, 46%) as a yellow solid.¹HNMR(300MHz，DMSO):13.23(s，1H)，10.15(s，1H)，9.42(s，1H)，8.98(s，1H)，8.61(d，1H，J=7.8Hz)，8.09(d，1H，J=7.8Hz)，7.68-7.62(m，2H)，7.41(d，1H，J=8.1Hz)，7.23(t，1H，J=8.4Hz)，6.65(d，1H，J=8.4Hz)，4.44(s，2H)，3.43-3.36(m，2H)，2.89(d，1H，J=9.3Hz)，1.86(s，4H)。LC-MS：460[M+1]⁺，t_R=1.64 minutes. HPLC: 95.36%, at 214nm, 96.48%, at 254nm, t_R=5.20 min.

Example 35

N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- 1H-indazole-5-carboxamides

The method comprises the following steps:

to 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]To a solution of pyrimidin-7-amine (100mg, 0.27mmol) and 1H-indazole-5-carboxylic acid (44mg, 0.27mmol) in dichloromethane (20mL) was added a solution of 1-methyl-1H-imidazole (88mg, 1.1mmol) and EDCI (206mg, 1.1mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hours, and the solid formed during the reaction was collected by filtration and washed with MeOH to give N- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) -1H-indazole-5-carboxamide (78mg, 56.1%) as an off-white solid.¹HNMR(300MHz，DMSO):13.25(s，1H)，9.58(s，1H)，8.81(s，1H)，8.61(d，1H，J=6.3Hz)，8.36(s，1H)，8.19(s，1H)，7.88-7.86(m，2H)，7.56(d，1H，J=8.7Hz)，7.50(s，1H)，6.91(d，1H，J=8.4Hz)，4.61-4.59(m，1H)，3.73(s，3H)，3.65(s，3H)，3.62(brs，3H)，2.28-2.09(m，2H)。LC-MS：517[M+H]⁺，t_R=1.34 minutes. HPLC: 95.89%, at 214nm, 97.39%, at 254nm, t_R=4.52 minutes.

Example 36

(S) -N- (3- (2-methylpyrrolidin-1-yl) phenyl) -5- (3- ((piperidin-4-ylamino) methyl) phenyl) thia-ne Azolo [5,4-d]Pyrimidin-7-amine 2, 2, 2-trifluoroacetate salt

Step 1

(S) -2-methyl-1- (3-nitrophenyl) pyrrolidine

The method comprises the following steps:

to a mixture of 1-bromo-3-nitrobenzene (2.02g, 0.01mol) and (S) -2-methylpyrrolidine (1.02g, 0.012mol) in 20mL1, 4-bis under nitrogen and with stirringAdding Cs into solution in alkane₂CO₃(6.5g, 0.02mol), followed by the addition of Pd (dba)₂(1.15g, 0.002mmol) and X-Phos (476mg, 0.001 mol.) the mixture was refluxed under nitrogen for 16 h after cooling, the mixture was filtered, then the filtrate was evaporated by rotary evaporation, the residue was diluted with water and extracted with EtOAc (3 × 30mL), the organic layer was washed with brine and Na₂SO₄And (5) drying. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with (petroleum ether: EtOAc =10:1), to give (S) -2-methyl-1- (3-nitrophenyl) pyrrolidine (1.2g, 57%) as an oil.¹HNMR(300MHz，CDCl₃)7.47-7.44(m，1H)，7.37-7.35(m，1H)，7.32-7.27(m，1H)，6.86-6.83(m，1H)，3.95-3.91(m，1H)，3.50-3.44(m，1H)，3.26-3.18(m，1H)，2.18-1.99(m，3H)，1.80-1.72(m，1H)，1.21(d，2H，J=6.3Hz)。LC-MS：207[M+H]⁺，t_R=1.75 minutes.

Step 2

(S) -3- (2-methylpyrrolidin-1-yl) aniline

The method comprises the following steps:

to a mixture of (S) -2-methyl-1- (3-nitrophenyl) pyrrolidine (1.2g, 5.83mmol) and Zn powder (5.68g, 87.4mmol) in 20mL of 1, 4-bisTo the solution in alkane was added HCl (aq) (5mL) dropwise, the mixture was stirred at room temperature for 1h, the solvent was removed under reduced pressure, the residue was diluted with water and extracted with EtOAc (3 × 15mL), the organic layer was washed with brine, and Na was used to wash the organic layer₂SO₄And (5) drying. After filtration and concentration, the residue was used in the next step without purification. LC-MS: 177[ M + H ]]⁺，t_R=1.10 minutes.

Step 3

(S) -5-chloro-N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]A mixture of pyrimidine (1g, 4.85mmol), (S) -3- (2-methylpyrrolidin-1-yl) aniline and DIEA (1.25g, 9.7mmol) in 15mL LDMSO was stirred at room temperature for 2 hours, the mixture was poured into water and extracted with EtOAc (3 × 20mL), the organic layer was washed with brine, and Na was used to wash the organic layer₂SO₄And (5) drying. After filtration and concentration, the residue was used in the next step without purification. LC-MS: 346[ M + H ]]⁺，t_R=1.79 min.

Step 4

Tert-butyl-4-oxopiperidine-1-carboxylate

The method comprises the following steps:

to a solution of piperidin-4-one hydrochloride (1.53g, 0.01mol) in 20mL of MeOH was added di-tert-butyl dicarbonate (2.62g, 0.012mol) and triethylamine (2.02g, 0.02mol), the mixture was stirred at room temperature for 2 hours, the solvent was removed under reduced pressure, the residue was diluted with water and extracted with EtOAc (3 × 15mL), the organic layer was washed with brine, and Na was used to wash the organic layer₂SO₄And (5) drying. After filtration and concentration, the residue (1.5g, 75%) was used in the next step without purification.¹HNMR(300MHz，CDCl₃)3.71(t，4H，J=6.3Hz)，2.44(t，4H，J=6.3Hz)，1.49(s，9H)。

Step 5

4- (3-Bromobenzylamino) piperidine-1-carboxylic acid tert-butyl ester

The method comprises the following steps:

to a solution of (3-bromophenyl) methylamine (670mg, 3.6mmol), tert-butyl 4-oxopiperidine-1-carboxylate (600mg, 3mmol) and sodium triacetoxyborohydride (1.27g, 6mmol) in 10mL dichloromethane was added acetic acid (360mg, 6 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluting with petroleum ether: EtOAc =3: 1) to give tert-butyl 4- (3-bromobenzylamino) piperidine-1-carboxylate (0.9g, 68%) as an oil.¹HNMR(300MHz，CDCl₃)7.48-7.47(m，1H)，7.38-7.35(m，1H)，7.25-7.17(m，2H)，4.10(brs，1H)，3.79(s，2H)，2.85-2.76(m，2H)，2.67-2.61(m，1H)，1.87-1.82(m，2H)，1.45(s，9H)，1.37-1.29(m，2H)。

Step 6

Tert-butyl-4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylamino) Piperidine-1-carboxylic acid ester

The method comprises the following steps:

to a solution of tert-butyl 4- (3-bromobenzylamino) piperidine-1-carboxylate (500mg, 1.36mmol), 4, 4, 4 ', 4 ', 5, 5, 5 ', 5 ' -octamethyl-2, 2 ' -bis (1,3, 2-dioxaborolane) (413mg, 1.63mmol) and KOAc (266mg, 2.71mmol) in 10mL of DMSO was added Pd (dppf) Cl under nitrogen with stirring₂(43mg, 0.04 mmol.) the mixture was heated at 80 ℃ under nitrogen for 15 h, after cooling, the mixture was poured into water and extracted with EtOAc (3 × 10mL), the organic layer was washed with brine (2 × 10mL) and MgSO₄And (5) drying. After filtration and concentration, the residue was filtered through a pad of silica gel to give the crude product, which was used in the next step without further purification. LC-MS: 417[ M + H ]]⁺，t_R=1.38 minutes.

Step 7

(S) -tert-butyl-4- (3- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidines -5-yl) benzylamino) piperidine-1-carboxylic acid ester

The method comprises the following steps:

to (S) -5-chloro-N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d under nitrogen and with stirring]Pyrimidin-7-amine (200mg, 0.58mmol) and crude tert-butyl 4- (3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzylamino) piperidine-1-carboxylate in 10mL1, 4-bisTo a solution of alkane and 2mL of water was added Na₂CO₃(184mg, 1.74mmol) followed by the addition of Pd (PPh)₃)₄(184mg, 0.03 mmol.) the mixture was refluxed under nitrogen for 15 h, cooled, the solvent evaporated under reduced pressure by rotary evaporation the residue was poured into water and extracted with EtOAc (3 × 15mL), the organic layer was washed with brine and Na₂SO₄And (5) drying. After filtration and concentration, the residue was purified by column chromatography (silica gel, eluted with EtOAc) to give (S) -4- (3- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzylamino) piperidine-1-carboxylic acid tert-butyl ester (110mg, 32% over two steps). LC-MS: 250.6[ M/2+ H]⁺，600[M+H]⁺，t_R=1.57 min.

Step 8

The method comprises the following steps:

to the stirred (S) -4- (3- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzylamino) piperidine-1-carboxylic acid tert-butyl ester (110mg, 0.184mmol) to a solution of 2mL dccm was added 2mL2, 2, 2-trifluoroacetic acid. The solution was stirred at room temperature overnight. With NaHCO₃The mixture was washed (aq.) and the organic layer concentrated the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were 40% acetonitrile/60% water (0.1% TFAV/V) initially and then carried out in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V) after 9 min) to give (S) -N- (3- (2-methylpyrrolidin-1-yl) phenyl) -5- (3- ((piperidin-4-ylamino) methyl) phenyl) thiazolo [5,4-d ]]Pyrimidin-7-amine 2, 2, 2-trifluoroacetate salt (40mg, 43%) as an oil.¹HNMR(300MHz，DMSO):9.18(s，1H)，8.60(s，1H)，8.51(dd，1H，J₁=7.5Hz，J₂=1.2Hz)，7.92(s，1H)，7.84(brs，1H)，7.68-7.52(m，3H)，7.15(brs，1H)，4.40(s，2H)，4.08-4.01(m，2H)，3.87-3.85(m，1H)，3.64-3.55(m，4H)，3.17-3.08(m，2H)，2.48-2.21(m，5H)，2.03-1.87(m，3h)，1.34(d，3H，J=6.3Hz)。LC-MS：250[M/2+H]⁺，500[M+H]⁺，t_R=1.20 min. HPLC: 100% at 214nm, 100% at 254nm, t_R=4.59 minutes.

Example 37

N5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-yl) Pyridine-2, 5-dicarboxamide hydrochloride

The method comprises the following steps:

to 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]To a solution of pyrimidin-7-amine (95mg, 0.26mmol) and 6-carbamoylnicotinic acid (42mg, 0.26mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (85mg, 1.04mol) and EDCI (199mg, 1.04mol) in dichloromethane (15mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo and the residue was washed with MeOH, then purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 20% acetonitrile/80% water (0.1% TFAV/V) and then after 9 min proceeding in a linear fashion to 40% acetonitrile/60% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate salt, which was exchanged with concentrated HCl to give N5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d-phenyl-thiazolo [5, 5 d-5 d ] thiazolo [5, 5 d-D ] in a]Pyrimidin-5-yl) pyrrolidin-3-yl) pyridine-2, 5-dicarboxamide hydrochloride (25mg, 16.2%) as the HCL salt and as an orange solid.¹HNMR(300MHz，DMSO):9.00-8.93(m，2H)，8.36-8.33(m，1H)，8.10(d，1H，J=8.1Hz)，7.73(s，1H)，7.45-7.38(m，1H)，6.95(d，1H，J=8.7Hz)，4.63(s，1H)，3.93-3.75(m，10H)，2.31-2.17(m，2H)。LC-MS：520.9[M+H]⁺，t_R=1.33 minutes. HPLC: 98.94%, at 214nm, 98.61%, at 254nm, t_R=3.64 minutes.

Example 38

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) picolinic acid methyl ester

The method comprises the following steps:

to 5- (3-aminopyrrolidin-1-yl) -N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]To a solution of pyrimidin-7-amine (80mg, 0.22mmol) and 6- (methoxycarbonyl) nicotinic acid (39mg, 0.22mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (71mg, 0.88mmol) and EDCI (164mg, 0.88mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 15 hours, the solid was collected by filtration and washed with MeOH to give 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) picolinic acid methyl ester (90mg, 80.3%) as an off-white solid.¹HNMR(300MHz，DMSO):9.57(s，1H)，9.07(s，1H)，8.99(d，1H，J=6.3Hz)，8.79(s，1H)，8.36(dd，1H，J₁=8.1Hz，J₂=2.1Hz)，8.11(d，1H，J=8.1Hz)，7.86(s，1H)，7.45(s，1H)，6.90(d，1H，J=8.7Hz)，4.60-4.58(m，1H)，3.89(s，3H)，3.75(s，3H)，3.71(s，3H)，3.64(brs，4H)，2.28-2.24(m，1H)，2.11-2.06(m，1H).LC-MS：536[M+H]⁺，t_R=1.37 minutes. HPLC: 95.95%, at 214nm, 96.44%, at 254nm, t_R=4.85 min.

Example 39

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylamino Carbamoyl) picolinic acid

The method comprises the following steps:

to the 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) pyrrolidine-3-ylcarbamoyl) picolinic acid methyl ester (80mg, 0.15mmol) in bisalkane/H₂To a solution in O (60mL/6mL) was added NaOH (60mg, 1.5mol), the reaction mixture was heated to 35 ℃ with stirring for 1 hour, then dioxane was removed in vacuo, and the aqueous layer was adjusted to pH 4-5 with concentrated HCl, the precipitate was collected by filtration and washed with water (5mL), and dried to give 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) picolinic acid as a brown solid (67mg, 84.8%).¹HNMR(300MHz，DMSO):9.56(s，1H)，9.06(s，1H)，8.96(d，1H，J=6.3Hz)，8.79(s，1H)，8.33(dd，1H，J₁=8.1Hz，J₂=1.8Hz)，8.07(d，1H，J=8.1Hz)，7.86(s，1H)，7.50(brs，1H)，6.90(d，1H，J=8.7Hz)，4.60-4.58(brs，1H)，3.76-3.52(m，10H)，2.30-2.24(m，1H)，2.11-2.07(m，1H)。LC-MS：522[M+H]⁺，t_R=1.31 minutes. HPLC: 98.03%, at 214nm, 97.82%, at 254nm, t_R=3.20 min.

Example 40

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2-oxodihydro Indol-5-yl) piperidine-3-carboxamide

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (100mg, 0.24mmol) and 5-aminoindolin-2-one (36mg, 0.24mmol) in dichloromethane (20mL) was added 1-methyl-1H-imidazole (79mg, 0.96mmol) and EDCI (183mg, 0.96mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 15 hoursThe solid was collected by filtration and washed with methanol (4mL) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2-oxoindolin-5-yl) piperidine-3-carboxamide as an orange solid (68mg, 51.8%).¹HNMR(300MHz，DMSO):10.31(s，1H)，9.87(s，1H)，9.67(s，1H)，8.86(s，1H)，7.68(d，1H，J=2.4Hz)，7.53(s，1H)，7.37(s，1H)，7.35(s，1H)，6.83-6.81(m，1H)，6.75(d，1H，J=8.4Hz)，4.82-4.67(m，2H)，3.71-3.65(m，6H)，3.48(s，2H)，3.12-2.95(m，2H)，1.98-1.74(m，5H)。LC-MS：546[M+H]⁺，t_R=1.493 minutes. HPLC: 98.74%, at 214nm, 98.67%, at 254nm, t_R=3.60 minutes.

EXAMPLE 41

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1H-indazol-5-yl) Piperidine-3-carboxamide hydrochloride

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (110mg, 0.27mmol) and 1H-indazol-5-amine (36mg, 0.27mmol) in dichloromethane (20mL) was added a solution of 1-methyl-1H-imidazole (87mg, 1.08mol) and EDCI (203mg, 1.08mol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 15 hours, the precipitate was collected by filtration and washed with methanol, then purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were initial 30% acetonitrile/70% water (0.1% TFAV/V) then after 9 minutes to 50% acetonitrile/50% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate salt (8mL) and the mixture was suspended in dichloromethane (5mL) and added dropwise HCl (0.5mL) to obtain a solution of the corresponding trifluoroacetate saltStirring for 10 min and concentrating to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) -N- (1H-indazol-5-yl) piperidine-3-carboxamide hydrochloride (45mg, 29.4%) as an orange solid with the HCl salt.¹HNMR(300MHz，DMSO+H₂O):8.85(d，1H，J=3.0Hz)，8.07(s，1H)，7.99(s，1H)，7.52-7.38(m，3H)，7.26(d，1H，J=8.7Hz)，6.79(brs，1H)，4.66-4.47(m，2H)，3.66-3.54(m，6H)，3.20(t，1H，J=12.6Hz)，3.09-3.01(m，1H)，2.60-2.53(m，1H)，2.02-1.99(m，1H)，1.82-1.70(m，2H)，1.51-1.47(m，1H)。LC-MS：531[M+H]⁺，t_R=1.44 minutes. HPLC: 95.98%, at 214nm, 95.22%, at 254nm, t_R=4.55 minutes.

Example 42

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides Yl) picolinic acid

Step 1

5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides Yl) picolinic acid methyl ester

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (200mg, 0.48mmol) and methyl 5-aminopyralid (73mg, 0.48mmol) in dichloromethane (30mL) was added a solution of 1-methyl-1H-imidazole (158mg, 1.92mmol) and EDCI (368mg, 1.92mmol) in dichloromethane (10mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo and methanol (6mL) was added and stirred for 30 minutes, the solid was collected by filtration and washed with methanol to give 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazoleAnd [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) picolinic acid methyl ester (230mg, 87.1%) as an orange solid. LC-MS: 550[ M + H ]]⁺，t_R=1.58 minutes.

Step 2

The method comprises the following steps:

to the 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) picolinic acid methyl ester (130mg, 0.24mmol) in bisalkane/H₂To a solution in O (8mL/8mL) was added NaOH (70mg, 1.75mmol), the reaction mixture was heated to 35 ℃ with stirring for 30 minutes, and the bis were removed in vacuoAlkane, and the aqueous layer was adjusted to pH =4-5 with concentrated HCl, the precipitate was collected by filtration and washed with methanol (5mL) to give 5- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) picolinic acid (98mg, 76.2%) as an orange solid.¹HNMR(300MHz，DMSO):10.58(s，1H)，9.68(s，1H)，8.87(s，2H)，8.24(dd，1H，J₁=8.7Hz，J₂=2.4Hz)，8.03(d，1H，J=8.7Hz)，7.67(d，1H，J=2.1Hz)，7.35(dd，1H，J₁=8.7Hz，J₂=2.1Hz)，6.82(brs，1H)，4.84-4.65(m，2H)，3.77-3.65(m，6H)，3.18-3.00(m，2H)，2.67-2.64(m，1H)，2.05-1.75(m，4H)。LC-MS：536[M+H]⁺，t_R=1.50 minutes. HPLC: 97.47%, at 214nm, 97.48%, at 254nm, t_R=4.096 minutes.

Example 43

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides 2-methoxybenzoic acid radical

Step 1

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides 2-Methoxybenzoic acid methyl ester

The method comprises the following steps:

to a solution of 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidine-3-carboxylic acid (110mg, 0.27mmol) and methyl 4-amino-2-methoxybenzoate (48mg, 0.27mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (87mg, 1.1mmol) and EDCI (203mg, 1.1mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed in vacuo, then methanol (5mL) was added, the precipitate was collected by filtration and washed with methanol (5mL) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] pyrimidin-5-yl) piperidine-3-carboxamido) -2- Methyl methoxybenzoate (126mg, 80.8%) as an orange solid. LC-MS: 579[ M + H ] +, tR =1.58 min.

Step 2

To 4- (1- (7- (3, 4-dimethoxyphenylamino) benzeneYl) thiazolo [5,4-d]Pyrimidin-5-yl) piperidine-3-carboxamido) -2-methoxybenzoic acid methyl ester (126mg, 0.22mmol) in bisalkane/H₂To a solution in O (8mL/8mL) was added NaOH (75mg, 1.9mmol), the reaction mixture was heated to 35 ℃ with stirring for 1 hour, and the di-n-oxide was removed in vacuoAlkane, and the aqueous layer was adjusted to pH =4-5 with concentrated HCl, the precipitate was collected by filtration and washed with methanol (5mL) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) -2-methoxybenzoic acid (68mg, 54.8%) as an off-white solid.¹HNMR(300MHz，DMSO):10.23(s，1H)，9.63(s，1H)，8.83(s，1H)，7.63(d，1H，J=2.1Hz)，7.58(d，1H，J=8.4Hz)，7.46(s，1H)，7.33(dd，1H，J₁=8.7Hz，J₂=2.4Hz)，7.14(dd，1H，J₁=8.4Hz，J₂=1.5Hz)，6.80-6.78(m，1H)，4.79(d，1H，J=11.7Hz)，4.65(d，1H，J=12.6Hz)，3.68-3.61(m，9H)，3.10-2.89(m，2H)，2.58-2.54(m，1H)，2.03-1.99(m，1H)，1.78-1.71(m，2H)，1.48-1.44(m，1H)。LC-MS：585[M+H]⁺，t_R=1.48 minutes. HPLC: 96.06%, at 214nm, 97.26%, at 254nm, t_R=5.66 minutes.

Example 44

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-oxo) -4, 5-dihydro-1, 2,4- Oxadiazol-3-yl) phenyl) piperidine-3-carboxamide hydrochloride

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxylic acid (50mg, 0.12mmol) and 3- (4-aminophenyl) -1,2,4-Diazol-5 (4H) -one hydrochloride (26mg, 0.12mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (40mg, 0.48mmol) and EDCI (92mg, 0.48mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, methanol (5mL) was added, the precipitate was collected by filtration and then purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were 35% acetonitrile/65% water (0.1% TFAV/V) initially, then after 9 minutes in a linear fashion to 50% acetonitrile/50% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate salt, the salt was suspended in dichloromethane (8mL) and concentrated dropwise to give the mixture [0.5 mL ], the mixture was stirred at reduced pressure [ 1- (4-dimethoxyphenyl) and then concentrated to [ 4-d ] phenyl ] at room temperature, and then the mixture was concentrated under reduced pressure [ 3-5-4-d ] to give 4-phenyl]Pyrimidin-5-yl) -N- (4- (5-oxo-4, 5-dihydro-1, 2, 4-)Oxadiazol-3-yl) phenyl) piperidine-3-carboxamide hydrochloride (53mg, 68.8%) as an orange solid.¹HNMR(300MHz，DMSO):12.88(s，1H)，10.45(s，1H)，9.84(s，1H)，8.88(s，1H)，7.81-7.74(m，4H)，7.61(d，1H，J=2.1Hz)，7.32(dd，1H，J₁=8.7Hz，J₂=2.1Hz)，6.80(brs，1H)，4.77-4.59(m，2H)，3.68(s，3H)，3.62(s，3H)，3.18-2.97(m，2H)，2.72-2.64(m，1H)，2.05-2.02(m，1H)，1.90-1.69(m，2H)，1.22-1.18(m，1H)。LC-MS：575[M+H]⁺，t_R=1.64 minutes. HPLC: 99.98% at 214nm, 98.99% at 254nm, t_R=6.29 min.

Example 45

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1H-indazol-6-yl) Piperidine-3-carboxamide hydrochloride

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxylic acid (80mg, 0.19mmol) and 1H-indazol-6-amine (26mg, 0.19mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (63mg, 0.76mmol) and EDCI (147mg, 0.76mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, then methanol (5mL) was added, the precipitate was collected by filtration and purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 30% acetonitrile/70% water (0.1% TFAV/V) then after 9 minutes in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate salt (8. the salt was suspended in dichloromethane (5mL), then the mixture was concentrated under reduced pressure [ 5H-5-phenyl ] and the mixture was stirred at room temperature [ 5mL ] to give 4H-5-L ] HCl and then the mixture was concentrated in dichloromethane (4mL) and stirred at room temperature]Pyrimidin-5-yl) -N- (1H-indazol-6-yl) piperidine-3-carboxamide hydrochloride (25mg, 21.9%) as an orange solid.¹HNMR(300MHz，DMSO):10.19(s，1H)，9.81(s，1H)，8.87(s，1H)，8.16(s，1H)，7.96(s，1H)，7.66-7.60(m，2H)，7.34(dd，1H，J₁=8.7Hz，J₂=2.1Hz)，7.11(dd，1H，J₁=8.4Hz，J₂=1.5Hz)，6.80(brs，1H)，4.81-4.63(m，2H)，3.68(s，3H)，3.55(s，3H)，3.16-2.95(m，2H)，2.72-2.59(m，1H)，2.04-2.02(m，1H)，1.82-1.51(m，2H)，1.25-1.20(m，1H)。LC-MS：531[M+H]⁺，t_R=1.60 minutes. HPLC: 99.21%, at 214nm, 98.92%, at 254nm，t_R=5.94 minutes.

Example 46

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1-oxoisoindol) Hydroindol-5-yl) piperidine-3-carboxamide

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxylic acid (70mg, 0.17mmol) and 5-aminoisoindolin-1-one (25mg, 0.17mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (55mg, 0.68mmol) and EDCI (129mg, 0.68mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, then methanol (5mL) was added, the precipitate was collected by filtration and washed with (3mL) methanol to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1-oxoisoindolin-5-yl) piperidine-3-carboxamide (48mg, 51.8%) as a brown solid.¹HNMR(300MHz，DMSO):10.29(s，1H)，9.64(s，1H)，8.84(s，1H)，8.38(s，1H)，7.96(s，1H)，7.64-7.53(m，3H)，7.33(dd，1H，J₁=8.4Hz，J₂=1.8Hz)，6.80(brs，1H)，4.81-4.63(m，2H)，4.33(s，2H)，3.68(s，3H)，3.59(s，3H)，3.14-2.92(m，2H)，2.65-2.60(m，1H)，2.04-2.00(m，1H)，1.81-1.69(m，2H)，1.49-1.45(m，1H)。LC-MS：545.9[M+H]⁺，t_R=1.42 minutes. HPLC: 99.69%, at 214nm, 99.44%, at 254nm, t_R=4.87 minutes.

Example 47

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidines-5-yl) piperidine-3-carboxamides 2-hydroxybenzoic acid hydrochloride

Step 1

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides 2-hydroxybenzoic acid methyl ester

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (80mg, 0.19mmol) and methyl 4-amino-2-hydroxybenzoate (32mg, 0.19mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (63mg, 0.76mmol) and EDCI (147mg, 0.76mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, methanol (5mL) was added, and the precipitate was collected by filtration to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) -2-hydroxybenzoic acid methyl ester (110mg, crude) was used in the next step without further purification. LC-MS: t is t_R=565[M+H]⁺1.64 minutes.

Step 2

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) piperidine-3-carboxamides 2-hydroxybenzoic acid hydrochloride

The method comprises the following steps:

to 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) -2-hydroxybenzoic acid methyl ester (110mg, 0.20mmol) in bisalkane/H₂To a solution in O (8mL/8mL) was added NaOH (100mg, 2.5mmol), the reaction mixture was heated to 40 ℃ with stirring for 5 hours, and the di-O was removed in vacuoAlkane and the aqueous layer was adjusted to pH =4-5 with concentrated HCl and the precipitate was collected by filtration and purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 10% acetonitrile/90% water (0.1% TFAV/V) then done in a linear fashion to 60% acetonitrile/40% water (0.1% TFAV/V) after 9 minutes) to give the corresponding trifluoroacetate salt, the salt was suspended in dichloromethane (8mL) and concentrated HCl (0.5mL) was added dropwise, the mixture was stirred for 10 minutes and concentrated under reduced pressure to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxamido) -2-hydroxybenzoic acid hydrochloride (25mg, 21.9%) as an orange solid.¹HNMR(300MHz，DMSO+D₂O):8.81(s，1H)，7.71(d，1H，J=8.7Hz)，7.54(s，1H)，7.33(d，1H，J=2.1Hz)，7.27(d，1H，J=8.4Hz)，7.05(dd，J₁=8.7Hz，J₂=2.1Hz)，6.80(brs，1H)，4.65(d，1H，J=13.2Hz)，4.52(d，1H，J=12.6Hz)，3.66(s，3H)，3.60(s，3H)，3.15(t，1H，J=11.7Hz)，3.01(t，1H，J=12.6Hz)，2.58-2.54(m，1H)，2.00-1.69(m，3H)，1.48-1.43(m，1H)。LC-MS：551[M+H]⁺，t_R=1.532 min. HPLC: 99.65%, at 214nm, 99.71%, at 254nm, t_R=5.77 minutes.

Example 48

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (5-oxopyrroles Alk-3-yl) piperidine-3-carboxamide hydrochloride

The method comprises the following steps:

to the reaction solution, 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) piperidine-3-carboxylic acid (80mg, 0.19mmol) and 4-aminopyrrolidin-2-one (19mg, 0.19mmol) in dichloromethane (15mL) was added a solution of 1-methyl-1H-imidazole (63mg, 0.76mmol) and EDCI (151mg, 0.76mmol) in dichloromethane (5mL), the reaction mixture was stirred at room temperature for 24 hours, the solvent was removed in vacuo, then methanol (5mL) was added, the precipitate was collected by filtration and purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 30% acetonitrile/70% water (0.1% TFAV/V) then after 9 minutes in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate salt (8. the salt was suspended in dichloromethane (4-5 mL), then the mixture was concentrated under reduced pressure [ 5-5 mL ], 3-phenyl-5-HCl ] and the mixture was concentrated [ 4-drops (5mL) and then stirred at room temperature for 4-5 mL) followed by stirring]Pyrimidin-5-yl) -N- (5-oxopyrrolidin-3-yl) piperidine-3-carboxamide hydrochloride (33mg, 28.2%) as an orange solid.¹HNMR(300MHz，DMSO+D₂O):8.86(d，1H，J=3.0Hz)，7.57(s，1H)，7.27-7.24(m，1H)，6.89(d，1H，J=8.1Hz)，4.58-4.48(m，2H)，4.33(brs，1H)，3.73(s，3H)，3.71(s，3H)，3.59-3.46(m，1H)，3.11-2.94(m，3H)，2.45-2.33(m，2H)，2.04-1.97(m，1H)，1.89-1.84(m，1H)，1.76-1.60(m，2H)，1.44-1.21(m，1H)。LC-MS：498[M+H]⁺，t_R=1.35 min. HPLC: 98.69%, at 214nm, 99.23%, at 254nm, t_R=4.27 min.

Example 49

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (pyrazin-2-yl) piperazines Pyridine-3-carboxamides

The method comprises the following steps:

to (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at 0 DEG C]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (30mg, 0.07mmol) and pyrazin-2-amine (7mg, 0.07mmol) in pyridine (6mL) was added POCl₃(0.2mL, 2.19mmol), the reaction mixture was stirred at room temperature for 15 h and saturated NaHCO was added slowly₃The solution was removed in vacuo, and water (5mL) and methanol (3mL) were added. The precipitate was collected by filtration and washed with water (3mL) and methanol (3mL) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (pyrazin-2-yl) piperidine-3-carboxamide (30mg, 87.2%) as a brown solid.¹HNMR(300MHz，DMSO):10.87(s，1H)，9.62(s，1H)，9.30(s，1H)，8.83(s，1H)，8.39-8.33(m，2H)，7.61(d，1H，J=2.1Hz)，7.31(dd，1H，J₁=8.7Hz，J₂=2.4Hz)，6.82(d，1H，J=8.4Hz)，4.76(d，1H，J=11.4Hz)，4.60(d，1H，J=12.3Hz)，3.68(s，3H)，3.64(s，3H)，3.13(t，1H，J=10.8Hz)，3.01-2.93(m，1H)，2.79-2.71(m，1H)，2.04-2.00(m，1H)，1.81-1.67(m，2H)，1.46-1.42(m，1H)。LC-MS：493[M+H]⁺，t_R=1.50 minutes. HPLC: 95.75%, at 214nm, 96.29%, at 254nm, t_R=5.38 minutes.

Example 50

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1, 3-dioxoiso-forms Indolin-5-yl) piperidine-3-carboxamide

The method comprises the following steps:

at 0 deg.C to 1- (7-, (3, 4-Dimethoxyphenylamino) thiazolo [5,4-d]To a solution of pyrimidin-5-yl) piperidine-3-carboxylic acid (50mg, 0.12mmol) and 5-aminoisoindoline-1, 3-dione (19mg, 0.12mmol) in pyridine (8mL) was added POCl₃(0.3mL, 3.23mmol), the reaction mixture was stirred at room temperature for 4 hours and saturated NaHCO was added slowly₃The solution was removed in vacuo and water (5mL) and methanol (2mL) were added. The precipitate was collected by filtration and washed with water (5mL) and methanol (5mL) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (1, 3-dioxoisoindolin-5-yl) piperidine-3-carboxamide (27mg, 40.0%) as an orange solid.¹HNMR(300MHz，DMSO):11.20(s，1H)，10.59(s，1H)，9.64(s，1H)，8.83(s，1H)，8.13(s，1H)，7.86-7.73(m，2H)，7.63(s，1H)，7.38-7.29(m，1H)，6.78(s，1H)，4.77(d，1H，J=12.0Hz)，4.62(d，1H，J=12.3Hz)，3.66(s，3H)，3.61(s，3H)，3.16-2.94(m，2H)，2.60-2.55(m，1H)，2.04-2.01(m，1H)，1.76-1.72(m，2H)，1.52-1.41(m，1H)。LC-MS：560[M+H]⁺，t_R=1.49 minutes. HPLC: 99.49% at 214nm, 99.47% at 254nm, t_R=5.33 minutes.

Example 51

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-mercapto) -acetic acid -1，3，4- Oxadiazol-2-yl) phenyl) piperidine-3-carboxamide

The method comprises the following steps:

to 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at 0 DEG C]Pyrimidin-5-yl) piperidine-3-carboxylic acid (50mg, 0.12mmol) and 5- (4-aminophenyl) -1,3,4-To a solution of diazole-2-thiol (23mg, 0.12mmol) in pyridine (10mL) was added POCl₃(0.3mL, 3.29mmol), the reaction mixture was stirred at room temperature for 6 hours and saturated NaHCO was added slowly₃The solution was removed in vacuo, methanol (20mL) was added and filtered. The filtrate was collected, concentrated, and purified by silica gel column chromatography (silica gel 200-300 mesh, eluting with methylene chloride: methanol =40: 1) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (4- (5-mercapto-1, 3, 4-)Oxadiazol-2-yl) phenyl) piperidine-3-carboxamide (8.0mg, 11.3%) as a white solid.¹HNMR(300MHz，DMSO):10.42(s，1H)，9.67(s，1H)，8.86(s，1H)，7.86-7.78(m，4H)，7.66(s，1H)，7.35(d，1H，J=8.7Hz)，6.81(brs，1H)，4.81(d，1H，J=11.7Hz)，4.66(d，1H，J=13.2Hz)，3.69(s，3H)，3.63(s，3H)，3.15-3.07(m，1H)，3.01-2.93(m，1H)，2.73-2.61(m，1H)，2.07-1.74(m，3H)，1.78-1.74(m，1H)。LC-MS：591[M+H]⁺，t_R=1.56 minutes. HPLC: 97.80%, at 214nm, 97.26%, at 254nm, t_R=5.91 minutes.

Example 52

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-mercapto-4-) methyl-4H-1, 2, 4-triazol-3-yl) phenyl) piperidine-3-carboxamide

The method comprises the following steps:

to 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at 0 DEG C]Pyrimidin-5-yl) piperidine-3-carboxylic acid (50mg,0.12mmol) and 5- (4-aminophenyl) -4-methyl-4H-1, 2, 4-triazole-3-thiol (25mg, 0.12mmol) in pyridine (10mL) was added POCl₃(0.3mL, 3.29mmol), the reaction mixture was stirred at room temperature for 8 hours and saturated NaHCO was added slowly₃Solution (15mL), solvent was removed in vacuo, dichloromethane (40mL) was added and filtered, the filtrate was collected, concentrated, and purified by silica gel column chromatography (silica gel 200-300 mesh, eluting with dichloromethane: methanol =50:1) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (5-mercapto-4-methyl-4H-1, 2, 4-triazol-3-yl) phenyl) piperidine-3-carboxamide (24.0mg, 33.1%) as a white solid.¹HNMR(300MHz，DMSO):13.88(s，1H)，10.34(s，1H)，9.68(s，1H)，8.87(s，1H)，7.82-7.66(m，5H)，7.38-7.35(m，1H)，6.83(brs，1H)，4.83(d，1H，J=12.0Hz)，4.68(d，1H，J=11.7Hz)，3.71(s，3H)，3.63(s，3H)，3.58(s，3H)，3.15-3.07(m，1H)，3.00-2.93(m，1H)，2.62-2.58(m，1H)，2.07-2.03(m，1H)，1.83-1.71(m，2H)，1.51-1.47(m，1H)。LC-MS：604[M+H]⁺，t_R=1.50 minutes. HPLC: 99.39%, at 214nm, 99.39%, at 254nm, t_R=5.36 min.

Example 53

3- (7- (3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) phenylamino) thiazolo [5,4-d]Pyrimidine-5- Yl) benzoic acid

Step 1

6- (toluene-4-sulfonyl) -2-oxa-6-azaspiro [3.3]Heptane (Heptane)

The method comprises the following steps:

to a solution of KOH (4.98g, 0.089mol) and 4-methylbenzenesulfonamide (5.7g, 0.033mol) in 90mL of ethanol was added 3-bromo-2, 2 at room temperature-bis (bromomethyl) propan-1-ol (9g, 0.0277mol), and the reaction mixture was heated to reflux for 45 hours. The solvent was removed by evaporation, 75mL of 1m koh was added, and the white suspension was stirred at room temperature for an additional 2 hours. The mixture was filtered and the white filter cake was washed with water until the wash water was neutral. The filter cake was dried under high vacuum to give 4.87g 6-toluene-4-sulfonyl-2-oxa-6-azaspiro [3.3]Heptane (69%) as a white solid.¹HNMR(300MHz，CDCl₃)7.70-7.68(m，2H)，7.36-7.34(m，2H)，4.58(s，4H)，3.90(s，4H)，2.45(s，3H)。

Step 2

2-oxa-6-azaspiro [3.3]Heptane hemioxalate

The method comprises the following steps:

reacting 6- (toluene-4-sulfonyl) -2-oxa-6-azaspiro [3.3]Heptane (510mg, 2mmol) and magnesium particles (336mg, 14mmol) were sonicated in methanol (100mL) for 1 hour. Almost all of the solvent was removed from the gray reaction mixture with a rotary transponder to give a viscous gray residue. Diethyl ether (10mL) and sodium sulfate decahydrate (1g) were added, and the resulting light gray mixture was stirred vigorously for 30 minutes, then filtered. The filtrate was dried over anhydrous sodium sulfate, and anhydrous oxalic acid (90mg, 1mmol) dissolved in ethanol (-0.5 mL) was added to the organic phase. A thick white precipitate formed immediately. Filtered off and dried in vacuo to give 2-oxa-6-azaspiro [3.3]Heptane hemioxalate (140mg, 37%) as an off-white solid.¹HNMR(300MHz，CDCl₃)4.64(s，4H)，4.11(s，4H)。

Step 3

6- (3-Nitrophenyl) -2-oxa-6-azaspiro [3.3]Heptane (Heptane)

The method comprises the following steps:

under nitrogen and stirring to 2-oxa-6-azaspiro [3.3]]Heptane hemioxalate (144mg, 0.766mmol) and 1-bromo-3-nitrobenzene (170mg, 0.84mmol) were in 10mL1, 4-bisAdding Cs into solution in alkane₂CO₃(500mg, 1.5mmol) followed by the addition of Pd (dba)₂(88mg, 0.15mmol) and X-Phos (37mg, 0.076 mmol). The mixture was refluxed under nitrogen for 16 hours. After cooling, the mixture was filtered and the filtrate was evaporated by rotary evaporation. The residue was purified by silica gel column chromatography, eluting with (petroleum ether: EtOAc =2:1), to give 6- (3-nitrophenyl) -2-oxa-6-azaspiro [3.3]Heptane (130mg, 77%) as a yellow solid.¹HNMR(300MHz，CDCl₃)7.56(dq，1H，J₁=8.1Hz，J₂=1.0Hz)，7.31(t，1H，J=8.0Hz)，7.20(t，1H，J=2.2Hz)，6.68(dq，1H，J₁=8.0Hz)，4.85(s，4H)，4.10(s，4H)。

Step 4

3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) anilines

The method comprises the following steps:

to 6- (3-nitrophenyl) -2-oxa-6-azaspiro [3.3]To a solution of heptane (130mg, 0.59mmol) in 5mL of LEtOH was added 10% Pd/C (20mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. Removing insoluble materials, and vacuum concentrating the filtrate to obtain 3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) aniline (100mg, 98%). LC-MS: 191[ M + H ]]⁺，t_R=0.99 min.

Step 5

N- (3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) phenyl) -5-chlorothiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]Pyrimidine (108mg, 0.526mmol), 3- (2-oxa-6-azaspiro [3.3]]A mixture of hept-6-yl) aniline (100mg, 0.526mmol) and DIEA (102mg, 0.789mmol) in 5mL of DMMSO was stirred at room temperature for 16 h. The mixture was poured into water and the precipitate was filtered. Crude N- (3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) phenyl) -5-chlorothiazolo [5,4-d]Pyrimidin-7-amine (160mg, 85%) was used in the next step without purification. LC-MS: 360[ M + H ]]⁺，t_R=1.53 min.

Step 6

3- (7- (3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) phenylamino) thiazolo [5,4-d]Pyrimidine-5- Yl) benzoic acid methyl ester

The method comprises the following steps:

to N- (3- (2-oxa-6-azaspiro [3.3] under nitrogen with stirring]Hept-6-yl) phenyl) -5-chlorothiazolo [5,4-d]Pyrimidin-7-amine (160mg, 0.5mmol) and methyl 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (145mg, 0.55mmol) in 9mL1, 4-bisTo a solution of alkane and 1mL of water was added Na₂CO₃(159mg, 1.5mmol) followed by the addition of Pd (PPh)₃)₄(58 mg). The mixture was refluxed under nitrogen for 15 hours. After cooling, the solvent was evaporated by rotary evaporation. The residue is poured into water and washed with EtOAc (3 × 10mL) extraction the organic layer was washed with brine and Na₂SO₄And (5) drying. After filtration and concentration, the residue was purified by silica gel column chromatography, eluting with (petroleum ether: EtOAc =1:1) to give 3- (7- (3- (2-oxa-6-azaspiro [3.3]]Hept-6-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester (70mg, 30%). LC-MS: 460[ M + H ]]⁺，t_R=1.74 minutes.

Step 7

The method comprises the following steps:

stirring of 3- (7- (3- (2-oxa-6-azaspiro [3.3 ]) solution at room temperature]Hept-6-yl) phenylamino) thiazolo [5,4-d]After addition of 1N NaOH solution (2mL) to a solution of pyrimidin-5-yl) methyl benzoate (70mg, 0.15mmol) in 5mL THF and 5mL methanol, the reaction was stirred at that temperature for 15 h, the solvent was evaporated and the residue was diluted with water and adjusted to pH =2 with HCl (aq.) the precipitate was filtered and the filter cake was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions were 40% acetonitrile/60% water (0.1% TFAV/V) initially and then carried out in a linear fashion to 70% acetonitrile/30% water (0.1% TFAV/V) after 9 min to give 3- (7- (3- (2-oxa-6-azaspiro [ 3.3.3 ]).3]Hept-6-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid (10mg, 15%).¹HNMR(300MHz，DMSO):10.13(s，1H)，9.41(s，1H)，9.00(s，1H)，8.66(d，1H，J=8.1Hz)，8.12-8.10(m，1H)，7.70(t，1H，J=7.9Hz)，7.45(s，1H)，7.24-7.18(m，2H)，6.23(d，1H，J=7.5Hz)，4.75(s，4H)，4.03(s，4H)。LC-MS：446[M+H]⁺，t_R=1.59 minutes. HPLC: 97.95%, at 214nm, 100%, at 254nm, t_R=7.31 minutes.

Example 54

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid Amino) benzoic acid

Step 1

5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]A mixture of pyrimidine (0.925g, 4.49mmol), 3, 4-dimethoxyaniline (0.89g, 5.8mmol) and DIEA (0.86g, 6.66mmol) in 12mL of DMSO was stirred at room temperature for 24 h. The reaction mixture was then poured into 50mL of water, the solid filtered, and washed with water (50mL) to give the crude product as a solid. Purification by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) afforded 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (1.2g, 82.8%) as a grey solid. LC-MS: 322.9[ M + H]⁺，t_R=1.51 minutes.

Step 2

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid methyl ester Esters

The method comprises the following steps:

5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d at room temperature under nitrogen]Pyrimidin-7-amine (140mg, 0.433mmol), pyrrolidine-3-carboxylic acid methyl ester hydrochloride (107.7mg, 0.65mmol)l), X-Phos (115mg, 0.24mmol) and Cs₂CO₃(580mg, 1.78mmol) in 60mL dry EriAdding Pd into the solution in the alkane at one time₂(dba)₃(60mg, 0.065 mmol). The reaction mixture was then degassed with nitrogen for 15 minutes. The mixture was then stirred at 95 ℃ under nitrogen for 24 hours. The solvent was evaporated under reduced pressure at 40 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (2: 1)) to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid methyl ester (160mg, 88.7%) as a yellow solid. LC-MS: 416.1[ M + H]⁺，t_R=1.60 minutes.

Step 3

1- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid

The method comprises the following steps:

stirring of 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]To a solution of pyrimidin-5-yl) pyrrolidine-3-carboxylic acid methyl ester (160mg, 0.38mmol) in 10mL of methanol was added a solution of sodium hydroxide (154mg, 3.8mmol) in 2mL of water. The reaction mixture was then stirred at this temperature for 24 hours. The solvent was then evaporated at 40 ℃ under reduced pressure and the residue was suspended in 30ml thf and then treated with 2n hcl to pH =2. The solvent was evaporated, and the residue was dissolved in 50mL THF, followed by filtration, and the filtrate was evaporated to give 1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid (95mg, 61.4%) as a yellow solid. LC-MS: 402.1[ M + H]⁺，t_R=1.33 minutes.

Step 4

4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxylic acid Amino) benzoic acid tert-butyl ester

The method comprises the following steps:

1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) pyrrolidine-3-carboxylic acid (95mg, 0.236mmol), tert-butyl 4-aminobenzoate (59mg, 0.306mmol), HATU (116mg, 0.306mmol), and DIEA (91mg, 0.708mmol) in 10mL of DMF was stirred at room temperature for 72 h. The solvent was evaporated under reduced pressure at 80 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1: 1)) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxamido) benzoic acid tert-butyl ester (105mg, 77%) as a solid. LC-MS: 577.2[ M + H]⁺，t_R=1.69 minutes.

Step 5

The method comprises the following steps:

stirring 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ] at room temperature]Trifluoropyrimidin-5-yl) pyrrolidine-3-carboxamido) benzoic acid tert-butyl ester (105mg, 0.18mmol) in 10mL dichloromethane was added trifluoroacetic acid (5mL) in one portion, the reaction mixture was then stirred at that temperature for 24 hours, the solvent was evaporated at 37 ℃ under reduced pressure, and the residue was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; Bow wave chromatographyLength: 214nm and 254 nm; the gradient conditions were: starting with 30% acetonitrile/70% water (0.1% TFAV/V) and then proceeding in a linear fashion after 9 minutes to 60% acetonitrile/40% water (0.1% TFAV/V)) to give 4- (1- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3-carboxamido) benzoic acid (56mg, 59%) as a white solid.¹HNMR(300MHz，DMSO):10.42(s，1H)，9.64(s，1H)，8.84(s，1H)，7.92-7.73(m，6H)，7.48(brs，1H)，6.93(d，1H，J=9.0Hz)，3.92-3.36(m，11H)，2.29-2.21(m，2H)。LC-MS：521[M+H]⁺，t_R=1.38 minutes. HPLC: 99.34% at 214nm, 99.25% at 254nm, t_R=4.75 minutes.

Example 55

4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- Hydroxycarbamoyl) benzoic acid

Step 1

5-chloro-N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

reacting 5, 7-dichlorothiazolo [5,4-d ]]A solution of pyrimidine (300mg, 1.45mmol), 5, 6-dimethoxypyridin-2-amine (269mg, 1.74mmol) and DIEA (281mg, 2.17mmol) in 5mL of DMSO was stirred at room temperature for 24 h. The mixture was then poured into 30mL of water and the solid formed was filtered and washed with water. The resulting crude product was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5, 4-d)]Pyrimidin-7-amine (344mg, 73%) as an off-white solid. LC-MS: 324.1[ M + H]⁺，t_R=1.69 minutes.

Step 2

1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5,4-d]Pyrimidin-5-yl) pyrrolidin-3-yl Carbamic acid tert-butyl ester

The method comprises the following steps:

5-chloro-N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5,4-d ] stirred at room temperature under nitrogen]Pyrimidin-7-amine (344mg, 1.06mmol), pyrrolidin-3-ylcarbamic acid tert-butyl ester (289mg, 1.55mmol), X-Phos (256mg, 0.53mmol) and Cs₂CO₃(1.3g, 3.9mmol) in 120mL of ErbBAdding Pd into the solution in the alkane at one time₂(dba)₃(138mg, 0.24 mmol). The reaction was then stirred at 95 ℃ under nitrogen for 4 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (2: 1)) to give 1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (260mg, 51.7%) as an oil. LC-MS: 474.2[ M + H]⁺，t_R=1.67 minutes.

Step 3

5- (3-Aminopyrrolidin-1-yl) -N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5,4-d]Pyrimidines -7-amine hydrochloride

The method comprises the following steps:

1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamic acid tert-butyl ester (260mg,0.549mmol) in 20mL of saturated HCl (in two)In an alkane) was stirred at room temperature for 24 hours. Evaporation of the solvent afforded 5- (3-aminopyrrolidin-1-yl) -N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5,4-d]Pyrimidin-7-amine hydrochloride (283mg, crude) as a yellow solid. Used in the next step without further purification. LC-MS: 187.6[ M/2+ H]⁺，374.0[M+H]⁺，t_R=1.18 min.

Step 4

4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- Hydroxycarbamoyl) benzoic acid methyl ester

The method comprises the following steps:

stirring 5- (3-Aminopyrrolidin-1-yl) -N- (5, 6-dimethoxypyridin-2-yl) thiazolo [5,4-d at room temperature]To a solution of pyrimidin-7-amine hydrochloride (283mg, 0.69mmol), 4- (methoxycarbonyl) benzoic acid (161mg, 0.89mmol) in 10mL of DMF was added HATU (340mg, 0.89mmol), DIEA (267mg, 2.07mmol), EDCI (145mg, 0.759mmol) and DMAP (93mg, 0.76 mmol). The reaction mixture was then stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure at 80 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of dichloromethane and methanol (20: 1)) to give 4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid methyl ester (350mg, 94%) as a yellow solid. LC-MS: 536.1[ M + H]⁺，t_R=1.68 minutes.

Step 5

4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) pyrrolidine-3- Radical carbamoylYl) benzoic acid

The method comprises the following steps:

stirring 4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5,4-d ] at room temperature]Solution of pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid methyl ester (350mg, 0.65mmol) in 20mL methanol and 40mL THF in one portion LiOH₂O solution (274mg, 6.5 mmol.) the solution is then stirred at room temperature for 24 h the solution is acidified to pH =4 with 1N Cl the solvent is evaporated and the residue is purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions are initial 30% acetonitrile/70% water (0.1% TFAV/V) and then after 9 min in a linear fashion to 55% acetonitrile/45% water (0.1% TFAV/V)) to give 4- (1- (7- (5, 6-dimethoxypyridin-2-ylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) pyrrolidin-3-ylcarbamoyl) benzoic acid (70mg, 20.5%) as a pale yellow solid.¹HNMR(300MHz，DMSO):8.87-8.18(m，2H)，8.67(s，1H)，8.03-7.96(m，5H)，7.44(d，1H，J=8.7Hz)，4.66(brs，1H)，4.11(brs，2H)，3.90(s，3H)，3.78(s，3H)，3.68(brs，2H)，2.27(brs，1H)，2.08(brs，1H)。LC-MS：522[M+H]⁺，t_R=1.44 minutes. HPLC: 99.68% at 214nm, 99.31% at 254nm, t_R=6.98 min.

Example 56

3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester

Step 1

5-chloro-N- (3- (trifluoromethyl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

5, 7-dichlorothiazolo [5,4-d ] stirred at room temperature]To a solution of pyrimidine (300mg, 1.45mmol) and 3- (trifluoromethyl) aniline (304.8mg, 1.89mmol) in 10ml of DMSO was added DIEA (282mg, 2.18mmol) in one portion. The reaction mixture was then stirred at room temperature for 5 hours. The reaction mixture was poured into 40mL of water, and the resulting solid was filtered, washed with water, and dried. The desired product 5-chloro-N- (3- (trifluoromethyl) phenyl) thiazolo [5,4-d is obtained]Pyrimidin-7-amine (356mg, 74%) as a yellow solid. LC-MS: 331.0[ M + H]⁺，t_R=1.70 minutes.

Step 2

The method comprises the following steps:

5-chloro-N- (3- (trifluoromethyl) phenyl) thiazolo [5,4-d ] stirred at room temperature under nitrogen]Pyrimidin-7-amine (330mg, 1mmol), methyl 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (314mg, 1.2mmol), and Na₂CO₃(498mg, 4.7mmol) in 2mL of water and 20mL of bisPd (PPh) was added to the solution in alkane in one portion₃)₄(93mg, 0.075 mmol). The mixture was then stirred at 95 ℃ under nitrogen for 16 hours. The solvent was evaporated under reduced pressure at 40 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4: 1)) to give 3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid methyl ester(365mg, 84.8%) as a yellow solid.¹HNMR(300MHz，DMSO):9.18(s，1H)，8.93(s，1H)，8.74(d，1H，J=7.8Hz)，8.61(s，1H)，8.21(brs，2H)，7.94(d，1H，J=7.8Hz)，7.65-7.60(m，2H)，7.48-7.46(m，1H)，4.01(s，3H)。LC-MS：431[M+H]⁺，429[M-H]^-，t_R=1.92 minutes. HPLC: 95.92%, at 214nm, 97.01%, at 254nm, t_R=5.14 minutes.

Example 57

3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid

The method comprises the following steps:

stirring of 3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5,4-d ] at room temperature]To a solution of pyrimidin-5-yl) benzoic acid methyl ester (100mg, 0.23mmol) in 3mL of HF and 3mL of methanol was added a solution of sodium hydroxide (46.5mg, 1.16mmol) in 1mL of water. The reaction mixture was then stirred at room temperature for 16 hours. HCl was added to pH =4. The solvent was evaporated under reduced pressure at 40 ℃ and the residue was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1: 1)) to give 3- (7- (3- (trifluoromethyl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid (65mg, 67.2%) as a light yellow solid.¹HNMR(300MHz，DMSO):13.15(brs，1H)，10.65(s，1H)，9.46(s，1H)，9.00(s，1H)，8.67(s，1H)，8.60(d，1H，J=7.8Hz)，8.26(d，1H，J=7.8Hz)，8.10(d，1H，J=7.5Hz)，7.68-7.63(m，2H)，7.49(d，1H，J=7.8Hz)。LC-MS：417[M+H]⁺，415[M-H]^-，t_R=1.65 minutes. HPLC: 95.14%, at 214nm, 95.28%, at 254nm, t_R=7.71 minutes.

Example 58

3- (7- (3,4, 5-trimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzamides

Step 1

5-chloro-N- (3,4, 5-trimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amines

The method comprises the following steps:

5, 7-dichlorothiazolo [5,4-d ] stirred at room temperature]To a solution of pyrimidine (200mg, 0.97mmol) and 3,4, 5-trimethoxyaniline (230mg, 1.25mmol) in 7mL of DMMSO was added DIEA (188mg, 1.45mmol) in one portion. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was poured into 40mL of water, and the resulting solid was filtered, washed with water (10mL) to give the crude product. Purification by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) afforded 5-chloro-N- (3,4, 5-trimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (337mg, 98.6%) as a yellow solid. LC-MS: 353.0[ M + H]⁺，726.9[2M+H]⁺，t_R=1.56 minutes.

Step 2

The method comprises the following steps:

5-chloro-N- (3,4, 5-trimethoxyphenyl) thiazolo [5,4-d ] stirred at room temperature under nitrogen]Pyrimidin-7-amine (337mg, 0.95mmol), 3- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (190mg, 1).15mmol) and Na₂CO₃(347mg, 3.27mmol) in 2mL of water and 50mL of twoPd (PPh) was added to the solution in alkane in one portion₃)₄(100mg, 0.086 mmol.) the mixture is then stirred at 97 ℃ under nitrogen for 16 h.the solvent is evaporated at 40 ℃ under reduced pressure and the residue is purified by chromatography on silica gel (200 mesh on silica gel, 300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1: 2)) to give the crude product purification by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 20% acetonitrile/80% water (0.1% TFAV/V) and then proceeding in a linear fashion to 45% acetonitrile/55% water (0.1% TFAV/V) after 9 min to give 3- (7- (3,4, 5-trimethoxyphenylamino) thiazolo [5,4-d ] -%]Pyrimidin-5-yl) benzamide (120mg, 27.4%) as a solid.¹HNMR(300MHz，DMSO):10.10(s，1H)，9.43(s，1H)，8.93(s，1H)，8.58(d，1H，J=8.1Hz)，8.03-8.00(m，2H)，7.65-7.60(m，3H)，7.50(brs，1H)，3.87(s，3H)，3.71(s，3H)，3.30(s，3H)。LC-MS：438[M+H]⁺，t_R=1.43 minutes. HPLC: 99.77%, at 214nm, 99.84%, at 254nm, t_R=5.68 minutes.

Example 59

1- (7- (3- ((S) -2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) piperidines -3-alchoholate salt

The method comprises the following steps:

reacting (S) -5-chloro-N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (138mg, 0.4mmol), piperidin-3-ol (50mg, 0.48mmol), Pd₂(dba)₃(24mg，0.04mmol)、X-Phos(78mg, 0.16mmol), Cs2CO3(392mg, 1.2mmol) and bisA mixture of alkanes (10mL) was stirred under N₂Heated to 100 ℃ for 16 h under vacuum the solvent is removed and the resulting mixture is first purified by column chromatography (petroleum ether: ethyl acetate =5:1) then by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions are: initial 30% acetonitrile/70% water (0.1% TFAV/V) then after 9 min proceed in a linear fashion to 50% acetonitrile/50% water (0.1% TFAV/V)) purification of the resulting mixture to the corresponding trifluoroacetate salt then concentrated HCl (0.5mL) is added and the mixture is stirred for 10 min and concentrated under reduced pressure to give 1- (7- (3- ((S) -2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d ] (S)]Pyrimidin-5-yl) piperidin-3-ol hydrochloride (93mg, 51.8%).¹HNMR(300MHz，DMSO):8.99(s，1H)，8.19(s，1H)，7.88(d，1H，J=8.1Hz)，7.73(t，1H，J=8.1Hz)，7.61(d，1H，J=7.8Hz)，4.16-4.03(m，3H)，3.89-3.69(m，5H)，2.57-2.51(m，1H)，2.43-2.29(m，2H)，2.10-1.99(m，3H)，1.77-1.69(m，2H)，1.39(d，3H，J=6.3Hz)。LC-MS：411[M+H]⁺，t_R=1.655 minutes. HPLC: 97.67%, at 214nm, 97.98%, at 254nm, t_R=4.983 minutes.

Example 60

(S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidines -5-yl) benzamides

Step 1

(S) -1- (3-methoxy-5-nitrophenyl) -2-methylpyrrolidine

Method of producing a composite material

1-bromo-3-methoxy-5-nitrobenzene (500mg, 2.16mmol), (S) -2-methylpyrrolidine (200mg, 2.37mmol), Pd2(dba)3(248mg, 0.43mmol), BINAP (538mg, 0.86mmol), Cs₂CO₃(2.11g, 6.48mmol) and bisA mixture of alkanes (20mL) was stirred under N₂Heated to 100 ℃ for 16 hours. The solvent was removed in vacuo, and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate =5:1) to give (S) -1- (3-methoxy-5-nitrophenyl) -2-methylpyrrolidine (430mg, 85%) as a yellow oil. LC-MS: 237[ M + H ]]⁺，t_R=1.77 minutes.

Step 2

(S) -3-methoxy-5- (2-methylpyrrolidin-1-yl) aniline

Method of producing a composite material

To (S) -1- (3-methoxy-5-nitrophenyl) -2-methylpyrrolidine (430mg, 1.82mmol) and zinc (1.18g, 18.2mmol) in bis at room temperatureTo a suspension in alkane (20mL) and H2O (10mL) was added concentrated HCl (1.8mL) dropwise, and the mixture was stirred for 2 hours. The reaction mixture was filtered and the filtrate was adjusted to pH-8 by addition of solid NaHCO3 and then extracted with ethyl acetate (50 mL). The organic layer was dried over Na2SO4, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =20:1) to give (S) -3-methoxy-5- (2-methylpyrrolidin-1-yl) aniline (269mg, 72%) as a yellow oil. LC-MS: 207[ M + H]⁺，t_R=1.193 min.

Step 3

(S) -5-chloro-N- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidine-7- Amines as pesticides

Method of producing a composite material

Reacting 5, 7-dichlorothiazolo [5,4-d ]]A mixture of pyrimidine (200mg, 0.97mmol), (S) -3-methoxy-5- (2-methylpyrrolidin-1-yl) aniline (220mg, 1.07mmol), and DIPEA (150mg, 1.17mmol) in DMSO (50mL) was heated with stirring to 30 ℃ for 16 hours, the mixture was diluted with water, extracted with ethyl acetate (50mL), the combined organic phases were washed with water (10mL × 4), then brine (10mL × 2), dried with Na2SO4, and concentrated to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate =20:1) to give (S) -5-chloro-N- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d ] - [1]Pyrimidin-7-amine (280mg, 77%) as a yellow oil. LC-MS: 376[ M + H]⁺，t_R=1.825 min.

Step 4

(S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidines -5-yl) benzoic acid methyl ester

Method of producing a composite material

Reacting (S) -5-chloro-N- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (200mg, 0.53mmol), methyl 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (153mg, 0.585mmol), Pd₂(dba)₃(61mg, 0.11mmol), X-Phos (102mg, 0.21mmol) and Na₂CO₃(169mg, 1.6mmol) in IIMixture of alkane (20mL) and water (5mL) under stirring in N₂Heated to 100 ℃ for 16 hours. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (petroleum ether: ethyl acetate =20:1) to give (S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid methyl ester (121mg, 48%) as a yellow oil. LC-MS: 476[ M + H ]]⁺，t_R=1.999 min.

Step 5

(S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidines -5-yl) benzoic acid

Method of producing a composite material

Reacting (S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid methyl ester (121mg, 0.25mmol) and NaOH (102mg, 2.54mmol) in bisA mixture in alkane (20mL) and H2O (10mL) was heated to 30 ℃ for 2 hours, the reaction mixture was concentrated, and the aqueous residue was adjusted to pH4 by addition of concentrated HCl, the solution was extracted with ethyl acetate (10mL × 3), then the combined organics were dried over Na2SO4, and concentrated to give (S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzoic acid (50mg, crude) was used in the next step without further purification as a yellow solid. LC-MS: 462[ M + H ]]⁺，t_R=1.699 min.

Step 6

(S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidines -5-yl) benzoylAmines as pesticides

Method of producing a composite material

Reacting (S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]A mixture of pyrimidin-5-yl) benzoic acid, EDCI (56mg, 0.29mmol), HOBt (39mg, 0.29mmol) and Et3N (39mg, 0.39mmol) in DCM (20mL) was stirred at room temperature for 3 hours, and then ammonia gas was bubbled through the mixture for 3 hours. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by column chromatography (DCM: MeOH =50:1) to give (S) -4- (7- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzamide (12mg, 10%) as a yellow solid.¹HNMR(300MHz，DMSO):9.99(s，1H)，9.40(s，1H)，8.49(s，1H)，8.46(s，1H)，8.12(s，1H)，8.01(s，1H)，7.98(s，1H)，7.49(s，1H)，7.15(s，1H)，7.05(s，1H)，5.88(s，1H)，3.93-3.90(m，1H)，3.79(s，3H)，3.43-3.40(m，1H)，3.18-3.15(m，1H)，2.06-1.98(m，3H)，1.69(s，1H)，1.15(d，3H，J=6.0Hz)。LC-MS：461[M+H]⁺，t_R=1.6 minutes. HPLC: 95.06%, at 214nm, 95.01%, at 254nm, t_R=5.55 minutes.

Example 61

(S) -5- (6-methoxypyridin-3-yl) -N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d] Pyrimidin-7-amines

Step 1

(S) -2-methyl-1- (3-nitrophenyl) pyrrolidine

Method of producing a composite material

1-bromo-3-nitrobenzene (1.43g, 7.06mmol), (S) -2-methylpyrrolidine (0.5g, 5.88mmol), Pd2(dba)3(0.34g, 0.59mmol), X-Phos (0.56g, 1.18mmol) and sodium carbonate (1.77g, 16.74mmol) were added to 1, 4-bisA mixture of an alkane (20mL) and water (20mL) mixture was heated to reflux for 16 hours. Then water was added, extracted with ethyl acetate, and the organic layer was washed with brine, Na₂SO₄Dried and filtered. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether: ethyl acetate =10:1) to give (S) -2-methyl-1- (3-nitrophenyl) pyrrolidine (1.1g, 91%) as a red solid. LC-MS: 207[ M + 1]]⁺，t_R=1.77 minutes.

Step 2

(S) -3- (2-methylpyrrolidin-1-yl) aniline

Method of producing a composite material

By H₂A mixture of (S) -2-methyl-1- (3-nitrophenyl) pyrrolidine (1.1g, 5.34mmol) and Pd/C (0.2g) in MeOH (50mL) was purified then in H₂Stirred under atmosphere for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated to give crude (S) -3- (2-methylpyrrolidin-1-yl) aniline (1g, 100%) which was used in the next step without further purification. LC-MS: 177[ M + 1]]⁺，t_R=1.09 minutes.

Step 3

Method of producing a composite material

Mixing (S) -3- (2-methylpyrrolidin-1-yl) aniline (0.9g, 5.34mmol), 5, 7-dichlorothiazolo [5, 4-d)]A mixture of pyrimidine (1.1g, 5.34mmol), DIEA (1.4g, 10.68mmol) in IPA (15mL) was heated to reflux for 2 h. The reaction mixture was then concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =8:1) to give (S) -5-chloro-N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (1.6g, 91.4%) as a yellow solid. LC-MS: 346[ M + 1]]⁺，t_R=1.82 minutes.

Step 4

Method of producing a composite material

Reacting (S) -5-chloro-N- (3- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (200mg, 0.58mmol), 6-methoxypyridin-3-ylboronic acid (134mg, 0.87mmol), Pd2(dba)3(34mg, 0.058mmol), X-Phos (0.58mg, 0.12mmol) and sodium carbonate (185mg, 1.74mmol) in 1, 4-bisA mixture of alkane and water (5mL:5mL) was heated to reflux for 16 h. Then water was added, the mixture was extracted with ethyl acetate, the combined organics were washed with brine, Na₂SO₄The crude product was purified by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 20% acetonitrile/80% water (0.1% TFAV/V) and then linear to 45% acetonitrile/55% water (0.1% TFAV/V) after 9 minutes) to give (S) -5- (6-methoxypyridin-3-yl) -N- (3- (2-methyl-pyridin-3-yl) -N- (3-methyl-2-yl-L-methyl-amino-ethyl-4-yl-methyl-4-hydroxy-methyl-ethyl-4-hydroxy-methyl-ethyl-methyl-4-Pyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (60mg, 24.8%) as a yellow solid.¹HNMR(300MHz，CD3OD):9.19(s，1H)，9.08(s，1H)，8.63(dd，1H，J1=8.7Hz，J2=2.4Hz)，7.33(s，1H)，7.23-7.12(m，2H)，6.88(d，1H，J=8.7Hz)，6.42(d，1H，J=6.9Hz)，3.96(s，3H)，3.51-3.46(m，1H)，3.30-3.24(m，2H)，2.17-2.03(m，3H)，1.80-1.75(m，1H)，1.22(d，3H，J=6.3Hz)。LC-MS：419[M+H]⁺，t_R=2.04 min. HPLC: 100% at 214nm, 100% at 254nm, t_R=6.299 min.

Example 62

(S) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzathines Amides of carboxylic acids

Step 1

4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide

Method of producing a composite material

To a mixture of 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoic acid (200mg, 0.746mmol), EDCI (214mg, 1.12mmol), HOBt (151mg, 1.12mmol) and Et3N (151mg, 1.49mmol) in DCM (20mL) was bubbled ammonia gas to saturation. The mixture was stirred at room temperature for 3 hours, then filtered, and the filtrate was concentrated to give a residue which was purified by column chromatography (DCM: MeOH =50:1) to give 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (90mg, 45%) as a yellow solid. LC-MS: 248[ M + 1]]⁺，t_R=1.421 minutes.

Step 2

(S) -4- (7- (3- (2-methylpyrrolidine)-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzathines Amides of carboxylic acids

Method of producing a composite material

Reacting (S) -5-chloro-N- (3-methoxy-5- (2-methylpyrrolidin-1-yl) phenyl) thiazolo [5,4-d]Pyrimidin-7-amine (100mg, 0.29mmol), 4- (4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide (77mg, 0.29mmol), Pd2(dba)3(33mg, 0.058mmol), X-Phos (55mg, 0.116mmol), and Na₂CO₃(123mg, 1.16mmol) in bisMixture of alkane (20mL) and water (5mL) under stirring in N₂Heated to 100 ℃ for 16 hours. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (DCM: MeOH =80:1) to give (S) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzamide (26mg, 21%) as a yellow solid.¹HNMR(300MHz，DMSO):10.02(s，1H)，9.39(s，1H)，8.46-8.44(m，2H)，8.10(s，1H)，8.00-7.97(m，2H)，7.48-7.39(m，2H)，7.29-7.15(m，2H)，6.35(d，1H，J=7.8Hz)，3.91(brs，1H)，3.41-3.31(m，1H)，3.19-3.16(m，1H)，2.08-1.98(m，2H)，1.71(brs，1H)，1.15(d，3H，J=6.3Hz)。LC-MS：431[M+H]⁺，t_R=1.57 min. HPLC: 95.67% at 214nm, 95.15% at 254nm, t_R=3.14 minutes.

Example 63

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (4- (2, 4-dioxo) Thiazolidin-5-yl) phenyl) benzamide

Method of producing a composite material

To the 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidine-5-yl) benzoic acid (100mg, 0.25mmol) and 5- (4-aminophenyl) thiazolidine-2, 4-dione (50mg, 0.25mmol) in DCM (10mL) were added 1-methyl-1H-indazole (78mg, 1.0mmol) and EDCI (129mg, 1.0mmol) in DCM (5mL), the reaction mixture was stirred at room temperature for 15H, the solvent was removed in vacuo and the reaction mixture was purified by column chromatography (DCM: MeOH =50:1), then by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions: initial 30% acetonitrile/70% water (0.1% TFAV/V), then after 9 min in a linear fashion to 45% acetonitrile/55% water (0.1% TFAV/V)) the residue, the corresponding mixture was purified to obtain a concentrated TFAV/trifluoroacetic acid salt (0.1% HCl), then the corresponding TFAV/5-dimethoxy) was suspended in dichloromethane (3mL) and the resulting in 3-5-4-dichloromethane (7mL) and the corresponding salt was stirred and the mixture was added dropwise]Pyrimidin-5-yl) -N- (4- (2, 4-dioxothiazolidin-5-yl) phenyl) benzamide (2.4mg, 1.5%) as the HCl salt.¹HNMR(300MHz，DMSO):12.29(s，1H)，10.57(s，1H)，10.19(s，1H)，9.41(s，1H)，8.95(s，1H)，8.59(d，1H，J=7.5Hz)，8.07(d，1H，J=7.8Hz)，7.84-7.81(m，2H)，7.69(t，1H，J=7.5Hz)，7.55(d，2H，J=9.0Hz)，7.42(d，1H，J=8.4Hz)，6.97(d，1H，J=8.4Hz)，5.74(s，1H)，3.80(s，3H)，3.72(s，3H)。LC-MS：599[M+H]⁺，t_R=1.54 minutes. HPLC: 95.59%, at 214nm, 95.99%, at 254nm, t_R=4.594 minutes.

Example 64

4- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzamides

Method of producing a composite material

To 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoic acid (210mg, 0.52mmol), EDCI (147mg, 0.77mmol), HOBt (104mg, 0.77mmol) and Et3N (104mg, 1.07mmol) in DCM (20mL) was bubbled with ammonia gas to saturation. The mixture was stirred at room temperature for 3 hours, then filtered, and the filtrate was concentrated to give a residue, which was purified by column chromatography (DCM: MeOH =50:1) to give 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzamide (38mg, 22%) as a yellow solid.¹HNMR(300MHz，DMSO):9.14(s，1H)，8.30(s，1H)，8.27(s，1H)，7.87(s，1H)，7.84(s，1H)，7.62(d，1H，J=2.4Hz)，7.32-7.28(m，1H)，6.92(d，1H，J=9.0Hz)，3.75(s，3H)，3.72(s，3H)。LC-MS：599[M+H]⁺，t_R=1.54 minutes. HPLC: 95.59%, at 214nm, 95.99%, at 254nm, t_R=4.594 min LC-MS: 408[ M + H]⁺，t_R=1.392 minutes. HPLC: 95.38% at 214nm, 96.23% at 254nm, t_R=5.259 min.

Example 65

(S) -N- (2- (dimethylamino) ethyl) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thia-ne Azolo [5,4-d]Pyrimidin-5-yl) benzamides

Method of producing a composite material

To (S) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzoic acid (80mg, 0.19mmol) and a solution of N1, N1-dimethylethylene-1, 2-diamine (18mg, 0.2mmol) in DCM (20mL) were added 1-methyl-1H-indazole (92mg, 1.12mmol) and EDCI (217mg,1.12 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (DCM: MeOH =50:1) and the product was treated with concentrated HCl to give (S) -N- (2- (dimethylamino) ethyl) -4- (7- (3- (2-methylpyrrolidin-1-yl) phenylamino) thiazolo [5,4-d]Pyrimidin-5-yl) benzamide (22mg, 24%) as the HCl salt.¹HNMR(300MHz，CD3OD):9.15(s，1H)，8.37(s，1H)，8.34(s，1H)，8.27(s，1H)，7.97-7.91(m，3H)，7.63-7.57(m，1H)，7.41(d，1H，J=8.1Hz)，4.06-3.93(m，2H)，3.77-3.68(m，3H)，3.37-3.33(m，2H)，2.91(s，6H)，2.53-2.42(m，1H)，2.35-2.18(m，2H)，2.06-1.87(m，1H)，1.36(d，3H，J=6.6Hz)。LC-MS：502[M+H]⁺，t_R=1.344 min. HPLC: 97.57% at 214nm, 97.17% at 254nm, t_R=4.793 minutes.

Example 66

4- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) -N- (2- (dimethylamino) Yl) ethyl) benzamide

Method of producing a composite material

4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]A mixture of pyrimidin-5-yl) benzoic acid (158mg, 0.387mmol) and N1, N1-dimethylethyl-1, 2-diamine (37mg, 0.41mmol), 1-methyl-1H-indazole (127mg, 1.56mmol) and EDCI (296mg, 1.56mmol) in DCM (20mL) was stirred at room temperature for 3 hours the solvent was removed in vacuo and the residue was purified by column chromatography (DCM: MeOH =50:1), then by preparative HPLC (Gemini5uC18150 × 21.2.2 mm; injection volume: 3 mL/injection, flow rate: 20 mL/min; wavelength: 214nm and 254 nm; gradient conditions starting with 20% acetonitrile/80% water (0.1% TFAV/V) and then after 9 min proceeding in a linear fashion to 45% acetonitrile/55% water (0.1% TFAV/V)) to give the corresponding trifluoroacetate saltThe salt was suspended in MeOH (10mL) and concentrated HCl (0.5mL) was added, the mixture was stirred for 15 min and concentrated under reduced pressure to give 4- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) -N- (2- (dimethylamino) ethyl) benzamide (49mg, 25%) was the HCl salt.¹HNMR(300MHz，DMSO):9.16(s，1H)，8.35(s，1H)，8.33(s，1H)，7.88(s，1H)，7.86(s，1H)，7.62(s，1H)，7.32-7.29(m，1H)，6.96(d，1H，J=9.0Hz)，3.76(s，3H)，3.72(s，3H)，3.62-3.59(m，2H)，3.26-3.23(m，2H)，2.79(s，6H)。LC-MS：479[M+H]⁺，t_R=1.23 min. HPLC: 99.54% at 214nm, 99.49% at 254nm, t_R=4.884 minutes.

Example 67

(3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenyl) methanols

Method of producing a composite material

Reacting 5-chloro-N- (3, 4-dimethoxyphenyl) thiazolo [5,4-d]Pyrimidin-7-amine (200mg, 0.62mmol), 3- (hydroxymethyl) phenylboronic acid (104mg, 0.68mmol), Pd₂(dba)₃(71mg，0.12mmol)、X-Phos(118mg，0.25mmol)、Na₂CO₃(131mg, 1.2mmol) in bisMixture of alkane (20mL) and H2O (5mL) with stirring in N₂Heated to 90 ℃ for 16 hours. The solvent was removed in vacuo and the resulting mixture was purified by column chromatography (MeOH: DCM =1:80) to give (3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) phenyl) methanol (51mg, 21%) as a yellow solid.¹HNMR(300MHz，CDCl3):8.84(s，1H)，8.49(s，1H)，8.42(d，1H，J=6.9Hz)，7.97(s，1H)，7.87(s，1H)，7.49-7.46(m，2H)，7.18(dd，1H，J1=8.7Hz，J2=2.7Hz)，6.93(d，1H，J=8.4Hz)，4.79(s，2H)，4.00(s，3H)，3.93(s，3H)。LC-MS：395[M+H]⁺，t_R=1.48 minutes. HPLC: 98.36%, at 214nm, 98.69%, at 254nm, t_R=6.086 minutes.

Example 68

3- (7- (3, 4-Dimethoxyphenylamino) thiazolo [5, 4-d)]Pyrimidin-5-yl) benzamides

Method of producing a composite material

To the 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzoic acid (100mg, 0.25mmol), EDCI (70mg, 0.37mmol), HOBt (50mg, 0.37mmol) and Et3N (49mg, 0.49mmol) in DCM (20mL) was bubbled with ammonia gas to saturation. The mixture was stirred at room temperature for 3 hours, then filtered, and the filtrate was concentrated to give a residue, which was purified by column chromatography (DCM: MeOH =50:1) to give 3- (7- (3, 4-dimethoxyphenylamino) thiazolo [5,4-d ]]Pyrimidin-5-yl) benzamide (22mg, 14%) as a yellow solid.¹HNMR(300MHz，DMSO):10.13(s，1H)，9.37(s，1H)，8.88(t，1H，J=1.5Hz)，8.51(d，1H，J=7.8Hz)，8.10(s，1H)，7.98(d，1H，J=7.5Hz)，7.86(d，1H，J=2.4Hz)，7.58(t，1H，J=7.8Hz)，7.49-7.44(m，2H)，7.99(d，1H，J=8.7Hz)，3.82(s，3H)，3.77(s，3H)。LC-MS：408[M+H]⁺，t_R=1.39 minutes. HPLC: 97.78%, at 214nm, 97.42%, at 254nm, t_R=1.39 minutes. LC-MS: 408[ M + H]⁺，t_R=1.392 minutes. HPLC: 95.38% at 214nm, 96.23% at 254nm, t_R=3.53 min.

Biological examples

SYK test information

Spleen tyrosine kinase (SYK) inhibited IC₅₀And (3) determination:

the SYK kinase assay is a standard kinase assay suitable for use in a well plate format. The assay was performed in 96-well format to determine IC with 8 samples₅₀The 8 samples represent 10 semilog dilutions and a 40 μ L reaction volume. The assay determining radiolabeling³³The PATP incorporated the amount of N-terminally biotinylated peptide substrate derived from the naturally occurring consensus sequence of the phosphorus receptor (biotin-11 aaDY. times.e). Phosphorylated products were detected when the reaction with EDTA was stopped and streptavidin-coated beads were added. Representative results are shown in table II above.

Test panel: 96-well MultiScreen0.65um filter plate (Millipore catalog number: MADVNOB10)

Streptavidin-coated beads: streptavidin Sepharose TM, 5.0mL suspension, diluted with 50mM EDTA/PBS (1:100), (Amersham, Cat: 17-5113-01)

A compound: 10mM in 100% Dimethylsulfoxide (DMSO), final concentration: compounds 0.003-100uM in 10% DMSO

Enzyme: SYKRPA purified, truncated constructs of spleen tyrosine kinase aa360-635, stock solution 1mg/mL, MW: 31.2KDa, final concentration: 0.0005. mu.M

Peptide 1: biotinylated peptides were derived from the naturally occurring phosphoreceptor consensus sequence (biotin-EPEGDYEEVLE), proprietary grade from QCB, stock solution 20mM, final concentration: 5.0. mu.M.

ATP: adenosine-5' -triphosphate 20mM, (ROCHE, Cat: 93202720), final concentration: 20 μ M

Buffer solution: HEPES (high efficiency particulate air): 2-Hydroxyethylpiperazine-2-ethanesulfonic acid (Sigma, cat # H-3375), final concentration: 50mM HEPES pH7.5

BSA: bovine serum albumin fraction V, free of fatty acids (Roche diagnostics GmbH, Cat. No. 9100221), diluted to a final concentration of 0.1%

EDTA: EDTA stock solution 500mM, (GIBCO, Cat. No.: 15575-038), final concentration: 0.1mM

DTT: 1, 4-dithiothreitol (Roche diagnostics GmbH, Cat. No: 197777), final concentration: 1mM

MgCl₂×6H₂O: MERCK, Cat No.: 105833.1000, final concentration: 10mM

Assay Dilution Buffer (ADB) 50mM HEPES, 0.1mM MEGTA, 0.1mM Na vanadate, 0.1mM β -glycerophosphate, 10mM MgCl₂、1mMDTT、0，1%BSA，pH7.5

Bead wash buffer: 10g/LPBS (phosphate buffered saline) containing 2M NaCl +1% phosphoric acid.

The test method comprises the following steps:

in a 40 μ L volume, 26 μ LADB diluted purified recombinant human SYK360-635[0.5nM ] was mixed with 4 μ L10 × concentration of test compound [ typically 100 μ M-0.003 μ M ] (in [10% ] DMSO) and the mixture was incubated at RT for 10 min.

By addition of a peptide substrate containing DYE [0 or 5. mu.M ]]、ATP[20μM]And³³PγATP[2μCi/rxn]after 15 minutes incubation at 30 ℃, the reaction was stopped by transferring 25 μ L of the reaction sample to a 96 well 0.65 μm millipore madpnob membrane/plate containing 200 μ L of 5mm edta and 20% streptavidin coated beads in PBS.

Using 3 × 250 uL 2MNaCl, 2 × 250 uL 2MNaCl +1% phosphoric acid, 1 × 250 uLH₂And O, washing the unbound radionuclide under vacuum. After transfer of the final washed membrane/plate to the connector plate, dry heat was carried out at 60 ℃ for 15 minutes and 50 μ L of scintillation cocktail was added to each well and the amount of radioactivity was counted after 4 hours using a top counter.

Percent inhibition was calculated based on the uninhibited enzyme ratio:

% inhibition =100/(1+ (IC)₅₀Inhibitor concentration)ⁿ)

IC was calculated using nonlinear curve fitting with XLFit software (IDBusinessSolutionLtd., Guilford, Surrey, UK)₅₀。

The foregoing invention has been described in some detail by way of illustration and example for purposes of clarity and understanding. It will be apparent to those skilled in the art that changes and modifications may be made within the scope of the appended claims. Accordingly, it is to be understood that the above description is intended to be illustrative, and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but instead should be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications, and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each patent, patent application, or publication were individually indicated.

Claims

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

Wherein:

R¹is phenyl, optionally substituted by one or more C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylsulfonyl or R^1’Substitution;

R^1’is pyrrolidinyl, whichIs selected by one or more R^1”Substitution;

R^1”is C_1-6Alkyl or C_1-6An alkoxy group;

b is phenyl, pyridyl, pyrrolidinyl or piperidinyl;

x is OH, C_1-6Alkoxy, NHC (═ O) Y, C (═ O) NH₂、C(＝O)NHY、C(＝O)X’、C(＝O)Y、CH₂NHY、CH₂CH₂Y、CF＝CHY、CH＝CHY、CH₂OH、C(＝O)NHCH₂CH₂N(CH₃)₂Or C (═ O) NHCH₂CH₂Y；

X' is OH or C_1-6An alkoxy group;

y is heterocycloalkyl, phenyl or heteroaryl, each of which is optionally substituted by one or more Y³Substitution;

Y³is hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, oxo, amino, amido, C (═ O) NH (CH)₃)、C(＝O)OH、C(＝O)OY⁴Or heteroaryl, optionally substituted by one or more C_1-6Alkyl, oxo or SH substitution;

Y⁴is C_1-6An alkyl group;

wherein

"Heterocycloalkyl" is a monovalent saturated cyclic group consisting of 1 to 2 rings of 3 to 8 atoms per ring to which is bonded one or more atoms selected from N, O or S (O)_0-2A ring heteroatom of (a);

"heteroaryl" is a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic or partially unsaturated ring, each ring containing 4 to 8 atoms, to which is bonded one or more N, O or S heteroatoms, the remaining ring atoms being carbon.

2. A compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof

Wherein:

R^1’is pyrrolidinyl, optionally substituted with one or more R^1”Substitution;

R^1”is C_1-6Alkyl or C_1-6An alkoxy group;

b is phenyl, pyrrolidinyl or piperidinyl;

x is OH, NHC (O) Y, C (O) NH₂、C(＝O)NHY、C(＝O)X’、C(＝O)Y、CH₂NHY、CH₂CH₂Y、CF＝CHY、CH＝CHY、CH₂OH、C(＝O)NHCH₂CH₂N(CH₃)₂Or C (═ O) NHCH₂CH₂Y；

X' is OH or C_1-6An alkoxy group;

Y³is hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy, oxo, amino, amido, C (═ O) OH or C (═ O) OY⁴；

Y⁴Is C_1-6An alkyl group;

wherein

3. The compound of claim 1, wherein B is phenyl.

4. The compound of claim 2, wherein B is phenyl.

5. The compound of claim 1, wherein B is pyrrolidinyl.

6. The compound of claim 2, wherein B is pyrrolidinyl.

7. The compound of claim 1, wherein B is piperidinyl.

8. The compound of claim 2, wherein B is piperidinyl.

9. A compound according to any one of claims 1 to 8, wherein X is NHC (═ O) Y, C (═ O) NH₂、C(＝O)NHY、C(＝O)X’、C(＝O)Y、C(＝O)NHCH₂CH₂N(CH₃)₂Or C (═ O) NHCH₂CH₂Y。

10. A compound according to any one of claims 1 to 8, wherein X is NHC (═ O) Y, C (═ O) NHY, CH₂NHY or CH₂OH。

11. The compound of claim 9, wherein X is NHC (═ O) Y, C (═ O) NHY, CH₂NHY or CH₂OH。

12. The compound of any one of claims 1 to 8 and 11, wherein R¹Is 3, 4-dimethoxy-phenyl.

13. The compound of claim 9, wherein R¹Is 3, 4-dimethoxy-phenyl.

14. The compound of claim 10, wherein R¹Is 3, 4-dimethoxy-phenyl.

15. The compound of any one of claims 1 to 8 and 11, wherein Y is phenyl, optionally substituted with one or more Y³And (4) substitution.

16. The compound of claim 9, wherein Y is phenyl, optionally substituted with one or more Y³And (4) substitution.

17. The compound of claim 10, wherein Y is phenyl, optionally substituted with one or more Y³And (4) substitution.

18. The compound of any one of claims 1 to 8 and 11, wherein Y is heteroaryl, optionally substituted with one or more Y³Substitution;

wherein

19. The compound of claim 9, wherein Y is heteroaryl, optionally substituted with one or more Y³Substitution;

wherein

20. The compound of claim 10, wherein Y is heteroaryl, optionally substituted with one or more Y³Substitution;

wherein

21. The compound of any one of claims 1 to 8 and 11, wherein Y is heterocycloalkyl, optionally substituted with one or more Y³Substitution;

wherein

"Heterocycloalkyl" is a monovalent saturated cyclic group consisting of 1 to 2 rings of 3 to 8 atoms per ring to which is bonded one or more atoms selected from N, O or S (O)_0-2A ring heteroatom of (a).

22. The compound of claim 9, wherein Y is heterocycloalkyl, optionally substituted with one or more Y³Substitution;

wherein

23. The compound of claim 10, wherein Y is heterocycloalkyl, optionally substituted with one or more Y³Substitution;

wherein

24. A compound, wherein the compound is selected from:

25. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of an inflammatory or autoimmune disorder.

26. Use of a compound according to any one of claims 1 to 24 and an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, in the manufacture of a medicament for treating an inflammatory or autoimmune condition.

27. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of an inflammatory disorder.

28. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of rheumatoid arthritis.

29. The use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of asthma.

30. Use of a compound according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of an immune disorder selected from lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, organ transplant complications, xenotransplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, and alzheimer's disease.

31. The use of claim 30, wherein the diabetes is type I diabetes.

32. Use of an anti-inflammatory compound in combination with a compound according to any one of claims 1 to 24 for the manufacture of a medicament for the treatment of an inflammatory disorder.

33. Use of an immunosuppressive compound in combination with a compound of any one of claims 1-24 for the manufacture of a medicament for the treatment of an immune disorder.

34. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 in admixture with at least one pharmaceutically acceptable carrier, excipient or diluent.

35. The pharmaceutical composition of claim 34, further comprising an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating immunodeficiency disorders.

36. Use of a compound according to any one of claims 1-24 in the manufacture of a medicament for the treatment of a Syk-related disorder.