Salts, crystal forms and preparation methods of heteroaromatic derivatives

Abstract

This invention relates to a salt containing a heteroaromatic derivative and its crystal form. Specifically, it relates to a salt of a compound having general formula (I) and its crystal form, a method for preparation, and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and its use as a JAK kinase inhibitor in the treatment of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease, as well as tumors such as colon cancer and non-small cell lung cancer.

Description

[0001] This application claims priority to Chinese patent application CN202010451845.8, filed on May 25, 2020. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of biomedicine, specifically relating to a salt, crystal form, preparation method, and application of a heteroaromatic derivative. Background Technology

[0003] Janus kinases (JAKs) are intracellular non-receptor tyrosine kinases that mediate the signal transduction and activation of various cytokines. The JAK kinase family contains four subfamilies: JAK1, JAK2, JAK3, and TYK2. Each subfamily mediates different types of cytokine signaling pathways. JAK1, JAK2, and TYK2 are expressed in all human tissues and cells, while JAK3 is mainly expressed in hematopoietic cells. A common characteristic of cytokine receptors is that the receptors themselves do not possess kinase activity, but their intracellular domains contain binding sites for tyrosine kinases (JAKs). When a cytokine receptor binds to its ligand, it activates receptor-coupled JAKs, leading to receptor phosphorylation. The phosphorylated tyrosine residues can bind to STAT proteins containing SH2 domains, thereby recruiting STAT to the receptor and phosphorylating it through JAKs. Subsequently, phosphotyrosine mediates STAT dimerization. The activated STAT dimers translocate into the nucleus and activate the transcription of their target genes, thereby regulating various cellular functions such as growth, activation, and differentiation.

[0004] The JAK / STAT signaling pathway mediates the signal transduction of most intracellular cytokines and plays a crucial role in biological processes such as immune regulation and immune cell proliferation. The JAK / STAT signaling pathway has a wide range of functions, participating in many important biological processes such as cell proliferation, differentiation, apoptosis, and immune regulation. It is closely related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease (ulcerative colitis and Crohn's disease). Simultaneously, the JAK / STAT signaling pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera, and essential thrombocythemia. Mutations in the JAK molecule itself can also lead to neoplastic diseases such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), ductal carcinoma of the breast, and non-small cell lung cancer (NSCLC).

[0005] Inflammatory bowel disease (IBD) is a chronic inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease (CD). Currently, the main medications for treating IBD include aminosalicylic acid preparations, glucocorticoids, immunosuppressants, and antibiotics. The treatment of UC primarily focuses on modulating the immune response and suppressing inflammation. Clinically, sulfasalazine is mainly used to treat mild to moderate UC. For moderate to severe UC, glucocorticoids are commonly used, but because the risks outweigh the benefits, they are not used as a long-term treatment. Monoclonal antibodies, however, present challenges due to their high cost, the potential for antibody production affecting drug safety and efficacy, and the inconvenience of intravenous administration. This area still represents a significant unmet medical need. Many patients receiving treatment do not achieve remission, and up to 80% of Crohn's disease patients and 30% of UC patients ultimately require surgical treatment.

[0006] Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of adult patients with moderate to severe active ulcerative colitis (UC). It exhibits significant inhibitory activity against JAK1, 2, and 3 subtypes, which enhances its efficacy but also brings relatively serious side effects. Adverse reactions include infections, tuberculosis, tumors, anemia, liver damage, and increased cholesterol. The tofacitinib package insert contains numerous boxed warnings: serious infections (tuberculosis, bacterial, fungal, viral) and malignancies (lymphoma, etc.). Because each JAK has a broad range of functions, these side effects are caused by the drug's simultaneous inhibition of multiple JAKs. Since JAKs are widely involved in the regulation of immune cells, JAK inhibitors inevitably cause immunosuppressive-related side effects, such as severe infections and even tumorigenesis. Even with many highly selective inhibitors currently under development, such side effects caused by target inhibition are unavoidable.

[0007] Given the good efficacy of JAK inhibitors and their serious side effects related to multiple targets, developing a safer JAK inhibitor drug has become an urgent problem to solve. Since inflammatory bowel disease occurs on the surface of the gastrointestinal tract and can exert its effects without entering the bloodstream, developing a drug that reduces systemic exposure in the bloodstream while increasing local exposure at the site of inflammation is a good strategy to improve safety. International application WO2016191524A1 reports that Theravance has synthesized a series of compounds with extremely low systemic exposure, which accumulate at the site of inflamed intestines. These compounds effectively treat intestinal inflammation without causing serious side effects, indicating that this strategy is highly feasible and may have significant clinical application value.

[0008] The PCT patent (application number: PCT / CN2019 / 121944) discloses the structures of a series of heteroaromatic derivative inhibitors. In subsequent research and development, in order to facilitate the processing, filtration and drying of the products, and to seek suitable crystals that are easy to store, have long-term product stability and high bioavailability, this invention has conducted a comprehensive study on the free base crystal forms of the above compounds. Summary of the Invention

[0009] All contents relating to patent PCT / CN2019 / 121944 are incorporated herein by reference.

[0010] The purpose of this invention is to provide an acid salt of the compound represented by general formula (I), the structure of which is shown below:

[0011]

[0012] in:

[0013] L1 is selected from the bond, -(CH2). r -、-(CH2) r S(O)2-、-S(O)2(CH2) r -、-(CH2) r S(O)2NR a -、-(CH2) r NR a -、-C(O)(CH2) r -、-C(O)(CH2) r NR a -、-C(O)(CH2) r NR a (CH2) s -、-(CH2) r C(O)- or -(CH2) r C(O)NR a -;

[0014] R a Selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy;

[0015] R1 is selected from hydrogen, cyano, halogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-12 Aryl or 5-10 heteroaryl groups, optionally further converted to cyano, halogen, or C 1-6 Alkyl, C 1-6 Alkoxy or C1-6 The hydroxyalkyl group is substituted with one or more substituents, preferably hydrogen, cyano, halogen, or C. 1-3 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, phenyl, or 5-6 membered nitrogen-containing heteroaryl, optionally further converted to cyano, halogen, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 One or more substituents in the hydroxyalkyl group are substituted;

[0016] R2 is selected from hydrogen or C. 1-6 alkyl;

[0017] R3 is selected from hydrogen, hydroxyl, halogen, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkyl monosubstituted amino, C 1-6 Alkyl disubstituted amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 aryl or 5-10 heteroaryl groups, optionally further bonded by halogens, amino groups, cyano groups, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Alkyl monosubstituted amino, C 1-6 Alkyl disubstituted amino, C 3-8 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-12 The aryl group or one or more substituents of 5-10 heteroaryl groups are preferred, including hydrogen, hydroxyl, halogen, amino, and C. 1-3 Alkyl, C 3-6 Cycloalkyl, 4-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, O or S, phenyl or 5-6 membered nitrogen-containing heteroaryl, optionally further modified by halogen, amino, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Alkyl monosubstituted amino, C 1-3 Alkyl disubstituted amino, C 3-6 The alkyl group is replaced by one or more substituents from cycloalkyl, 4-7 membered heterocyclic, phenyl or 5-6 membered nitrogen-containing heteroaryl groups;

[0018] R4 is selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl or C 1-6 Alkoxy;

[0019] Ring A is selected from aryl, five-membered sulfur-containing heterocyclic groups, preferably phenyl, , , or ;

[0020] Ring B is selected from 5-10 member nitrogen-containing heterocyclic groups, preferably , , , , , , , , , , , and ;

[0021] The acid is an inorganic acid or an organic acid. Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, or phosphoric acid; the organic acid is selected from 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, and tartaric acid. Dodecyl sulfuric acid, benzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthalic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-methylbenzenesulfonic acid, or L-malic acid;

[0022] m is 1, 2, or 3;

[0023] r can be 0, 1, 2, or 3;

[0024] s can be 1, 2, or 3.

[0025] In a further preferred embodiment of the present invention, the compound structure is shown as general formula (II):

[0026] ,

[0027] Where n is 1 or 2.

[0028] In a further preferred embodiment of the present invention, the compound structure is as shown in general formula (III):

[0029]

[0030] Where n is 1 or 2.

[0031] In a further preferred embodiment of the present invention, L1 is selected from bond, -(CH2). r -、-C(O)(CH2) r NR a -、-C(O)(CH2) r NR a (CH2) s -or-(CH2) r C(O)NR a -, preferred bonds, -(CH2)-, -(CH2)2-, -(CH2)3-, -C(O)(CH2)NR a -、-C(O)(CH2)2NR a -、-C(O)(CH2)NR a (CH2)-、-C(O)(CH2)NR a (CH2)2-、-(CH2)C(O)NR a -、-(CH2)2C(O)NR a -or-(CH2)3C(O)NR a -;

[0032] R a Selected from hydrogen or deuterium.

[0033] In a further preferred embodiment of the present invention, R1 is selected from hydrogen, cyano, halogen, and C. 1-3 Alkyl, phenyl, , , , , , , , , Optionally further modified by cyano, halogen, C 1-3 Alkyl, C 1-3 It is replaced by one or more substituents in the alkoxy group.

[0034] In a further preferred embodiment of the present invention, R2 is selected from hydrogen, methyl, ethyl, propyl or isopropyl; preferably hydrogen or methyl.

[0035] In a further preferred embodiment of the present invention, R3 is selected from hydrogen, hydroxyl, halogenated fluorine, chlorine, bromine, amino, methylamino, ethylamino, dimethylamino, methyl, ethyl, hydroxymethyl, methoxy, ethoxy, phenyl, etc. , , , , , , , , , , , , , , , Optionally further reacted with halogens, amino groups, and C 1-3 Alkyl monosubstituted amino, C 1-3 Alkyl disubstituted amino, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, phenyl , , , , , , , , , , , , or One or more substituents in are replaced.

[0036] In a further preferred embodiment of the present invention, R4 is selected from hydrogen, C 1-3 Alkyl, C 1-3 Hydroxyalkyl or C 1-3 Alkoxy, preferably hydrogen, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxy, ethoxy, or propoxy, preferably hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, or methoxy.

[0037] In a further preferred embodiment of the present invention, the acid is selected from phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, and stearic acid; preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid; further preferably phosphoric acid, maleic acid, or benzenesulfonic acid.

[0038] In a further preferred embodiment of the present invention, the general formula (I) is selected from the following compounds:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048] The specific structures of the compounds with the corresponding numbers are as follows:

[0049] and .

[0050] In a further preferred embodiment of the present invention, the general formula (I) is selected from the following compounds:

[0051]

[0052]

[0053]

[0054] The acid is selected from phosphoric acid, succinic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, or stearic acid, preferably phosphoric acid, succinic acid, maleic acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, or fumaric acid.

[0055] In a further preferred embodiment of the present invention, the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one is an acid salt, wherein the acid is selected from hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, or stearic acid.

[0056] In a further preferred embodiment of the present invention, the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-2-morpholinoethane-1-one is an acid salt, wherein the acid salt is selected from hydrochloride, maleate, benzenesulfonate, hydroxyethylsulfonate, 1,5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate, or stearate.

[0057] In a further preferred embodiment of the present invention, the compound 2-(ethylamino)-1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one is an acid salt, wherein the acid salt is selected from hydrochloride, maleate, benzenesulfonate, hydroxyethylsulfonate, 1,5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate, or stearate.

[0058] In a further preferred embodiment of the present invention, the acid salt of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile, wherein the acid salt is selected from phosphates, succinates, acetates, hydrochlorides, benzenesulfonates, hydrobromates, oxalates, adipates, ethanesulfonates, benzoates, 1,5-naphthalenedisulfonates, pamoate, hippurate, sulfates, malonates, p-toluenesulfonates, maleates, malates, tartrates, fumarates, preferably phosphates.

[0059] In a further preferred embodiment of the present invention, the number of acids is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0060] In a further preferred embodiment of the present invention, the acid salt is a hydrate or anhydrous form, and when the acid salt is a hydrate, the number of water molecules is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0061] In a further preferred embodiment of the present invention, the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one, ...3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)nonane-9-yl)amino)nonane-9-yl)amino)-2-(methylamino)ethane-1-one, 1-(3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)nonane-9-yl)amino)nonane-9-yl)amino)nonane-2-(methylamino)ethane-1-one, 1-(3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)nonane-2-yl)amino)nonane-2-yl)amino)nonane-2-yl)nonane-2-yl)amino)nonane-2-yl)nonane-2-yl)nonane-2-yl)nonane-2-yl)nonane-2-yl)nonane-2-yl)non Acid salts of 2-(acetyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinoethane-1-one and 2-(ethylamino)-1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethane-1-one, wherein the acid salt is a maleate and the number of acids is 1 or 2.

[0062] In a further preferred embodiment of the present invention, the compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile is an acid salt, wherein the acid salt is a phosphate and the number of acids is 1 or 2.

[0063] In a further preferred embodiment of the present invention, the acid salt crystal form of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one is used, wherein the acid salt is selected from hydrochloride, maleate, benzenesulfonate, hydroxyethylsulfonate, 1,5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate, or stearate.

[0064] In a further preferred embodiment of the present invention, the acid salt crystal form of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile is used, wherein the acid salt is selected from phosphates, succinates, acetates, hydrochlorides, benzenesulfonates, hydrobromates, oxalates, adipates, ethanesulfonates, benzoates, 1,5-naphthalenedisulfonates, pamoate, hippurate, sulfates, malonates, p-toluenesulfonates, maleates, malates, tartrates, fumarates, preferably phosphates.

[0065] In a further preferred embodiment of the present invention, the number of acids is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0066] In a further preferred embodiment of the present invention, the maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one, having an acid number of 1, has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 22.9±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 12.9±0.2° and 27.9±0.2°; further, it also contains diffraction peaks at 2θ (±0.2°) of 22.9±0.2°. It exhibits diffraction peaks at 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, and 23.1±0.2°; further, it also exhibits diffraction peaks at 2θ (±0.2°) of 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 21.8±0.2°, and 28.2±0.2°; and even further, it exhibits diffraction peaks at 2θ (±0.2°) of 17.7±0.2°, 18.0±0.2°, 19.6±0.2°, 24.9±0.2°, and 25.6±0.2°.

[0067] For example, the X-ray powder diffraction pattern of maleate crystal form A shows diffraction peaks at the following positions with a 2θ value:

[0068] At 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2° and 17.4±0.2°;

[0069] Alternatively, at 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, and 18.9±0.2°;

[0070] Alternatively, at 22.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 18.9±0.2°, and 21.4±0.2°;

[0071] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 18.9±0.2°, 21.4±0.2°, and 28.2±0.2°;

[0072] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, and 18.9±0.2°;

[0073] Alternatively, at 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, and 21.4±0.2°;

[0074] Alternatively, at 22.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 18.9±0.2°, 21.4±0.2°, and 28.2±0.2°;

[0075] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, and 17.7±0.2°;

[0076] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, and 21.4±0.2°;

[0077] Alternatively, at 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, and 28.2±0.2°;

[0078] Alternatively, at 22.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, and 17.7±0.2°;

[0079] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, 17.7±0.2°, and 18.0±0.2°;

[0080] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, and 17.7±0.2°;

[0081] Alternatively, at 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, 17.7±0.2°, and 18.0±0.2°;

[0082] Alternatively, at 22.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, 17.7±0.2°, 18.0±0.2°, and 25.6±0.2°;

[0083] Alternatively, at 22.9±0.2°, 12.9±0.2°, 27.9±0.2°, 13.7±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, 17.7±0.2°, 18.0±0.2°, and 25.6±0.2°;

[0084] Alternatively, at 22.9±0.2°, 12.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 3.5±0.2°, 14.9±0.2°, and 16.4±0.2°;

[0085] Alternatively, at 12.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 3.5±0.2°, 14.9±0.2°, 16.4±0.2°, and 17.4±0.2°;

[0086] Alternatively, at 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, and 18.9±0.2°;

[0087] Alternatively, at 22.9±0.2°, 27.9±0.2°, 13.7±0.2°, 13.5±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 28.2±0.2°, 17.7±0.2°, 18.0±0.2°, and 25.6±0.2°;

[0088] Alternatively, at 22.9±0.2°, 12.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, and 18.9±0.2°;

[0089] Alternatively, at 22.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, and 21.4±0.2°;

[0090] Alternatively, at 27.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 21.8±0.2°, and 28.2±0.2°;

[0091] Alternatively, at 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 21.8±0.2°, 28.2±0.2°, and 17.7±0.2°;

[0092] Alternatively, at 22.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 21.8±0.2°, and 28.2±0.2°;

[0093] Alternatively, at 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, and 21.8±0.2°;

[0094] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 1.

[0095] Table 1

[0096]

[0097]

[0098] The maleate crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 1 As shown, its DSC spectrum is basically as follows: Figure 2 As shown, its TGA spectrum is basically as follows: Figure 3 As shown.

[0099] In a further preferred embodiment of the present invention, the maleate crystal form B of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one, having an acid number of 1, has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 4.4±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 6.2±0.2° and 8.8±0.2°; The step further includes having diffraction peaks at 2θ (±0.2°) of 14.0±0.2°, 16.4±0.2°, 18.9±0.2° and 19.7±0.2°; further includes having diffraction peaks at 2θ (±0.2°) of 8.5±0.2°, 9.9±0.2°, 13.3±0.2°, 14.9±0.2°, 16.0±0.2°, 17.8±0.2°, 20.3±0.2° and 20.7±0.2°; and further includes having diffraction peaks at 2θ (±0.2°) of 22.4±0.2° and 24.5±0.2°.

[0100] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 2.

[0101] Table 2

[0102]

[0103]

[0104] The maleate crystal form B of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 4 As shown, its DSC spectrum is basically as follows: Figure 5 As shown, its TGA spectrum is basically as follows: Figure 6 As shown.

[0105] In a further preferred embodiment of the present invention, the hydroxyethyl sulfonate crystal form C of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 20.0±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 18.5±0.2° and 21.4±0.2°; further, it also contains diffraction peaks at 2θ (±0.2°) of 15.7±0.2°, 18.7±0.2°, 19.7±0.2° and 23.4±0.2°; further... The first step also includes diffraction peaks at 2θ (±0.2°) of 6.6±0.2°, 11.3±0.2°, 12.8±0.2°, 14.6±0.2°, 17.7±0.2°, 20.3±0.2°, 20.6±0.2°, and 23.0±0.2°; further, it also includes diffraction peaks at 2θ (±0.2°) of 23.8±0.2°, 26.2± Diffraction peaks are observed at 0.2°, 26.6±0.2°, 27.1±0.2°, 30.2±0.2°, and 32.1±0.2°; further, diffraction peaks are observed at 2θ (±0.2°) of 13.5±0.2°, 16.5±0.2°, 20.9±0.2°, 25.7±0.2°, 28.3±0.2°, and 33.5±0.2°.

[0106] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 3.

[0107] Table 3

[0108]

[0109]

[0110] The hydroxyethyl sulfonate crystal form C of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 7 As shown; its DSC spectrum is basically as follows Figure 8 As shown.

[0111] In a further preferred embodiment of the present invention, the p-toluenesulfonate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 9.3±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 14.7±0.2° and 17.8±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 10.7±0.2°, 13.3±0.2°, 21.1±0.2° and 25.1±0.2°; further, it also contains diffraction peaks at 2θ (±0.2°). The diffraction peaks (2θ) are 8.6±0.2°, 14.4±0.2°, 14.9±0.2°, 18.5±0.2°, 21.7±0.2°, 22.2±0.2°, 22.8±0.2°, and 28.7±0.2°; further, the diffraction peaks (2θ) are also present at 16.6±0.2°, 19.5±0.2°, 19.8±0.2°, and 20°. Diffraction peaks are observed at 0.3±0.2°, 24.2±0.2°, 24.5±0.2°, and 25.5±0.2°; further, diffraction peaks are observed at 2θ (±0.2°) of 17.3±0.2°, 22.4±0.2°, 26.1±0.2°, 26.7±0.2°, 27.5±0.2°, 29.7±0.2°, and 33.2±0.2°.

[0112] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 4.

[0113] Table 4

[0114]

[0115]

[0116] The p-toluenesulfonate crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 9 As shown; its DSC spectrum is basically as follows Figure 10 As shown; its TGA spectrum is basically as follows. Figure 11 As shown.

[0117] In a further preferred embodiment of the present invention, the fumarate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 20.1±0.2°; further comprising diffraction peaks at 2θ (±0.2°) of 12.1±0.2° and 17.6±0.2°. Furthermore, it also includes diffraction peaks at 2θ (±0.2°) of 14.4±0.2°, 15.5±0.2°, 17.8±0.2° and 21.6±0.2°; further still, it includes diffraction peaks at 2θ (±0.2°) of 8.8±0.2°, 11.2±0.2°, 20.9±0.2°, 22.7±0.2°, 24.4±0.2°, 24.7±0.2°, 25.1±0.2° and 26.4±0.2°; and even further, it includes a diffraction peak at 2θ (±0.2°) of 26.8±0.2°.

[0118] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 5.

[0119] Table 5

[0120]

[0121] The fumarate crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 12 As shown; its DSC spectrum is basically as follows Figure 13 As shown; its TGA spectrum is basically as follows. Figure 14 As shown.

[0122] In a further preferred embodiment of the present invention, the fumarate crystal form B of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 10.7±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 15.5±0.2° and 19.8±0.2°; further, it also contains diffraction peaks at 2θ (±0.2°) of 15.5±0.2° and 19.8±0.2°. The diffraction peaks are observed at 11.8±0.2°, 19.1±0.2°, 20.1±0.2°, and 21.3±0.2°; further, they also include diffraction peaks at 2θ (±0.2°) of 6.6±0.2°, 11.3±0.2°, 12.2±0.2°, 14.1±0.2°, 17.2±0.2°, 23.9±0.2°, 24.5±0.2°, and 24.8±0.2°; and even further, they include diffraction peaks at 2θ (±0.2°) of 16.5±0.2°, 17.6±0.2°, 18.0±0.2°, and 22.0±0.2°.

[0123] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 6.

[0124] Table 6

[0125]

[0126]

[0127] The fumarate crystal form B of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 15 As shown; its DSC spectrum is basically as follows Figure 16 As shown.

[0128] In a further preferred embodiment of the present invention, the fumarate crystal form C of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 6.1±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 15.5±0.2° and 19.3±0.2°; further comprising... It contains diffraction peaks at 2θ (±0.2°) of 10.8±0.2°, 19.9±0.2°, 20.4±0.2° and 21.6±0.2°; further contains diffraction peaks at 2θ (±0.2°) of 6.8±0.2°, 8.6±0.2°, 12.8±0.2°, 13.6±0.2°, 16.6±0.2°, 17.0±0.2°, 18.0±0.2° and 23.2±0.2°; and further contains diffraction peaks at 2θ (±0.2°) of 24.2±0.2° and 24.6±0.2°.

[0129] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 7.

[0130] Table 7

[0131]

[0132]

[0133] The fumarate crystal form C of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 17 As shown.

[0134] In a further preferred embodiment of the present invention, the oxalate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 19.3±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 11.2±0.2° and 18.0±0.2°; and further contains diffraction peaks at 2θ (±0.2°) of 9.0±0.2°. The diffraction peaks are present at 22.4±0.2°, 24.6±0.2°, and 25.8±0.2°; further, they also include diffraction peaks at 2θ (±0.2°) of 7.0±0.2°, 9.6±0.2°, 13.0±0.2°, 14.8±0.2°, 17.7±0.2°, 18.8±0.2°, 20.3±0.2°, and 23.6±0.2°; and even further, they include diffraction peaks at 2θ (±0.2°) of 14.3±0.2°, 15.6±0.2°, 16.3±0.2°, 20.6±0.2°, 20.9±0.2°, and 24.0±0.2°.

[0135] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 8.

[0136] Table 8

[0137]

[0138]

[0139] The oxalate crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 18 As shown; its DSC spectrum is basically as follows Figure 19 As shown; its TGA spectrum is basically as follows. Figure 20 As shown.

[0140] In a further preferred embodiment of the present invention, the hydrobromide crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern at 2θ (±0.2°) of 11.9 ± 0.2°. The peaks also include diffraction peaks at 2θ (±0.2°) of 22.4±0.2° and 27.1±0.2°; further include diffraction peaks at 2θ (±0.2°) of 14.9±0.2°, 18.6±0.2°, 20.5±0.2° and 24.4±0.2°; and even further include diffraction peaks at 2θ (±0.2°) of 20.8±0.2°, 21.6±0.2° and 25.2±0.2°.

[0141] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 9.

[0142] Table 9

[0143]

[0144] The hydrobromide crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 21 As shown; its DSC spectrum is basically as follows Figure 22 As shown; its TGA spectrum is basically as follows. Figure 23 As shown.

[0145] In a further preferred embodiment of the present invention, the 1,5-naphthalene disulfonate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 16.4±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 11.5±0.2° and 24.3±0.2°; further comprising... The diffraction peaks at 2θ (±0.2°) are 10.3±0.2°, 14.6±0.2°, 19.7±0.2° and 21.5±0.2°; further, the diffraction peaks at 2θ (±0.2°) are 6.1±0.2°, 12.1±0.2°, 12.8±0.2°, 15.0±0.2°, 19.0±0.2°, 20.5±0.2°, 21.1±0.2° and 23.9±0.2°; further, the diffraction peaks at 2θ (±0.2°) are 22.0±0.2°, 25.1±0.2° and 27.6±0.2°.

[0146] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 10.

[0147] Table 10

[0148]

[0149]

[0150] The 1,5-naphthalene disulfonate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern that is basically as follows: Figure 24 As shown; its DSC spectrum is basically as follows Figure 25 As shown; its TGA spectrum is basically as follows. Figure 26 As shown.

[0151] In a further preferred embodiment of the present invention, the tartrate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 21.6 ± 0.2°; and also contains 2θ (± The diffraction peaks are found at 16.0±0.2° and 17.7±0.2° at 2θ (±0.2°); further, they also include diffraction peaks at 17.1±0.2°, 19.8±0.2°, 20.7±0.2° and 22.5±0.2° at 2θ (±0.2°); and even further, they include diffraction peaks at 13.1±0.2°, 14.2±0.2°, 14.5±0.2°, 20.1±0.2° and 28.6±0.2° at 2θ (±0.2°).

[0152] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 11.

[0153] Table 11

[0154]

[0155]

[0156] The tartrate crystal form A of the compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 27 As shown; its DSC spectrum is basically as follows Figure 28 As shown; its TGA spectrum is basically as follows. Figure 29 As shown.

[0157] In a further preferred embodiment of the present invention, the phosphate crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile, having an acid number of 2, has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 21.7±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 21.2±0.2° and 23.0±0.2°; further comprising... It exhibits diffraction peaks at 2θ (±0.2°) of 7.5±0.2°, 16.6±0.2°, 23.4±0.2°, and 26.0±0.2°; further comprising diffraction peaks at 2θ (±0.2°) of 6.9±0.2°, 9.5±0.2°, 12.3±0.2°, 13.7±0.2°, 19.5±0.2°, 20.3±0.2°, 24.9±0.2°, and 27.6±0.2°; more preferably, further comprising diffraction peaks at 2θ (±0.2°) of 28.4±0.2°;

[0158] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 12.

[0159] Table 12

[0160]

[0161]

[0162]

[0163] The phosphate crystal form A of the compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 31 As shown, its DSC spectrum is basically as follows: Figure 32 As shown, its TGA spectrum is basically as follows: Figure 33 As shown.

[0164] In a further preferred embodiment of the present invention, the phosphate crystal form B of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 5.9±0.2°; it also contains peaks at 2θ (±0.2°) of 5.1±0.2° and 17.7°. It also includes diffraction peaks at ±0.2°; further includes diffraction peaks at 2θ (±0.2°) of 14.7±0.2°, 21.8±0.2°, 25.6±0.2° and 27.0±0.2°; even further includes diffraction peaks at 2θ (±0.2°) of 8.6±0.2°, 13.7±0.2°, 14.4±0.2°, 20.0±0.2°, 20.9±0.2°, 21.4±0.2° and 23.4±0.2°;

[0165] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 13.

[0166] Table 13

[0167]

[0168]

[0169] The phosphate crystal form B of the compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 34 As shown.

[0170] In a further preferred embodiment of the present invention, the succinate crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile has an X-ray powder diffraction pattern with a diffraction peak at 2θ (±0.2°) of 6.8±0.2°; it also contains diffraction peaks at 2θ (±0.2°) of 5.8±0.2° and 22.1±0.2°; and further contains diffraction peaks at 2θ (±0.2°) of 12. It exhibits diffraction peaks at 4±0.2°, 17.8±0.2°, 19.0±0.2°, and 26.4±0.2°; further, it also exhibits diffraction peaks at 2θ (±0.2°) of 9.0±0.2°, 11.7±0.2°, 13.7±0.2°, 14.8±0.2°, 16.7±0.2°, 18.6±0.2°, 20.6±0.2°, and 23.5±0.2°; and even further, it exhibits diffraction peaks at 2θ (±0.2°) of 20.1±0.2°, 25.0±0.2°, and 27.0±0.2°.

[0171] The characteristic X-ray diffraction peaks, expressed in terms of 2θ angle and interplanar spacing d, using Cu-Kα radiation are shown in Table 14.

[0172] Table 14

[0173]

[0174]

[0175] The succinate crystal form A of the compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile described in this invention has an X-ray powder diffraction pattern that is basically as follows: Figure 35 As shown.

[0176] In a further preferred embodiment of the present invention, the acid salt crystal form is a hydrate or anhydrous form, and when the acid salt crystal form is a hydrate, the number of water molecules is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.

[0177] The present invention also provides a method for preparing an acid salt of the compound shown in general formula (I), specifically comprising the following steps:

[0178] 1) Weigh an appropriate amount of free base and dissolve it in a good solvent;

[0179] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent;

[0180] 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate;

[0181] 4) Rapid centrifugation or static drying to obtain the target product;

[0182] in:

[0183] The beneficial solvent is selected from 2-butanol, methanol, isopropanol, 2-butanone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; preferably one or more of 2-butanol, methanol, or dimethyl sulfoxide.

[0184] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably one or more of methanol, ethanol, or acetonitrile.

[0185] The unsuitable solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; preferably one or more of water, methyl tert-butyl ether, or isopropyl ether.

[0186] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, and glucose. Acids, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2 - Sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenediol. Sulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid; more preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid; even more preferably phosphoric acid, maleic acid, or benzenesulfonic acid.

[0187] The present invention also provides a method for preparing an acid salt of the compound shown in general formula (I), specifically comprising the following steps:

[0188] 1) Weigh an appropriate amount of free base and suspend it in a poor solvent;

[0189] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent;

[0190] 3) Add the above solution to the above suspension and stir;

[0191] 4) Rapid centrifugation or static drying yields the salt of the compound;

[0192] in:

[0193] The undesirable solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 3-pentanone, isopropyl acetate, ethyl formate, 1,4-dioxane, chlorobenzene, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, or 2-butanone; preferably one or more of dichloromethane, toluene, acetonitrile, acetone, methanol, or ethyl acetate.

[0194] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably one or more of methanol, ethanol, or acetonitrile.

[0195] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, and glucose. Acids, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2 - Sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenediol. Sulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid; more preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid; even more preferably phosphoric acid, maleic acid, or benzenesulfonic acid.

[0196] The present invention also provides a method for preparing the acid salt crystal form of the compound shown in general formula (I), specifically comprising the following steps:

[0197] 1) Weigh an appropriate amount of the compound salt and suspend it in a poor solvent;

[0198] 2) Shake the suspension obtained above;

[0199] 3) Centrifuge the above suspension quickly to remove the supernatant, and dry the remaining solid to constant weight to obtain the target product;

[0200] in:

[0201] The undesirable solvent is selected from one or more of methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, tert-butanol, or 2-butanone.

[0202] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the acid salt or acid salt crystal form of the above-described compound and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0203] The present invention also aims to provide the use of the above-described acid salt or acid salt crystal form and pharmaceutical composition in the preparation of a drug for the prevention and / or treatment of JAK kinase-related diseases, wherein the JAK kinase-related diseases are preferably inflammatory diseases and / or tumor diseases.

[0204] The inflammatory diseases mentioned are selected from rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease; among which, chronic inflammatory bowel disease is preferred, and ulcerative colitis and Crohn's disease are further preferred.

[0205] The tumor diseases mentioned are selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myelocytic leukemia, acute lymphoblastic leukemia, ductal carcinoma of the breast and non-small cell lung cancer.

[0206] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0207] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups. The present invention preferably uses methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteralkyl, alkoxy-substituted alkyl, hydroxy-substituted alkyl, and cyano-substituted alkyl.

[0208] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl groups include spirocyclic, fused-ring, and bridged-ring cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl. The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester group.

[0209] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S(O). m (where m is an integer from 0 to 2) heteroatoms, but excluding the ring portions of -OO-, -OS-, or -SS-, with the remaining ring atoms being carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxobutyl, pyrrolyl, pyrrolidone, imidazolyl, tetrahydrofuranyl, tetrahydrothiophene, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., with oxobutyl, pyrrolidone, tetrahydrofuranyl, pyrrolidone, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. The heterocyclic group can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylic acid ester groups.

[0210] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, carboxyl, or carboxylic acid ester group.

[0211] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, pyrrololyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, etc., preferably oxazolyl, oxadiazole, tetrazolyl, triazolyl, thiophene, imidazolyl, pyridinyl, pyrimidinyl, or thiazolyl; more preferably oxazolyl, oxadiazole, tetrazolyl, triazolyl, thiophene, pyridinyl, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0212] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Alkoxy groups containing 1 to 8 carbon atoms are preferred, alkoxy groups containing 1 to 6 carbon atoms are more preferred, and alkoxy groups containing 1 to 3 carbon atoms are most preferred. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylic acid ester.

[0213] "Halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0214] "Haloalkoxy" refers to an alkoxy group that has been substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0215] "Hydroxyalkyl" refers to an alkyl group that has been replaced by a hydroxyl group, where the alkyl group is as defined above.

[0216] "Alkenyl" refers to alkenyl groups, also known as olefin groups. The alkenyl group can be further replaced by other related groups, such as: alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylic acid ester group.

[0217] "Hydroxy" refers to the -OH group.

[0218] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0219] "Amino" refers to -NH2.

[0220] “Cyano” refers to -CN.

[0221] "Nitro" refers to -NO2.

[0222] "THF" refers to tetrahydrofuran.

[0223] “EtOAc” refers to ethyl acetate.

[0224] "DMSO" refers to dimethyl sulfoxide.

[0225] "LDA" refers to lithium diisopropylamine.

[0226] "DMAP" refers to 4-dimethylaminopyridine.

[0227] “EtMgBr” refers to ethyl magnesium bromide.

[0228] “HOSu” refers to N-hydroxysuccinimide.

[0229] “EDCl” refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0230] "IPA" refers to isopropyl alcohol.

[0231] “MeOH” refers to methanol.

[0232] “EtOH” refers to ethanol.

[0233] "DMF" refers to N,N-dimethylformamide.

[0234] "DIPEA" refers to N,N-diisopropylethylamine.

[0235] “HEPES” refers to 4-hydroxyethylpiperazine ethanesulfonic acid.

[0236] The different terms such as "X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" all express the same meaning, that is, X can be any one or more of A, B, and C.

[0237] "Optional" or "optionally" means that the event or situation described below may, but does not have to, occur, and the description includes the circumstances under which the event or situation may or may not occur.

[0238] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0239] "Stereoheterogeneity" includes three categories: geometric heterogeneity (cis-trans heterogeneity), optical heterogeneity, and conformational heterogeneity.

[0240] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0241] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.

[0242] X-ray powder diffraction (XRPD) refers to the experimentally observed diffraction pattern or parameters derived from it, characterized by peak positions (x-axis) and peak intensities (y-axis). Those skilled in the art will understand that experimental errors depend on instrument conditions, sample preparation, and sample purity. In particular, it is known to those skilled in the art that X-ray diffraction patterns typically change with instrument conditions, and appropriate error tolerances for XRPD can be: 2θ ± 0.5°; 2θ ± 0.4°; 2θ ± 0.3°; 2θ ± 0.2°. It is particularly important to note that the relative intensities of the X-ray diffraction pattern can also vary with experimental conditions, so the order of peak intensities cannot be considered the sole or decisive factor. Furthermore, the influence of experimental factors such as sample height can cause an overall shift in peak angles, which is generally permissible. Therefore, those skilled in the art will understand that any crystal form with characteristic peaks identical or similar to those of the patterns of this invention falls within the scope of this invention.

[0243] "TGA" refers to thermogravimetric analysis (TGA) experiments.

[0244] "DSC" refers to the Differential Scanning Calorimetry (DSC) experiment.

[0245] "HPLC" refers to High Performance Liquid Chromatography (HPLC) experiments.

[0246] "PK" refers to pharmacokinetic (PK) experiments. Attached Figure Description

[0247] Figures 1-3 XRPD, DSC, and TGA illustrations of maleate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0248] Figures 4-6 XRPD, DSC, and TGA illustrations of maleate form B of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0249] Figures 7-8XRPD and DSC diagrams of the hydroxyethyl sulfonate crystal form C of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0250] Figures 9-11 XRPD, DSC, and TGA illustrations of p-toluenesulfonate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one.

[0251] Figures 12-14 XRPD, DSC, and TGA illustrations of fumarate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0252] Figures 15-16 XRPD and DSC illustrations of fumarate form B of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0253] Figure 17 XRPD diagram of fumarate form C of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one.

[0254] Figures 18-20 XRPD, DSC, and TGA illustrations of the oxalate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0255] Figures 21-23XRPD, DSC, and TGA illustrations of the hydrobromide crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0256] Figures 24-26 XRPD, DSC, and TGA illustrations of the 1,5-naphthalenedisulfonate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one.

[0257] Figures 27-29 XRPD, DSC, and TGA illustrations of tartrate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0258] Figure 30 XRPD diagram of free base crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one.

[0259] Figures 31-33 XRPD, DSC, and TGA illustrations of phosphate crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile.

[0260] Figure 34 XRPD diagram of phosphate crystal form B of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile.

[0261] Figure 35XRPD illustration of succinate form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile.

[0262] Figure 36 XRPD diagram of free base crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile.

[0263] Figure 37 NMR spectra of maleate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one. Detailed Implementation

[0264] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present invention.

[0265] I. Preparation of Compounds

[0266] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0267] LC-MS analysis was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC analysis was performed using an Agilent 1200DAD high-performance liquid chromatograph (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-performance liquid chromatograph (Gimini C). 18 150 × 4.6 mm chromatographic column).

[0268] Thin-layer chromatography (TLC) uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The standard size for TLC is 0.15 mm to 0.20 mm, while the standard size for separating and purifying products using TLC is 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0269] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0270] Unless otherwise specified, all reactions in this invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is expressed in degrees Celsius.

[0271] Example 1

[0272] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0273]

[0274] Step 1: Preparation of 2-chloro-N-(5-methyl-1-hydro-pyrazol-3-yl)thienro[3,2-d]pyrimidine-4-amine

[0275]

[0276] To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidone (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were added sequentially, followed by heating and stirring at 70 °C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction mixture. The precipitated solid was filtered and slurried with ethyl acetate to obtain the title compound as a pale yellow solid (135 mg, 51%).

[0277] MS m / z (ESI): 266.0 [M+H] + .

[0278] Step 2: Preparation of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0279]

[0280] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thieno[3,2-d]pyrimidine-4-amine (135 mg, 0.51 mmol) in n-butanol (5 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (138 mg, 0.61 mmol) and DIPEA (129 mg, 1 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a pale yellow solid (146 mg, 63%).

[0281] MS m / z (ESI): 456.2 [M+H] + .

[0282] Step 3: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0283]

[0284] 146 mg, 0.32 mmol, of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL) (HCl In dioxane above means that hydrochloric acid is dissolved in 1,4-epoxyhexacyclohydrochloride, and HCl In dioxane in the following examples also means this). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (10 mL) was added to dissolve it, and DIPEA (166 mg, 1.28 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and acrylonitrile (25 mg, 0.48 mmol) was added. Stirring was continued for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (14.4 mg, 11%).

[0285] 1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 9.70 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.44 (d, J = 59.6 Hz, 2H), 4.14 (s, 1H), 3.29 (s, 2H), 2.62 (s, 4H), 2.22 (s, 3H), 1.89 (s, 2H), 1.64 (dd, J = 47.8, 17.6 Hz, 6H).

[0286] MS m / z (ESI): 409.2 [M+H] + .

[0287] Example 2

[0288] 3-((3-exo)-3-((7-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0289]

[0290] The preparation of 3-((3-exo)-3-((7-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 1.

[0291] MS m / z (ESI): 423.2 [M+H] + .

[0292] Example 3

[0293] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0294]

[0295] Step 1: Preparation of 2-chloro-N-(5-methyl-1-hydro-pyrazol-3-yl)thienro[2,3-d]pyrimidine-4-amine

[0296]

[0297] To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidone (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were added sequentially, followed by heating and stirring at 70 °C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction solution, resulting in the precipitation of a solid. The solid was filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (250 mg, 94%).

[0298] MS m / z (ESI): 266.0 [M+H] + .

[0299] Step 2: Preparation of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0300]

[0301] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thieno[2,3-d]pyrimidine-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (256 mg, 1.13 mmol) and DIPEA (242 mg, 1.88 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a pale yellow solid (200 mg, 47%).

[0302] MS m / z (ESI): 456.1 [M+H] + .

[0303] Step 3: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0304]

[0305] tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (200 mg, 0.44 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (10 mL) was added to dissolve it, and DIPEA (227 mg, 1.76 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then acrylonitrile (35 mg, 0.66 mmol) was added, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a white solid (31.6 mg, 18%).

[0306] 1 H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 9.93 (s, 1H), 7.73 (s, 1H), 6.88 (d, J = 117.2 Hz, 3H), 4.27 (s, 1H), 3.37 (s, 2H), 2.70 (s, 4H), 2.32 (s, 3H), 1.99 (s, 2H), 1.86-1.61 (m, 6H).

[0307] MS m / z (ESI): 409.2 [M+H] + .

[0308] Example 4

[0309] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazo[4,5-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0310]

[0311] The preparation of 3-((3-exo)-3-((7-(((5-methyl-1H-pyrazol-3-yl)amino)thiazo[4,5-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 1.

[0312] MS m / z (ESI): 410.2 [M+H] + .

[0313] Example 5

[0314] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0315]

[0316] Step 1: Preparation of 5-chloro-N-(5-methyl-1-hydro-pyrazol-3-yl)thiazo[5,4-d]pyrimidine-7-amine

[0317]

[0318] To a solution of 5,7-dichlorothiazo[5,4-d]pyrimidine (206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were added sequentially, followed by heating and stirring at 70 °C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction solution, resulting in the precipitation of a solid. The solid was filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (200 mg, 75%).

[0319] MS m / z (ESI): 267.0 [M+H] + .

[0320] Step 2: Preparation of tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0321]

[0322] To a solution of 5-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thiazo[5,4-d]pyrimidine-7-amine (200 mg, 0.75 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (204 mg, 0.9 mmol) and DIPEA (193 mg, 1.5 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a pale yellow solid (74 mg, 22%).

[0323] MS m / z (ESI): 457.1 [M+H] + .

[0324] Step 3: Preparation of 3-((3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0325]

[0326] Tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (74 mg, 0.16 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 2 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (10 mL) was added to dissolve it, and DIPEA (83 mg, 0.64 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then acrylonitrile (9 mg, 0.24 mmol) was added, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a white solid (16.3 mg, 25%).

[0327] 1 H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 9.33 (s, 1H), 8.76 (d, J =20.4 Hz, 1H), 6.96 (s, 1H), 6.55 (d, J = 12.0 Hz, 1H), 4.14 (s, 1H), 3.31 (s, 2H), 2.61 (s, 4H), 2.21 (s, 3H), 1.91 (s, 2H), 1.78-1.54 (m, 6H).

[0328] Example 6

[0329] 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile

[0330]

[0331] Step 1: Preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol

[0332]

[0333] 2,4-Dichlorothiopheno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-1H-pyrazol-5-yl)methanol (55 mg, 0.49 mmol), and DIPEA (190 mg, 1.47 mmol) were added to N'N-dimethylformamide (2 mL), and the reaction solution was heated to 70 °C. o The mixture was stirred overnight at C. The crude product was concentrated under reduced pressure and purified by rapid silica gel column chromatography to give the title compound as a yellow solid (100 mg, 73%).

[0334] MS m / z (ESI): 282.0 [M+H] + .

[0335] Step 2: Preparation of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0336]

[0337] (3-((2-chlorothiopheno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.36 mmol), tert-butyl(3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (135 mg, 0.53 mmol), and DIPEA (140 mg, 1.08 mmol) were added to n-butanol (2.5 mL), mixed well, and microwaved at 150 °C. o The reaction was carried out at C for 10 hours, cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain the target product as a white solid (70 mg, 39%).

[0338] MS m / z (ESI): 500.1 [M+H] + .

[0339] Step 3: Preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxylonitrile

[0340]

[0341] Dioxane hydrochloride (4N, 2.5 mL) was slowly added dropwise to a methanol (10 mL) solution of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (70 mg, 0.14 mmol). The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in DMF (5 mL). o DIPEA (0.3 mL) and 3-cyanoazacyclobutane-1-sulfonyl chloride (22 mg, 0.12 mmol) were added separately under ice-water bath conditions, and the reaction was carried out overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC to obtain the target compound as a white solid (9.7 mg, 13%).

[0342] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.68 (d, J = 4.4 Hz, 1H), 7.04 (d, J = 6.0 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H),5.33-5.35 (m,1H), 4.44 (d, J = 5.2 Hz, 2H), 4.05-4.01 (m, 4H), 3.94-3.90 (m, 2H), 382-3.79(m,1 H), 2.89 (d, J = 8.4 Hz, 3H), 2.08-1.68 (m, 11H).

[0343] MS m / z (ESI): 544.1 [M+H] + .

[0344] Example 7

[0345] 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile

[0346]

[0347] The preparation of 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile was carried out according to Example 6.

[0348] MS m / z (ESI): 545.2 [M+H] + .

[0349] Example 8

[0350] 1-(((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0351]

[0352] 200 mg (0.439 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 20 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (1.45 mL, 8.78 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (95 mg, 0.527 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (70 mg, 32%).

[0353] 1H NMR (400 MHz, MeOD-d4) δ 7.37 (d, J = 6.0 Hz, 1H), 6.94 (d, J = 6.0 Hz, 1H), 6.25 (s, 1H), 4.44-4.34 (m, 1H), 4.26 (s, 2H), 4.16 (t, J = 8.5 Hz, 2H), 4.12-4.05 (m, 2H), 3.57 (ddd, J = 15.3, 8.7, 6.5 Hz, 1H), 2.31 (s, 3H), 2.23-2.10 (m, 4H), 2.01 (d, J = 7.4 Hz, 2H), 1.73 (dd, J = 18.2, 7.1 Hz, 2H).

[0354] MS m / z (ESI): 500.1 [M+H] + .

[0355] Example 9

[0356] 3-((3-exo)-3-(((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino))-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azacyclobutane-3-nitrile

[0357]

[0358]

[0359] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, it was dissolved in N,N-dimethylformamide (10 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then 3-acrylazetane-1-sulfonyl chloride (45 mg, 0.25 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the product was subjected to prep-HPLC to give the title compound as a white solid (14.4 mg, 13%).

[0360] 1H NMR (400 MHz, DMSO) δ = 12.02 (s, 1H), 9.81 (s, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 6.59 (d, J = 57.6 Hz, 2H), 4.74 (s, 1H), 3.96 (t, J = 8.4 Hz, 2H), 3.85 (dd, J = 16.8 Hz, 6.4, 4H), 3.75-3.67 (m, 1H), 2.14 (s, 3H), 2.00 (d, J = 8.4 Hz, 2H), 1.87-1.60 (m, 8H).

[0361] MS m / z (ESI): 514.1 [M+H] + .

[0362] Example 10

[0363] 1-(((3-exo)-3-(methyl(4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azacyclobutane-3-nitrile

[0364]

[0365] Step 1: Preparation of tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0366]

[0367] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (287 mg, 1.13 mmol) and DIPEA (242 mg, 1.88 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a pale white solid (228 mg, 50%).

[0368] MS m / z (ESI): 484.2 [M+H] + .

[0369] Step 2: Preparation of 1-(((3-exo)-3-(methyl(4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azacyclobutane-3-nitrile

[0370]

[0371] tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-1-hydropyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, it was dissolved in N,N-dimethylformamide (10 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then 3-acrylazacyclobutane-1-sulfonyl chloride (45 mg, 0.25 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the product was subjected to prep-HPLC to obtain the title compound as a white solid (46.0 mg, 42%).

[0372] 1 H NMR (400 MHz, DMSO) δ = 12.09 (s, 1H), 9.79 (s, 1H), 7.68 (d, J = 6.0Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.43 (s, 1H), 5.77 (s, 1H), 3.98 (dt, J = 14.4, 8.4Hz, 6H), 3.84-3.74 (m, 1H), 2.90 (s, 3H), 2.22 (s, 3H), 2.13-1.61 (m, 10H).

[0373] MS m / z (ESI): 528.2 [M+H] + .

[0374] Example 11

[0375] 1-(((3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0376]

[0377] Step 1 reaction: Preparation of tert-butyl(3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0378]

[0379] 2-Chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (150 mg, 0.536 mmol) and tert-butyl(3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (257 mg, 1.072 mmol) were added to n-butanol (10 mL) and heated to 170°C in a microwave synthesizer. o The reaction was carried out at C for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in dichloromethane. The residue was washed successively with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column chromatography to obtain the title compound (73 mg, 28%).

[0380] MS m / z (ESI): 484.2 [M+H] + .

[0381] Second step reaction: Preparation of 1-(((3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0382]

[0383] 73 mg (0.151 mmol) of tert-butyl(3-exo)-3-(methyl(6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 20 mL of 1,4-epoxyhexane in 4 M HCl and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the remaining solid was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. oAt C, DIPEA (0.75 mL, 4.53 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (30 mg, 0.166 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 4.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (31.5 mg, 40%).

[0384] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 9.66 (s, 1H), 7.35 (s, 1H), 6.48 (s, 1H), 5.31-5.15 (m, 1H), 4.18 (d, J = 1.0 Hz, 2H), 4.06 (t, J = 8.6 Hz, 2H), 4.00-3.91 (m, 2H), 3.80 (ddd, J = 12.8, 8.9, 6.5 Hz, 1H), 2.90 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 2.07-1.99 (m, 2H), 1.95 (dd, J = 18.2, 7.0 Hz, 2H), 1.88-1.79 (m, 2H), 1.62 (dd, J = 11.8, 4.1 Hz, 2H).

[0385] MS m / z (ESI): 528.2 [M+H] + .

[0386] Example 12

[0387] 1-(((3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0388]

[0389] Step 1 reaction: Preparation of tert-butyl(3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0390]

[0391] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol) and tert-butyl(3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (181 mg, 0.752 mmol) were added to n-butanol (3 mL) and heated to 170 °C using a microwave synthesizer. o The reaction was carried out at C for 18 hours. The solvent was removed by concentration under reduced pressure, and the residue was used directly in the next reaction step.

[0392] MS m / z (ESI): 470.2 [M+H] + .

[0393] Second step reaction: Preparation of 1-(((3-exo)-3-(methyl(4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0394]

[0395] tert-Butyl(3-exo)-3-(methyl(4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 20 mL of 1,4-epoxyhexane in 4 M HCl. The mixture was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure. The residue was separated by reversed-phase column chromatography to obtain 117 mg of white solid.

[0396] The above white solid was dissolved in anhydrous N,N-dimethylformamide (10 mL) and cooled to 0°C. o At C, DIPEA (0.14 mL, 0.632 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (57 mg, 0.316 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 17 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to obtain the title compound (16.4 mg, 10%).

[0397] 1H NMR (400 MHz, MeOD-d4) δ 7.37 (d, J = 5.9 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 6.40 (s, 1H), 5.40-5.28 (m, 1H), 4.31-4.24 (m, 2H), 4.17 (t, J = 8.5 Hz, 2H), 4.11-4.04 (m, 2H), 3.57 (ddd, J = 15.4, 8.9, 6.7 Hz, 1H), 3.04 (s, 3H), 2.31 (s, 3H), 2.17 (dd, J = 8.6, 3.3 Hz, 2H), 2.11-2.01 (m, 2H), 2.00-1.92 (m, 2H), 1.75 (ddd, J =10.8, 4.3, 2.7 Hz, 2H).

[0398] MS m / z (ESI): 514.1 [M+H] + .

[0399] Example 13

[0400] 2-(dimethylamino)-1-((3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)ethane-1-one

[0401]

[0402]

[0403] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.32 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and then dimethylglycine (24 mg, 0.23 mmol) was added and stirring continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (17.1 mg, 18%).

[0404] 1 H NMR (400 MHz, DMSO) δ = 12.00 (s, 1H), 9.80 (s, 1H), 7.61 (s, 1H), 6.98-6.45 (m, 3H), 4.76 (s, 1H), 4.59 (s, 1H), 4.27 (s, 1H), 3.30 (s, 6H), 3.05 (s, 2H), 2.16 (s, 3H), 2.14 (s, 2H), 2.07-1.92 (m, 2H), 1.86-1.40 (m, 6H).

[0405] MS m / z (ESI): 455.2 [M+H] + .

[0406] Example 14

[0407] 2-(dimethylamino)-1-((3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0408]

[0409]

[0410] Tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg, 0.09 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 2 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (51 mg, 0.13 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (46 mg, 0.36 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and then dimethylglycine (10 mg, 0.1 mmol) was added and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (4.4 mg, 11%).

[0411] 1H NMR (400 MHz, DMSO) δ = 12.08 (s, 1H), 9.88 (s, 1H), 7.65 (s, 1H), 7.11-6.46 (m, 3H), 4.47 (d, J = 30.0 Hz, 3H), 3.06 (s, 2H), 2.21 (s, 9H), 2.04-1.66 (m, 6H), 1.62-1.44 (m, 2H).

[0412] MS m / z (ESI): 441.2 [M+H] + .

[0413] Example 15

[0414] 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-2-morpholinoethane-1-one

[0415]

[0416]

[0417] Tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydropyrazole-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg, 0.09 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 2 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (51 mg, 0.13 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (46 mg, 0.36 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and 2-morpholinoacetic acid (14.5 mg, 0.1 mmol) was added and stirring continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (7.8 mg, 18%).

[0418] 1H NMR (400 MHz, DMSO) δ = 12.07 (s, 1H), 9.88 (s, 1H), 7.66 (s, 1H), 7.11-6.49 (m, 3H), 4.48 (d, J = 26.4 Hz, 3H), 3.60 (s, 4H), 3.17 (s, 2H), 2.46 (s, 4H), 2.23 (s, 3H), 1.98 (s, 2H), 1.90-1.45 (m, 6H).

[0419] MS m / z (ESI): 483.2 [M+H] + .

[0420] Example 16

[0421] 1-((3-exo)-3-(methyl(4-((5-methyl-1-hydropyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-2-morpholinoethane-1-one

[0422]

[0423] The preparation of 1-((3-exo)-3-(methyl(4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-2-morpholinoethane-1-one was carried out in accordance with Example 244.

[0424] 1 H NMR (400 MHz, DMSO-d6) δ = 9.85 (s, 1H), 8.22 (s, 1H), 7.68 (d, J =6.0 Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.53 (s, 1H), 5.37 (s, 1H), 4.54 (d, J= 16.4 Hz, 2H), 3.58 (d, J = 4.0 Hz, 4H), 3.04 (d, J = 13.2 Hz, 2H), 2.85 (s,3H), 2.45 (s, 4H), 2.23 (s, 3H), 2.03-1.97 (m, 2H) , 1.87-1.59 (m, 6H).

[0425] MS m / z (ESI): 497.2 [M+H] + .

[0426] Example 17

[0427] 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-morpholinoethane-1-one

[0428]

[0429] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and 2-morpholinoacetic acid (33 mg, 0.23 mmol) was added and stirring continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (18.0 mg, 17%).

[0430] 1 H NMR (400 MHz, DMSO) δ = 12.08 (s, 1H), 9.87 (s, 1H), 7.68 (s, 1H), 7.07-6.53 (m, 3H), 4.83 (s, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.59 (d, J = 4.0 Hz, 4H), 3.12 (dd, J = 25.2, 12.4 Hz, 2H), 2.39 (s, 4H), 2.21 (s, 3H), 2.11-1.51 (m, 10H).

[0431] MS m / z (ESI): 497.2 [M+H] + .

[0432] Example 18

[0433] 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one

[0434]

[0435] Step 1: Preparation of tert-butylmethyl (2-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-carbonylethyl)carbamate

[0436]

[0437] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (200 mg, 0.42 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 10 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated. 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (240 mg, 0.64 mmol) was then added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (216 mg, 1.68 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. N-(tert-butoxycarbonyl)-N-methylglycine (87 mg, 0.46 mmol) was then added. After adding mmol), stirring was continued for 1 hour. At the end of the reaction, the reaction mixture was extracted with dichloromethane (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a white solid (205 mg, 90%).

[0438] MS m / z (ESI): 541.2 [M+H] + .

[0439] Step 2: Preparation of 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one

[0440]

[0441] 205 mg, 0.38 mmol) of tert-butylmethyl (2-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-carbonylethyl)carbamate was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 10 mL). After stirring at room temperature for 30 minutes, ammonia (10 mL) was added dropwise to the reaction solution in an ice-water bath. The reaction solution was then concentrated under reduced pressure. The product was analyzed by prep-HPLC to give the title compound as a white solid (37.6 mg, 22%).

[0442] 1 H NMR (400 MHz, DMSO) δ = 12.10 (s, 1H), 9.88 (s, 1H), 7.68 (s, 1H), 6.96 (s, 1H), 6.61 (s, 2H), 4.84 (s, 1H), 4.69 (s, 1H), 4.12 (s, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.15-1.96 (m, 3H), 1.87-1.47 (m, 10H).

[0443] MS m / z (ESI): 441.2 [M+H] + .

[0444] Example 19

[0445] ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((R)-pyrrolidine-2-yl)methyl ketone

[0446]

[0447] The preparation of ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) ((R)-pyrrolidine-2-yl) methyl ketone was carried out in accordance with Example 18.

[0448] 1H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 9.89 (s, 1H), 7.66 (s, 1H), 7.06-6.51 (m, 3H), 4.55-4.35 (m, 3H), 3.73 (s, 1H), 3.01 (s, 1H), 2.64 (d, J = 6.8 Hz, 2H), 2.23 (s, 3H), 2.10-1.43 (m, 12H).

[0449] MS m / z (ESI): 453.1 [M+H] + .

[0450] Example 20

[0451] ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((S)-pyrrolidine-2-yl)methyl ketone

[0452]

[0453] The preparation of ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) ((S)-pyrrolidine-2-yl) methyl ketone was carried out in accordance with Example 18.

[0454] 1 H NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 9.90 (s, 1H), 7.67 (s, 1H), 5.98-6.54 (m, 3H), 4.58-4.35 (m, 3H), 4.09-4.02 (m, 1H), 3.11 (s, 1H), 2.97-2.64 (m, 2H), 2.23 (s, 3H), 2.10-1.37 (m, 10H).

[0455] MS m / z (ESI): 453.1 [M+H] + .

[0456] Example 21

[0457] ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((R)-morpholin-3-yl)methyl ketone

[0458]

[0459] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((R)-morpholin-3-yl) methyl ketone was carried out in accordance with Example 18.

[0460] MS m / z (ESI): 483.2 [M+H] + .

[0461] Example 22

[0462] ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((R)-pyrrolidine-2-yl)methyl ketone

[0463]

[0464] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)((R)-pyrrolidine-2-yl) methyl ketone was carried out in accordance with Example 18.

[0465] MS m / z (ESI): 467.2 [M+H] + .

[0466] Example 23

[0467] 2-((2-methoxyethyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)ethane-1-one

[0468]

[0469] The preparation of 2-((2-methoxyethyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)ethane-1-one was carried out in accordance with Example 18.

[0470] MS m / z (ESI): 485.2 [M+H] + .

[0471] Example 24

[0472] 1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-((pyridin-3-ylmethyl)amino)ethane-1-one

[0473]

[0474] The preparation of 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-((pyridin-3-ylmethyl)amino)ethane-1-one was carried out in accordance with Example 18.

[0475] MS m / z (ESI): 518.2 [M+H] + .

[0476] Example 25

[0477] 2-((4-methoxybenzyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0478]

[0479] The preparation of 2-((4-methoxybenzyl)amino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out in accordance with Example 18.

[0480] MS m / z (ESI): 533.2 [M+H] + .

[0481] Example 26

[0482] 2-(ethylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0483]

[0484] The preparation of 2-(ethylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out according to Example 18.

[0485] MS m / z (ESI): 441.2 [M+H] + .

[0486] Example 27

[0487] 2-(cyclopropylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0488]

[0489] The preparation of 2-(cyclopropylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out in accordance with Example 18.

[0490] MS m / z (ESI): 453.2 [M+H] + .

[0491] Example 28

[0492] 1-((3-exo)-3-(methyl(4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(4-methylpiperazin-1-yl)ethane-1-one

[0493]

[0494]

[0495] tert-butyl-(3-exo)-3-(methyl(4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. Then, 2-(4-methylpiperazin-1-yl)acetic acid (36 mg, 0.23 mmol) was added. After adding mmol), stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (43.8 mg, 40%).

[0496] 1 H NMR (400 MHz, DMSO) δ = 12.07 (s, 1H), 9.79 (s, 1H), 7.68 (d, J = 6.0Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.46 (s, 1H), 5.81 (s, 1H), 4.71 (s, 1H), 4.39 (s, 1H), 3.22 (d, J = 12.8 Hz, 1H), 3.06 (d, J = 12.8 Hz, 1H), 2.85 (s, 3H), 2.40 (s, 8H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12-2.02 (m 2H), 1.90-1.61 (m,8H).

[0497] MS m / z (ESI): 424.2 [M+H] + .

[0498] Example 29

[0499] 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(4-methylpiperazin-1-yl)ethane-1-one

[0500]

[0501]

[0502] tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated. 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was then added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. 2-(4-methylpiperazin-1-yl)acetic acid (36 mg, 0.23 mmol) was then added. After adding mmol), stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (25.2 mg, 24%).

[0503] 1 H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.92 (s, 1H), 7.68 (s, 1H), 6.96-6.61 (m, 3H), 4.85 (s, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.10 (s, 2H), 2.37 (s, 8H), 2.21 (s, 3H), 2.14 (s, 3H), 2.09-1.99 (m, 2H), 1.97-1.46 (m, 8H).

[0504] MS m / z (ESI): 510.2 [M+H] + .

[0505] Example 30

[0506] 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(piperazin-1-yl)ethane-1-one

[0507]

[0508] The preparation of 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(piperazin-1-yl)ethane-1-one was carried out in accordance with Example 18.

[0509] MS m / z (ESI): 496.2 [M+H] + .

[0510] Example 31

[0511] ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methyl ketone

[0512]

[0513] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), and the reaction solution was concentrated after stirring at room temperature for 30 minutes. Then, 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. Pyridine-2-carboxylic acid (28 mg, 0.23 mmol) was added and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (27.3 mg, 21%).

[0514] 1 H NMR (400 MHz, DMSO) δ = 12.07 (s, 1H), 9.86 (s, 1H), 8.59 (d, J = 4.4Hz, 1H), 7.94 (td, J = 7.7, 1.6 Hz, 1H), 7.73-7.44 (m, 3H), 7.05-6.50 (m, 3H), 4.84 (d, J = 28.0 Hz, 2H), 3.94 (s, 1H), 2.21 (s, 3H), 2.18-1.59 (m, 10H).

[0515] MS m / z (ESI): 475.1 [M+H] + .

[0516] Example 32

[0517] ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-3-yl)methyl ketone

[0518]

[0519]

[0520] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and then pyridine-3-carboxylic acid (28 mg, 0.23 mmol) was added and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (28.6 mg, 22%).

[0521] 1 H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.87 (s, 1H), 8.71-8.58 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.51 (dd, J = 7.6, 4.8 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 6.68-6.50 (m, 2H), 4.83 (d, J = 39.2 Hz, 2H), 3.78 (s, 1H), 2.21 (s, 3H), 2.13-1.61 (m, 10H).

[0522] MS m / z (ESI): 475.1 [M+H] + .

[0523] Example 33

[0524] ((3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-4-yl)methyl ketone

[0525]

[0526]

[0527] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and then pyridine-4-carboxylic acid (28 mg, 0.23 mmol) was added and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (34.5 mg, 27%).

[0528] 1 H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.87 (s, 1H), 8.69 (d, J = 6.0Hz, 2H), 7.69 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 5.6 Hz, 2H), 6.97 (d, J = 6.0 Hz, 1H), 6.57 (d, J = 7.6 Hz, 2H), 4.82 (d, J = 41.6 Hz, 2H), 3.68 (s, 1H), 2.21 (s, 3H), 2.14-1.59 (m, 10H).

[0529] MS m / z (ESI): 475.1 [M+H] + .

[0530] Example 34

[0531] (1-Methyl-1-hydro-imidazol-2-yl) ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) methyl ketone

[0532]

[0533]

[0534] tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydropyrazole-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was then concentrated. 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was then added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. 1-methyl-1-hydroimidazolium-2-carboxylic acid (29 mg, 0.23 mmol) was then added. After adding mmol), stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (15.0 mg, 12%).

[0535] 1 H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 9.87 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 6.97 (s, 2H), 6.65 (s, 2H), 4.91-4.80 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 2.14-1.60 (m, 10H).

[0536] MS m / z (ESI): 478.2 [M+H] + .

[0537] Example 35

[0538] (1-Methyl-1-hydro-imidazol-4-yl) ((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) methyl ketone

[0539]

[0540] The preparation of (1-methyl-1-hydro-imidazol-4-yl)((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) methyl ketone was carried out according to Example 21.

[0541] 1 H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 9.86 (s, 1H), 7.70-7.60 (m, 3H), 6.95 (s, 1H), 6.65 (s, 1H), 5.57 (s, 1H), 4.82 (d, J = 65.2 Hz, 3H), 3.68 (s, 3H), 2.22 (s, 3H), 2.13-1.58 (s, 10H).

[0542] MS m / z (ESI): 478.1 [M+H] + .

[0543] Example 36

[0544] N 4 -(5-Methyl-1-hydropyrazole-3-yl)-N 2 -((3-exo)-8(pyridin-3-ylsulfonyl)-8-azabicyclo[3.2.1]octane-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0545]

[0546]

[0547] Tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (40 mg, 0.09 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 2 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, N,N-dimethylformamide (5 mL) was added to dissolve it, and DIPEA (46 mg, 0.36 mmol) was slowly added dropwise. The mixture was stirred in an ice-water bath for 10 minutes, and then pyridine-3-sulfonyl chloride (18 mg, 0.1 mmol) was added, followed by stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a white solid (5.6 mg, 13%).

[0548] 1 H NMR (400 MHz, DMSO) δ = 12.01 (s, 1H), 9.86 (s, 1H), 9.05 (s, 1H), 8.87 (d, J = 4.4 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 7.8 56 (m, 4H), 1.35-1.26 (m, 2H).

[0549] MS m / z (ESI): 497.1 [M+H] + .

[0550] Example 37

[0551] N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8-azabicyclo[3.2.1]octane-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0552]

[0553] The preparation of N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8-azabicyclo[3.2.1]octane-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine was carried out in accordance with Example 23.

[0554] 1H NMR (400 MHz, CD3OD: CDCl3, v / v= 1:2) δ 8.70 (d, J = 4.6 Hz, 1H), 8.00 (dt, J = 8.0, 4.6 Hz, 2H), 7.60 (ddd, J = 6.8, 4.8, 1.8 Hz, 1H), 7.35(d, J = 6.0 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.19 (s, 1H), 4.43 (s, 2H),4.40-4.32 (m, 1H), 2.27 (s, 3H), 2.15 (ddd, J = 12.7, 5.3, 2.6 Hz, 2H), 1.88-1.81 (m, 2H), 1.80-1.70 (m, 2H), 1.62 (dd, J = 8.6, 4.7 Hz, 2H).

[0555] MS m / z (ESI): 497.1 [M+H] + .

[0556] Example 38

[0557] N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-2-ylsulfonyl)-9-azabicyclo[3.3.1]nonane-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0558]

[0559] 100 mg (0.213 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester was dispersed in 1,4-epoxyhexane (15 mL) in 4 M HCl. The mixture was stirred at room temperature for 60 minutes. The solvent was removed by concentration under reduced pressure. The remaining solid was dissolved in anhydrous N,N-dimethylformamide (10 mL) and cooled to 0 °C. o At C, DIPEA (1.05 mL, 6.39 mmol) and pyridine-2-sulfonyl chloride (40 mg, 0.224 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 2.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound as a white solid (12.4 mg, 25%).

[0560] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 9.85 (s, 1H), 8.78 (d, J =4.0 Hz, 1H), 8.08 (td, J = 7.7, 1.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.67(dd, J = 6.7, 4.7 Hz, 2H), 6.95 (s, 1H), 6.59 (d, J = 30.3 Hz, 2H), 4.85-4.71(m, 1H), 4.18 (s, 2H), 2.17 (s, 3H), 2.05 (dd, J = 12.8, 4.9 Hz, 3H), 1.68 (d, J = 2.6 Hz, 7H).

[0561] MS m / z (ESI): 511.1 [M+H] + .

[0562] Example 39

[0563] N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-3-ylsulfonyl)-9-azabicyclo[3.3.1]nonane-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0564]

[0565] The preparation of N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-9-(pyridin-3-ylsulfonyl)-9-azabicyclo[3.3.1]nonane-3-yl)thiopheno[2,3-d]pyrimidine-2,4-diamine was carried out in accordance with Example 38.

[0566] 1 H NMR (400 MHz, CD3OD:CDCl3, v / v =1:1) δ 9.11 (s, 1H), 8.84 (d, J =3.9 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.70-7.62 (m, 1H), 7.39 (d, J = 5.9Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 6.62 (s, 1H), 5.05-4.90 (m, 1H), 4.34 (d,J = 2.8 Hz, 2H), 2.55-2.19 (m, 5H), 2.19-1.61 (m, 8H).

[0567] MS m / z (ESI): 511.1 [M+H] + .

[0568] Example 40

[0569] N2-((3-exo)-9-((1-methyl-1H-imidazol-2-yl)sulfonyl)-9-azabicyclo[3.3.1]nonane-3-yl)-N4-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0570]

[0571] The preparation of N2-((3-exo)-9-((1-methyl-1H-imidazol-2-yl)sulfonyl)-9-azabicyclo[3.3.1]nonane-3-yl)-N4-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine was carried out in accordance with Example 38.

[0572] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.86 (s, 1H), 7.67 (d, J = 2.9Hz, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.96 (d, J = 4.9 Hz, 1H), 6.73-6.47 (m, 2H), 4.88-4.74 (m, 1H), 4.12 (s, 2H), 3.87 (s, 3H), 2.19 (s, 3H), 2.09 (ddd, J = 5.5, 5.1, 1.0 Hz, 3H), 1.91-1.58 (m, 7H).

[0573] MS m / z (ESI): 514.1 [M+H] + .

[0574] Example 41

[0575] N,N-Dimethyl-2-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)acetamide

[0576]

[0577]

[0578] 100 mg (0.21 mmol) of tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes and then concentrated. N,N-dimethylformamide (5 mL) was added to dissolve the ester, and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred in an ice-water bath for 10 minutes, followed by the addition of 2-bromo-N,N-dimethylacetamide (38 mg, 0.23 mmol) and stirring for another hour. The mixture was concentrated under reduced pressure, and the product was analyzed by prep-HPLC to give the title compound as a white solid (16.6 mg, 17%).

[0579] 1 H NMR (400 MHz, DMSO) δ = 12.00 (s, 1H), 9.80 (s, 1H), 7.63 (s, 1H), 6.74 (d, J = 128.0 Hz, 3H), 4.62 (s, 1H), 3.42 (s, 2H), 3.04 (s, 3H), 2.86 (s, 2H), 2.77 (s, 3H), 2.16 (s, 3H), 1.96-1.47 (m, 10H).

[0580] MS m / z (ESI): 455.2 [M+H] + .

[0581] Example 42

[0582] N 4 -(5-Methyl-1-hydropyrazole-3-yl)-N 2 -((3-exo)-9-(pyridin-2-ylmethyl)-9-azabicyclo[3.3.1]nonane-3-yl)thiopheno[2,3-d]pyrimidine-2,4-diamine

[0583]

[0584]

[0585] 100 mg (0.21 mmol) of tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, it was dissolved in N,N-dimethylformamide (5 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred in an ice-water bath for 10 minutes, and 2-(chloromethyl)pyridine hydrochloride (38 mg, 0.23 mmol) was added. The mixture was then heated to 70 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, and the product was analyzed by prep-HPLC to give the title compound as a white solid (20.8 mg, 22%).

[0586] 1 H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 9.85 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 7.81-7.48 (m, 3H), 7.33-6.52 (m, 4H), 4.74 (s, 1H), 3.92 (s, 2H), 2.89 (s, 2H), 2.23 (d, J = 13.6 Hz, 3H), 2.08-1.50 (m, 10H).

[0587] MS m / z (ESI): 461.1 [M+H] + .

[0588] Example 43

[0589] N 2 -((3-exo)-9-((1-methyl-1-hydro-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-yl)-N 4 -(5-methyl-1-hydropyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0590]

[0591] N 2 -((3-exo)-9-((1-methyl-1-hydro-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]nonane-3-yl)-N 4 The preparation of -(5-methyl-1-hydro-pyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine was carried out in accordance with Example 42.

[0592] 1H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 9.84 (s, 1H), 7.67 (s, 1H), 7.08 (s, 1H), 6.95 (s, 1H), 6.74-6.55 (m, 3H), 4.69 (s, 1H), 3.91 (s, 2H), 3.69 (s, 3H), 2.84 (s, 2H), 2.20 (s, 3H), 2.01-1.66 (m, 10H).

[0593] MS m / z (ESI): 464.2 [M+H] + .

[0594] Example 44

[0595] 3-((3-exo))-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0596]

[0597] Step 1: Preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol

[0598]

[0599] 2,4-Dichlorothiopheno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-1H-pyrazol-5-yl)methanol (55 mg, 0.49 mmol), and DIPEA (190 mg, 1.47 mmol) were added to N'N-dimethylformamide (2 mL), and the reaction solution was heated to 70 °C. o The mixture was stirred overnight at C. The crude product was concentrated under reduced pressure and purified by rapid silica gel column chromatography to give the title compound as a yellow solid (100 mg, 73%).

[0600] MS m / z (ESI): 282.0 [M+H] + .

[0601] Step 2: Preparation of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0602]

[0603] (3-((2-chlorothiopheno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.36 mmol), N-Boc-exo-3-aminotropane acetate (113 mg, 0.40 mmol), and DIPEA (140 mg, 1.08 mmol) were added to n-butanol (2.5 mL). After the reaction solution was thoroughly mixed, it was microwaved for 150 °C. o The reaction was carried out at C for 10 hours, cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by rapid silica gel column chromatography to obtain the title compound as a pale yellow solid (60 mg, 35%).

[0604] MS m / z (ESI): 472.0 [M+H] + .

[0605] Step 3: Preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0606]

[0607] 60 mg (0.13 mmol) of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in methanol (10 mL), and then dioxane hydrochloride (4N, 2.5 mL) was slowly added dropwise to the reaction solution. The reaction was carried out at room temperature for 2 hours, and the solution was concentrated under reduced pressure. The crude product was added to a solution of methanol (15 mL), DIPEA (0.5 mL), and acrylonitrile (1 mL), and the reaction was carried out at room temperature for 2 hours. The solution was concentrated under reduced pressure, and the title compound was purified by prep-HPLC to obtain a white solid (11.6 mg, 21%).

[0608] 1 H NMR (400 MHz, CD3OD) δ 7.39 (dd, J = 6.0 Hz, 1H), 6.99 (dd, J = 5.6 Hz, 1H), 6.02-6.04 (m, 1 H), 4.60 (s, 2 H), 4.21-4.24 (m, 1 H), 3.45-3.42 (m,2H), 2.83 (s, 2 H), 2.69-2.65 (m, 2 H), 2.08-1.91 (m, 6 H), 1.69 (t, J =12.4 Hz, 2 H).

[0609] MS m / z (ESI): 425.1 [M+H] + .

[0610] Example 45

[0611] 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0612]

[0613] The preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out in accordance with Example 44.

[0614] MS m / z (ESI): 439.2 [M+H] + .

[0615] Example 46

[0616] 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0617]

[0618] The preparation of 3-((3-exo)-3-((4-(((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out in accordance with Example 44.

[0619] MS m / z (ESI): 453.2 [M+H] + .

[0620] Example 47

[0621] 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile

[0622]

[0623] The preparation of 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile was carried out in accordance with Example 44.

[0624] MS m / z (ESI): 530.2 [M+H] + .

[0625] Example 48

[0626] 3-((3-exo)-3-((6-methyl-4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0627]

[0628] Step 1: Preparation of tert-butyl-(3-exo)-3-((6-methyl-4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0629]

[0630] To a solution of 2-chloro-6-methyl-N-(5-methyl-1-hydropyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (200 mg, 0.72 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (194 mg, 0.86 mmol) and DIPEA (186 mg, 1.44 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a pale yellow solid (124 mg, 37%).

[0631] MS m / z (ESI): 470.2 [M+H] + .

[0632] Step 2: Preparation of 3-((3-exo)-3-((6-methyl-4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0633]

[0634] tert-butyl-(3-exo)-3-((6-methyl-4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (124 mg, 0.26 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (10 mL) was added to dissolve it, and DIPEA (137 mg, 1.06 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then acrylonitrile (21 mg, 0.39 mmol) was added, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a white solid (12.7 mg, 12%).

[0635] 1 H NMR (400 MHz, DMSO) δ = 9.70 (s, 1H), 7.30 (s, 1H), 6.59 (s, 3H), 4.15 (s, 1H), 3.29 (s, 2H), 2.61 (s, 4H), 2.39 (s, 3H), 2.22 (s, 3H), 1.90(s, 2H), 1.78-1.50 (m, 6H).

[0636] MS m / z (ESI): 423.2 [M+H] + .

[0637] Example 49

[0638] 3-((3-exo)-3-((7-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0639]

[0640] Step 1: Preparation of 5-chloro-N-(5-methyl-1-hydro-pyrazol-3-yl)thiazo[5,4-d]pyrimidine-7-amine

[0641]

[0642] To a solution of 5,7-dichlorothiazo[5,4-d]pyrimidine (206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol) and DIPEA (258 mg, 2 mmol) were added sequentially, followed by heating and stirring at 70 °C for one hour. After the reaction was complete, water (50 mL) was added to the reaction solution, resulting in the precipitation of a solid. The solid was filtered and slurried with ethyl acetate to obtain the title compound as a yellow solid (200 mg, 75%).

[0643] MS m / z (ESI): 267.0 [M+H] + .

[0644] Step 2: Preparation of tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0645]

[0646] To a solution of 5-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thiazo[5,4-d]pyrimidin-7-amine (200 mg, 0.75 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (216 mg, 0.9 mmol) and DIPEA (193 mg, 1.5 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a pale yellow solid (232 mg, 66%).

[0647] MS m / z (ESI): 471.2 [M+H] + .

[0648] Step 3: Preparation of 3-((3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0649]

[0650] 232 mg (0.49 mmol) of tert-butyl-(3-exo)-3-((7-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiazo[5,4-d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (10 mL) was added to dissolve it, and DIPEA (127 mg, 0.98 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then acrylonitrile (39 mg, 0.74 mmol) was added, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a pale yellow solid (63 mg, 30%).

[0651] 1 H NMR (400 MHz, DMSO) δ = 12.06 (s, 1H), 9.29 (s, 1H), 8.76 (d, J = 18.8Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.57 (s, 1H), 4.67 (s, 1H), 3.31 (s, 2H), 2.58 (t, J =6.2 Hz, 4H), 2.19 (s, 3H), 2.00-1.65 (m, 10H).

[0652] MS m / z (ESI): 424.2 [M+H] + .

[0653] Example 50

[0654] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0655]

[0656] Step 1: Preparation of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0657]

[0658] At room temperature, NaH (120 mg, 3.01 mmol, 60%) was added in portions to a solution of tert-butyl(3-exo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (427 mg, 1.88 mmol) in N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 5 minutes, and then 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidine-4-amine (100 mg, 0.376 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. The mixture was heated to 120 °C and stirred for 2 hours under nitrogen protection. After cooling the reaction solution to room temperature, it was poured into ice water (10 mL) and stirred for 10 minutes. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride aqueous solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the organic solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a yellow oil (149 mg, 87%).

[0659] Step 2: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0660]

[0661] Tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxo)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (77 mg, 0.169 mmol) was dissolved in methanol (2 mL). 1,4-dioxane (2 mL) in 4M HCl was added with stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (1 mL). DIPEA (109 mg, 0.844 mmol) and acrylonitrile (45 mg, 0.844 mmol) were added sequentially. The resulting reaction mixture was stirred for another 1 hour at room temperature. After concentration under reduced pressure, the residue was initially purified by silica gel chromatography, and then further purified by preparative TLC to obtain the title compound as a gray solid (7 mg, 10%).

[0662] 1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 6.1 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.51 (s, 1H), 5.43-5.26 (m, 1H), 3.44-3.37 (m, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.12-2.00 (m, 4H), 1.86-1.74 (m, 4H).

[0663] MS m / z (ESI): 410.1 [M+H] + .

[0664] Example 51

[0665] 3-((3-exo)-3-((6-(methoxymethyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0666]

[0667] The preparation of 3-((3-exo)-3-((6-(methoxymethyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 48.

[0668] MS m / z (ESI): 453.2 [M+H] + .

[0669] Example 52

[0670] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinothieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0671]

[0672] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-morpholinothieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 48.

[0673] MS m / z (ESI): 494.2 [M+H] + .

[0674] Example 53

[0675] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-(morpholinomethyl)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0676]

[0677] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-(morpholinomethyl)thiopheno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 48.

[0678] MS m / z (ESI): 508.3 [M+H] + .

[0679] Example 54

[0680] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperazin-1-yl)methyl)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0681]

[0682] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-((4-methylpiperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out in accordance with Example 48.

[0683] MS m / z (ESI): 535.3 [M+H] + .

[0684] Example 55

[0685] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-ylthio)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0686]

[0687] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-6-(pyridin-3-ylthio)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 48.

[0688] MS m / z (ESI): 532.2 [M+H] + .

[0689] Example 56

[0690] 3-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)azacyclobutane-3-nitrile

[0691]

[0692]

[0693] tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.22 mmol) was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, it was dissolved in N,N-dimethylformamide (10 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then 3-acrylazacyclobutane-1-sulfonyl chloride (45 mg, 0.25 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the product was subjected to prep-HPLC to give the title compound as a white solid (23.2 mg, 21%).

[0694] 1H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.74 (s, 1H), 7.90 (s, 1H), 7.00 (s, 1H), 6.54 (s, 2H), 4.27 (s, 1H), 4.13 (s, 2H), 4.04 (t, J = 8.4 Hz, 2H), 3.98-3.89 (m, 2H), 3.80 (dd, J = 15.2, 6.0 Hz, 1H), 2.23 (s, 3H), 1.99 (s, 4H), 1.84 (d, J = 7.2Hz, 2H), 1.63 (s, 2H).

[0695] MS m / z (ESI): 500.1 [M+H] + .

[0696] Example 57

[0697] 1-(((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[0698]

[0699] The preparation of 1-(((3-exo)-3-((6-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile was carried out in accordance with Example 38.

[0700] 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 9.64 (s, 1H), 6.77-6.45 (m, 3H), 4.25-4.23 (m, 1H), 4.12 (s, 2H), 4.06-4.02 (m, 2H), 3.95-3.88 (m, 2H), 3.83-3.77 (m, 1H), 2.24-2.21 (m, 4H), 1.99-1.98 (m, 5H), 1.84-1.81 (m, 2H), 1.64-1.59 (m, 3H).

[0701] MS m / z (ESI): 513.1 [M+H] + .

[0702] Example 58

[0703] 2-(dimethylamino)-1-((3-exo)-3-((4-((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0704]

[0705] The preparation of 2-(dimethylamino)-1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out according to Example 56.

[0706] 1 H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 9.72 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.49 (d, J = 58.8 Hz, 2H), 4.59-4.28 (m, 3H), 3.04 (s, 2H), 2.15 (s, 9H), 1.98-1.80 (m, 6H), 1.59-1.45 (m, 2H).

[0707] MS m / z (ESI): 441.1 [M+H] + .

[0708] Example 59

[0709] 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-morpholinoethane-1-one

[0710]

[0711] Step 1: Preparation of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0712]

[0713] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thieno[3,2-d]pyrimidine-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (271 mg, 1.13 mmol) and DIPEA (242 mg, 1.88 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a pale white solid (150 mg, 34%).

[0714] MS m / z (ESI): 470.1 [M+H] + .

[0715] Step 2: Preparation of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0716]

[0717] tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL), stirred at room temperature for 30 minutes, and then the reaction solution was concentrated. Then 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred in an ice-water bath for 10 minutes, and 2-morpholinoacetic acid (33 mg, 0.23 mmol) was added and stirring continued for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (17.8 mg, 17%).

[0718] 1H NMR (400 MHz, DMSO-d6) δ = 11.99 (s, 1H), 9.69 (s, 1H), 7.84 (s, 1H), 7.07-6.23 (m, 3H), 4.77 (s, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.52 (d, J = 4.0 Hz, 4H), 3.10-3.01 (m, 2H), 2.32 (s, 3H), 2.14 (s, 2H), 2.09-1.39 (m, 10H).

[0719] MS m / z (ESI): 497.1 [M+H] + .

[0720] Example 60

[0721] 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one

[0722]

[0723] The preparation of 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one was carried out in accordance with Example 18.

[0724] MS m / z (ESI): 441.2 [M+H] + .

[0725] Example 61

[0726] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methyl ketone

[0727]

[0728] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)(pyridin-2-yl)methyl ketone was carried out in accordance with Example 59.

[0729] MS m / z (ESI): 475.2 [M+H] + .

[0730] Example 62

[0731] (1-Methyl-1H-imidazol-2-yl)((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)methyl ketone

[0732]

[0733] The preparation of (1-methyl-1H-imidazol-2-yl)((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl) methyl ketone was carried out in accordance with Example 59.

[0734] MS m / z (ESI): 478.2 [M+H] + .

[0735] Example 63

[0736] 2-(dimethylamino)-1-((1R,3r,5S)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[0737]

[0738] The preparation of 2-(dimethylamino)-1-((1R,3r,5S)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out according to Example 13.

[0739] MS m / z (ESI): 441.2 [M+H] + .

[0740] Example 64

[0741] N,N-Dimethyl-2-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)acetamide

[0742]

[0743]

[0744] 100 mg (0.21 mmol) of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 1,4-epoxyhexacyclohydrochloride solution (4.0 N, 5 mL). The mixture was stirred at room temperature for 30 minutes and then concentrated. N,N-dimethylformamide (5 mL) was added to dissolve the ester, and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred in an ice-water bath for 10 minutes, and then 2-bromo-N,N-dimethylacetamide (38 mg, 0.23 mmol) was added, followed by stirring for 1 hour. The mixture was concentrated under reduced pressure, and the product was analyzed by prep-HPLC to give the title compound as a white solid (16.4 mg, 17%).

[0745] 1 H NMR (400 MHz, DMSO-d6) δ = 12.05 (s, 1H), 9.74 (s, 1H), 7.90 (d, J = 4.0Hz, 1H), 7.14-6.30 (m, 3H), 4.15 (s, 1H), 3.32-3.23 (m, 4H), 3.08 (s, 3H), 2.83 (s, 3H), 2.22 (s, 3H), 1.97 (s, 2H), 1.82-1.55 (m, 6H).

[0746] MS m / z (ESI): 441.1 [M+H] + .

[0747] Example 65

[0748] 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthiopheno[3,2-dpyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0749]

[0750] Step 1: Preparation of (3-((2-chloro-6-methylthiopheno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol

[0751]

[0752] 2,4-Dichloro-6-methylthieno[3,2-d]pyrimidine (200 mg, 0.91 mmol), (3-amino-1H-pyrazol-5-yl)methanol (120 mg, 1.09 mmol), and DIPEA (350 mg, 2.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), mixed thoroughly, and then incubated at 70°C. o The reaction was carried out overnight at C. After cooling to room temperature, water (30 mL) and ethyl acetate (20 mL * 3) were added to the reaction solution for extraction. The organic phases were combined and concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain the title compound as a white solid (200 mg, 75%).

[0753] MS m / z (ESI): 296.0 [M+H] + .

[0754] Step 2: Preparation of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthiopheno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[0755]

[0756] (3-((2-chloro-6-methylthiopheno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (150 mg, 0.51 mmol), tert-butyl(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylic acid oxalate (200 mg, 0.61 mmol), and DIPEA (200 mg, 1.53 mmol) were added to n-butanol (3 mL), mixed thoroughly, and then microwaved at 165°C. o Under C conditions, the reaction was carried out for 8 hours, cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product (200 mg) was not purified and was used directly in the next step of the reaction.

[0757] MS m / z (ESI): 500.1 [M+H] + .

[0758] Step 3: Preparation of (3-((2-(((3-exo)-9-azabicyclo[3.3.1]nonane-3-yl)amino)-6-methylthiopheno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol

[0759]

[0760] To a methanol (10 mL) solution of tert-butyl(3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (200 mg, 0.40 mmol), dioxane hydrochloride (4N, 5 mL) was slowly added dropwise. The reaction was carried out at room temperature for 3 hours, and the solution was concentrated under reduced pressure. The crude product was purified by prep-HPLC to obtain the title compound as a yellow solid (100 mg, 63%).

[0761] MS m / z (ESI): 400.1 [M+H] + .

[0762] Step 4: Preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)-6-methylthiopheno[3,2-d-pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[0763]

[0764] (3-((2-((((3-exo)-9-azabicyclo[3.3.1]nonane-3-yl)amino)-6-methylthiopheno[3,2-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol (100 mg, 0.25 mmol), acrylonitrile (0.2 mL), and DIPEA (0.1 mL) were added to methanol (10 mL), mixed thoroughly, and reacted at room temperature for 1 hour. The mixture was then concentrated under reduced pressure, and the crude product was purified by prep-HPLC to obtain the title compound as a white solid (11.7 mg, 10%).

[0765] 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.12 (s, 1H), 7.09-6.64 (m, 2H), 6.29-6.23 (s, 1H), 5.22-4.94 (m, 1H), 4.67-4.37 (m, 3H), 2.95 (s, 2H), 2.85-2.81 (m, 2H), 2.70-2.57 (m, 5H), 1.95-1.49 (m, 10H).

[0766] MS m / z (ESI): 453.2 [M+H] + .

[0767] Example 66

[0768] 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile

[0769]

[0770] Step 1: Preparation of tert-butylcis-5-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester

[0771]

[0772] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol), tert-butylcis-5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester (102 mg, 0.452 mmol), and DIPEA (146 mg, 1.13 mmol) were added to NMP (1 mL) and reacted in a microwave oven at 160 °C for 8 hours under nitrogen protection. After cooling the reaction solution to room temperature, it was poured into ice water (10 mL) and stirred for 10 minutes. The mixture was filtered, the filter cake was washed with water (15 mL), and dried under vacuum to give the title compound as a yellow solid (171 mg, crude product).

[0773] Step 2: Preparation of 3-(cis-5-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)propionitrile

[0774]

[0775] tert-Butylcis-5-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid ester (86 mg, 0.188 mmol) was dissolved in methanol (2 mL). 1,4-dioxane (2 mL) of 4M HCl was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (2 mL). DIPEA (121 mg, 0.938 mmol) and acrylonitrile (15 mg, 0.282 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for another 16 hours. The reaction solution was diluted with DCM (20 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound as a white solid (17 mg, 22%).

[0776] 1 H NMR (400 MHz, CD3OD) δ 7.36 (d, J = 6.0 Hz, 1H), 7.02-6.86 (m, 1H), 6.54 (s, 0.6H), 5.80 (s, 0.4H), 4.34-4.09 (m, 1H), 2.86-2.72 (m, 4H), 2.73-2.57 (m, 4H), 2.40-2.19 (m, 7H), 1.57-1.37 (m, 2H).

[0777] MS m / z (ESI): 409.1 [M+H] + .

[0778] Example 67

[0779] 3-(cis-5-((4-((5-methyl-1-hydropyrazole-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadienzo[c]pyrrole-2(1-hydro)-yl)propionitrile

[0780]

[0781] Step 1: Preparation of tert-butyl-cis-5-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1-hydro)-carboxylic acid ester

[0782]

[0783] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (100 mg, 0.38 mmol) in n-butanol (5 mL), tert-butyl-cis-5-aminohexahydrocyclopentadien[c]pyrrole-2(1-hydro)-carboxylic acid ester (102 mg, 0.45 mmol) and DIPEA (98 mg, 0.76 mmol) were added sequentially, followed by stirring at 160 °C under microwave conditions for 15 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a pale yellow solid (80 mg, 46%).

[0784] MS m / z (ESI): 456.2 [M+H] + .

[0785] Step 2: Preparation of 3-(cis-5-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1-hydro)-yl)propionitrile

[0786]

[0787] tert-butyl-cis-5-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1-hydro)-carboxylic acid ester (80 mg, 0.18 mmol) was dissolved in 1,4-epoxyhexacyclooxygenate solution (4.0 N, 2 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, methanol (5 mL) was added to dissolve it, and DIPEA (93 mg, 0.72 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then acrylonitrile (14 mg, 0.27 mmol) was added, followed by stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to give the title compound as a white solid (26.3 mg, 37%).

[0788] 1 H NMR (400 MHz, DMSO-d6) δ = 12.30 (s, 1H), 9.92 (s, 1H), 7.90 (s, 1H), 7.51-6.25 (m, 3H), 4.11 (s, 1H), 2.66 (dd, J = 13.6, 7.2 Hz, 6H), 2.22 (s, 8H), 1.31 (s, 3H).

[0789] MS m / z (ESI): 409.1 [M+H] + .

[0790] Example 68

[0791] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile

[0792]

[0793] Step 1: Preparation of tert-butyl 4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester

[0794]

[0795] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol), 1-BOC-4-aminopiperidine (108 mg, 0.539 mmol), and DIPEA (146 mg, 1.13 mmol) were added to NMP (1 mL) and reacted in a microwave-safe atmosphere at 130 °C for 16 hours. The reaction mixture was cooled to room temperature and poured into ice water (10 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (5 mL) and dried under vacuum to give the title compound as a yellow solid (100 mg, crude product).

[0796] Step 2: Preparation of 3-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile

[0797]

[0798] 100 mg (0.233 mmol) of tert-butyl-4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylic acid ester was dissolved in methanol (2 mL). Ethyl acetate (2 mL) of 4M HCl was added with stirring at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (2 mL). DIPEA (150 mg, 1.17 mmol) and acrylonitrile (62 mg, 1.17 mmol) were added sequentially. The resulting reaction mixture was stirred for another 1 hour at room temperature. The reaction solution was diluted with DCM (20 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give the title compound as a white solid (18 mg, 20%).

[0799] 1 H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 6.0 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.55 (s, 0.5H), 5.81 (s, 0.5H), 3.92-3.74 (m, 1H), 3.04-2.88 (m, 2H), 2.81-2.57 (m, 4H), 2.44-2.15 (m, 5H), 2.14-1.97 (m, 2H), 1.73-1.52 (m, 2H).

[0800] MS m / z (ESI): 383.1 [M+H] + .

[0801] Example 69

[0802] 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile

[0803]

[0804] The preparation of 1-((4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile was carried out in accordance with Example 8.

[0805] 1H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1H), 6.49 (s, 0.5H), 5.83 (s, 0.5H), 4.20-4.10 (m, 2H), 4.07-3.99 (m, 2H), 3.99-3.89 (m, 1H), 3.77-3.61 (m, 3H), 3.09-2.99 (m, 2H), 2.28 (s, 3H), 2.17-2.06 (m, 2H), 1.67-1.51 (m, 2H).

[0806] MS m / z (ESI): 474.0 [M+H] + .

[0807] Example 70

[0808] 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-(methylamino)ethane-1-one

[0809]

[0810] The preparation of 1-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-(methylamino)ethane-1-one was carried out in accordance with Example 18.

[0811] MS m / z (ESI): 401.2 [M+H] + .

[0812] Example 71

[0813] 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one

[0814]

[0815] The preparation of 1-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one was carried out according to Example 17.

[0816] MS m / z (ESI): 457.2 [M+H] + .

[0817] Example 72

[0818] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methyl ketone

[0819]

[0820] The preparation of (4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methyl ketone was carried out in accordance with Example 31.

[0821] MS m / z (ESI): 435.2 [M+H] + .

[0822] Example 73

[0823] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile

[0824]

[0825] The preparation of 3-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile was carried out according to Example 1.

[0826] MS m / z (ESI): 383.2 [M+H] + .

[0827] Example 74

[0828] 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile

[0829]

[0830] The preparation of 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile was carried out in accordance with Example 1.

[0831] MS m / z (ESI): 474.1 [M+H] + .

[0832] Example 75

[0833] 1-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one

[0834]

[0835] The preparation of 1-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)-2-morpholinoethane-1-one was carried out in accordance with Example 17.

[0836] MS m / z (ESI): 457.2 [M+H] + .

[0837] Example 76

[0838] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methyl ketone

[0839]

[0840] The preparation of (4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[3,2-d]pyrimidin-2-yl)amino)piperidin-1-yl)(pyridin-2-yl)methyl ketone was carried out in accordance with Example 31.

[0841] MS m / z (ESI): 435.2 [M+H] + .

[0842] Example 77

[0843] 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile

[0844]

[0845] The preparation of 3-(endo-6-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile was carried out according to Example 3.

[0846] MS m / z (ESI): 381.2 [M+H] + .

[0847] Example 78

[0848] 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile

[0849]

[0850] The preparation of 3-(endo-6-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile was carried out according to Example 1.

[0851] MS m / z (ESI): 381.2 [M+H] + .

[0852] Example 79

[0853] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0854]

[0855] Step 1: Preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-4-amine

[0856]

[0857] 2,4-Dichloroquinazoline (199 mg, 1.0 mmol), 5-methyl-1H-pyrazole-3-amine (99 mg, 1.02 mmol), and triethylamine (213 mg, 2.1 mmol) were added to anhydrous ethanol (5 mL) and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was suspended in water-ethanol (v / v = 9:1, 20 mL). After filtration, the solid was washed with petroleum ether and dried to give the title compound (240 mg, 92%).

[0858] MS m / z (ESI): 260.1, 262.1 [M+H] + .

[0859] Step 2: tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0860]

[0861] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (40 mg, 0.154 mmol) and tert-butyl(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (70 mg, 0.308 mmol) were added to n-butanol (3 mL), stirred evenly at room temperature, and then microwaved at 150°C. o The reaction was carried out at C for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the crude title compound (120 mg), which was directly used in the next reaction.

[0862] MS m / z (ESI): 450.2 [M+H] + .

[0863] Step 3: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0864]

[0865] Crude tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (120 mg, 0.154 mmol) was dissolved in methanol (3 mL). A 1,4-dioxane solution of 4M HCl (10 mL) was added with stirring at room temperature. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure. The residue was dissolved in anhydrous methanol (10 mL). Diisopropylethylamine (0.51 mL, 3.08 mmol) and acrylonitrile (10 mg, 0.154 mmol) were added sequentially with stirring at room temperature. The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was removed by concentration under reduced pressure. The residue was purified sequentially by silica gel column chromatography and reversed-phase HPLC to obtain the title compound (6.0 mg, 10%).

[0866] 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.5Hz, 1H), 7.39 (s, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 4.35 (s, 1H),3.37 (s, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.31 (s,3H), 2.16-1.74 (m, 6H), 1.67 (t, J = 11.7 Hz, 2H).

[0867] MS m / z (ESI): 403.2 [M+H] + .

[0868] Example 80

[0869] 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0870]

[0871] Step 1: Preparation of 2-chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-4-amine

[0872]

[0873] 2,4-Dichloro-7-methoxyquinazoline (500 mg, 2.18 mmol), 5-methyl-1H-pyrazole-3-amine (223 mg, 2.29 mmol), and DIPEA (592 mg, 4.58 mmol) were added separately to anhydrous ethanol (10 mL) and stirred at room temperature for 3 days. The reaction solution was filtered, the filter cake was washed with acetonitrile (5 mL), and dried under vacuum to give the title compound as a white solid (355 mg, 56%).

[0874] MS m / z (ESI): 290.1 ​​[M+H] + .

[0875] Step 2: Preparation of (3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0876]

[0877] The compound 2-chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (355 mg, 1.23 mmol), tert-butyl(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate acetate (421 mg, 1.47 mmol), and DIPEA (475 mg, 3.68 mmol) were mixed in n-butanol (7 mL), and the mixture was microwaved to 150 °C. o The reaction mixture was stirred at C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white solid (259 mg, 44%).

[0878] MS m / z (ESI): 480.2 [M+H] + .

[0879] Step 3: Preparation of 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0880]

[0881] Tert-butyl(3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (259 mg, 0.540 mmol) was dissolved in methanol (3 mL). 1,4-dioxane (4 mL) in 4M HCl was added with stirring at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (3 mL). DIPEA (349 mg, 2.70 mmol) and acrylonitrile (43 mg, 0.810 mmol) were added sequentially. The resulting reaction mixture was stirred for another 0.5 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white solid (76.8 mg, 33%).

[0882] 1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.14-6.75 (m, 2H), 6.50 (s, 1H), 4.50-4.21 (m, 1H), 3.92 (s, 3H), 3.41 (s, 2H), 2.91-2.55 (m, 4H), 2.34 (s, 3H), 2.14-1.50 (m, 7H), 1.40-1.23 (m, 1H).

[0883] MS m / z (ESI): 433.2 [M+H] + .

[0884] Example 81

[0885] 3-((3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0886]

[0887] Step 1: Preparation of 7-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-4-amine

[0888]

[0889] 7-Bromo-2,4-dichloroquinazoline (3.36 g, 12.1 mmol), 5-methyl-1H-pyrazole-3-amine (1.29 g, 13.3 mmol), and TEA (2.57 g, 25.4 mmol) were added separately to anhydrous ethanol (67 mL) and stirred at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with anhydrous ethanol (20 mL), and dried under vacuum to give the title compound as a white solid (4.17 g, 100%).

[0890] Step 2: Preparation of tert-butyl(3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0891]

[0892] The compound 7-bromo-2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (500 mg, 1.48 mmol), tert-butyl(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate acetate (465 mg, 1.62 mmol), and DIPEA (591 mg, 4.58 mmol) were mixed in NMP (5 mL), and the mixture was microwaved to 130 °C. o The reaction mixture was stirred at C for 4 hours. After cooling the reaction solution to room temperature, it was poured into 25 mL of ice water and stirred for 30 minutes. The mixture was filtered, the filter cake was washed with acetonitrile (2 mL), and dried under reduced pressure to give the title compound as a gray solid (877 mg, 100%).

[0893] Step 3: Preparation of 3-((3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0894]

[0895] 220 mg (0.416 mmol) of tert-butyl(3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in methanol (2 mL). 1,4-dioxane (2 mL) in 4M HCl was added with stirring at room temperature. The mixture was stirred for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (2 mL). DIPEA (269 mg, 2.08 mmol) and acrylonitrile (66 mg, 1.25 mmol) were added sequentially. The resulting reaction mixture was stirred for another 1 hour at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a white solid (17.4 mg, 9%).

[0896] 1 H NMR (400 MHz, CD3OD) δ 7.94 (d, J = 8.8 Hz, 1H), 7.74-7.37 (m, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 6.59 (s, 0.8H), 5.92 (s, 0.2H), 4.51-4.12 (m, 1H), 3.42-3.35 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 2.09-1.61 (m, 8H).

[0897] MS m / z (ESI): 481.1 [M+H] + .

[0898] Example 82

[0899] 3-((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0900]

[0901] Step 1: Preparation of 2,7-dichloro-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-4-amine

[0902]

[0903] 2,4,7-trichloroquinazoline (2.0 g, 8.58 mmol), 5-methyl-1H-pyrazole-3-amine (915 mg, 9.42 mmol), and TEA (1.82 g, 18.0 mmol) were added separately to anhydrous ethanol (40 mL) and stirred at room temperature for 16 hours. The reaction solution was filtered, the filter cake was washed with anhydrous ethanol (5 mL), and dried under vacuum to give the title compound as a white solid (2.5 g, 99%).

[0904] MS m / z (ESI): 294.0 [M+H] + .

[0905] Step 2: Preparation of tert-butyl(3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0906]

[0907] Compound 2,7-dichloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (500 mg, 1.70 mmol), tert-butyl(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate acetate (535 mg, 1.87 mmol), and DIPEA (681 mg, 5.27 mmol) were mixed in NMP (7 mL), and the mixture was microwaved to 180°C. oThe reaction mixture was stirred at C for 2 hours. After cooling the reaction solution to room temperature, it was added to ice water and stirred. The precipitated solid was filtered. The filter cake was washed with water, dried under vacuum, and then purified by silica gel column chromatography to obtain the title compound as a white solid (405 mg, 49%).

[0908] MS m / z (ESI): 484.2 [M+H] + .

[0909] Step 3: Preparation of 3-((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0910]

[0911] 405 mg (0.837 mmol) of tert-butyl(3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in methanol (4 mL). 1,4-dioxane (2.5 mL) in 4 M HCl was added with stirring at room temperature. The mixture was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (4 mL). DIPEA (486 mg, 3.77 mmol) and acrylonitrile (53 mg, 1.00 mmol) were added sequentially. The resulting reaction mixture was stirred for another 16 hours at room temperature. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was initially purified by silica gel column chromatography and then further purified by prep-HPLC to obtain the title compound as a white solid (40 mg, 11%).

[0912] 1 H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J = 8.8 Hz, 1H), 7.54-7.22 (m, 1H), 7.14-7.07 (m, 1H), 6.71-6.49 (m, 0.6H), 6.05-5.76 (m, 0.4H), 4.44-4.17 (m, 1H), 3.40-3.35 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.46-2.12 (m, 3H), 2.07-2.00 (m, 2H), 1.96-1.75 (m, 4H), 1.71-1.61 (m, 2H).

[0913] MS m / z (ESI): 437.2 [M+H] + .

[0914] Example 83

[0915] 3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0916]

[0917] The preparation of 3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 82.

[0918] MS m / z (ESI): 421.2 [M+H] + .

[0919] Example 84

[0920] 3-((3-exo)-3-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0921]

[0922] The preparation of 3-((3-exo)-3-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[0923] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.62 (s, 1H), 7.45 (t, J = 8.0Hz, 1H), 7.33-6.92 (m, 3H), 6.92-6.55 (m, 1H), 4.32-4.15 (m, 1H), 3.33-3.25 (m, 2H), 2.68-2.56 (m, 4H), 2.26 (s, 3H), 2.00-1.85 (m, 2H), 1.83-1.54 (m, 6H).

[0924] MS m / z (ESI): 437.2 [M+H] + .

[0925] Example 85

[0926] 3-((3-exo)-3-((8-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0927]

[0928] The preparation of 3-((3-exo)-3-((8-methyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[0929] 1 H NMR (400 MHz, Methanol-d4) δ 7.86 (d, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.70-6.54 (m, 0.6H), 5.96-5.84 (m, 0.4H), 4.49-4.32 (m, 1H), 3.46-3.36 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.48 (s, 3H), 2.38-2.17 (m, 3H), 2.10-1.89 (m, 4H), 1.88-1.77 (m, 2H), 1.64 (t, J = 12.0 Hz, 2H).

[0930] MS m / z (ESI): 417.2 [M+H] + .

[0931] Example 86

[0932] 3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0933]

[0934] The preparation of 3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[0935] 1H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.83-5.77 (m, 1H), 4.52-4.26 (m, 1H), 3.57-3.36 (m, 2H), 2.94-2.71 (m, 2H), 2.71-2.53 (m, 2H), 2.32 (s, 3H), 2.19-1.49 (m, 8H).

[0936] MS m / z (ESI): 437.2 [M+H] + .

[0937] Example 87

[0938] 3-((3-exo)-3-((6-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0939]

[0940] The preparation of 3-((3-exo)-3-((6-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[0941] 1 H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 7.49-7.21 (m, 1H), 6.72-6.46 (m, 0.6H), 6.08-5.75 (m, 0.4H), 4.46-4.20 (m, 1H), 3.41-3.36 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.42-2.22 (m, 3H), 2.08-2.01 (m, 2H), 1.97-1.77 (m, 4H), 1.72-1.61 (m, 2H).

[0942] MS m / z (ESI): 437.2 [M+H] + .

[0943] Example 88

[0944] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0945]

[0946] Step 1: Preparation of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0947]

[0948] Tert-butyl(3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (400 mg, 0.758 mmol), 3-pyridineboronic acid (187 mg, 1.52 mmol), Pd(dppf)Cl2 (110 mg, 0.152 mmol), and cesium carbonate (740 g, 2.27 mmol) were added to a mixed solvent of dioxane (8 mL) and water (0.8 mL), respectively. The mixture was heated to 100 °C and stirred for 1 hour under nitrogen protection. After the reaction solution was concentrated, the residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow gel (160 mg, 40%).

[0949] Step 2: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0950]

[0951] 160 mg (0.302 mmol) of tert-butyl(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in methanol (4 mL). 4 M HCl (4 mL) was added under stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was redissolved in anhydrous methanol (2 mL). DIPEA (195 mg, 1.51 mmol) and acrylonitrile (48 mg, 0.906 mmol) were added in sequence. The resulting reaction mixture was stirred at room temperature for another 2 hours. After the reaction, the mixture was concentrated under reduced pressure. The residue was initially separated and purified by silica gel column chromatography to obtain a gray solid. The gray solid was slurried with N,N-dimethylformamide / acetonitrile (2 mL / 4 mL). The filtered solid was then slurried with N,N-dimethylformamide / acetonitrile (1.1 mL / 2.2 mL). The filtered solid was dried under vacuum to obtain the title compound as a white solid (49 mg, 34%).

[0952] 1 H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 2.3 Hz, 1H), 8.59 (dd, J = 4.9, 1.6Hz, 1H), 8.31-8.08 (m, 2H), 7.84-7.40 (m, 3H), 6.63 (s, 0.8H), 5.94 (s, 0.2H), 4.49-4.26 (m, 1H), 3.45-3.37 (m, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.34 (s, 3H), 2.13-1.63 (m, 8H).

[0953] MS m / z (ESI): 480.2 [M+H] + .

[0954] Example 89

[0955] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0956]

[0957] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 88.

[0958] 1 H NMR (400 MHz, CD3OD) δ 8.73-8.58 (m, 2H), 8.21 (d, J = 8.5 Hz, 1H), 7.95-7.64 (m, 3H), 7.59-7.49 (m, 1H), 6.64 (s, 1H), 4.49-4.22 (m, 1H), 3.45-3.35 (m, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.33 (s, 3H), 2.16-1.58 (m, 8H).

[0959] MS m / z (ESI): 480.2 [M+H] + .

[0960] Example 90

[0961] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-2-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0962]

[0963] The preparation of 3-((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 88.

[0964] MS m / z (ESI): 480.3 [M+H] + .

[0965] Example 91

[0966] 3-((3-exo)-3-((7-(5-methoxypyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0967]

[0968] The preparation of 3-((3-exo)-3-((7-(5-methoxypyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 88.

[0969] 1 H NMR (400 MHz, CD3OD) δ 8.54-8.41 (m, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.88-7.56 (m, 2H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H), 6.62 (s, 1H), 4.49-4.25 (m, 1H), 3.97 (s, 3H), 3.44-3.37 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 2.10-1.64 (m, 8H).

[0970] MS m / z (ESI): 510.2 [M+H] + .

[0971] Example 92

[0972] 3-((3-exo)-3-((7-(6-methoxypyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0973]

[0974] The preparation of 3-((3-exo)-3-((7-(6-methoxypyridin-3-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 88.

[0975] MS m / z (ESI): 510.3 [M+H] + .

[0976] Example 93

[0977] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-phenylquinazoline-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0978]

[0979] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-phenylquinazoline-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 88.

[0980] 1 ¹H NMR (400 MHz, DMSO-d6, trace CD₃OD) δ 8.47–8.23 (m, 1H), 7.88–7.69 (m, 2H), 7.67–7.25 (m, 5H), 6.92–6.62 (m, 0.8H), 5.88 (s, 0.2H), 4.41–4.20 (m, 1H), 3.58 (s, 2H), 2.76–2.57 (m, 4H), 2.38–2.11 (m, 3H), 2.06–1.47 (m, 8H).

[0981] MS m / z (ESI): 479.3 [M+H] + .

[0982] Example 94

[0983] 3-((3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0984]

[0985] Step 1: Preparation of tert-butyl(3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[0986]

[0987] tert-butyl(3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (100 mg, 0.189 mmol), (1-cyclopropyl-1H-pyrazol-4-yl)boronic acid (35 mg, 0.227 mmol), cesium carbonate (185 mg, 0.567 mmol), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (X-Phos Pd G2) (15 mg, 0.0189 mmol) were added to dioxane (2 mL) and water (0.4 mL), respectively. In a mixed solvent (mL), the mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 2 hours. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a brown oil (60 mg, 57%).

[0988] Step 2: Preparation of 3-((3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0989]

[0990] 60 mg of tert-butyl(3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (2 mL) was dissolved in methanol. 1,4-dioxane (2 mL) of 4M HCl was added with stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was redissolved in anhydrous methanol (1 mL). DIPEA (70 mg, 0.542 mmol) and acrylonitrile (17 mg, 0.324 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for another 16 hours. The reaction solution was diluted with DCM (30 mL), washed with water (10 mL), concentrated under reduced pressure, and the residue was preliminarily separated and purified by silica gel chromatography to obtain the title compound as a gray solid (20 mg, 36%).

[0991] 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.72-7.34 (m, 2H), 6.60 (s, 1H), 4.45-4.23 (m, 1H), 3.78-3.67 (m, 1H), 3.43-3.36 (m, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.09-1.64 (m, 8H), 1.24-1.00 (m, 4H).

[0992] MS m / z (ESI): 509.2 [M+H] + .

[0993] Example 95

[0994] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[0995]

[0996] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 94.

[0997] 1 H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.64-7.43 (m, 1H), 7.38 (dd, J = 8.6, 1.7 Hz, 1H), 6.62 (s, 0.8H), 5.92 (s, 0.2H), 4.42-4.28 (m, 1H), 3.95 (s, 3H), 3.42-3.36 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 2.08-2.01 (m, 2H), 2.00-1.80 (m, 4H), 1.77-1.62 (m, 2H).

[0998] MS m / z (ESI): 483.2 [M+H] + .

[0999] Example 96

[1000] 3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1001]

[1002] The preparation of 3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 94.

[1003] MS m / z (ESI): 515.3 [M+H] + .

[1004] Example 97

[1005] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazolyl-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1006]

[1007] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazo-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 94.

[1008] MS m / z (ESI): 486.2 [M+H] + .

[1009] Example 98

[1010] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1011]

[1012] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 88.

[1013] MS m / z (ESI): 494.3 [M+H] + .

[1014] Example 99

[1015] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1016]

[1017] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 88.

[1018] MS m / z (ESI): 497.3 [M+H] + .

[1019] Example 100

[1020] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1021]

[1022] Step 1: Preparation of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[1023]

[1024] tert-butyl(3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (300 mg, 0.568 mmol), morpholine (494 mg, 5.68 mmol), Pd2(dba)3 (104 mg, 0.114 mmol), DavePhos (90 mg, 0.227 mmol), and t-BuONa (109 mg, 1.14 mmol) were added to dioxane (6 mL), and the mixture was heated to 100 °C and stirred for 4 hours under nitrogen protection. After cooling the reaction solution to room temperature, ethyl acetate (20 mL) was added for dilution. The solution was washed with water (20 mL) and saturated sodium chloride aqueous solution (10 mL), respectively. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound as a pale yellow oil (66 mg, 22%).

[1025] Step 2: Preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1026]

[1027] Tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (66 mg, 0.123 mmol) was dissolved in methanol (2 mL). 1,4-dioxane (2 mL) in 4M HCl was added with stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (1 mL). DIPEA (80 mg, 0.617 mmol) and acrylonitrile (20 mg, 0.369 mmol) were added sequentially. The resulting reaction mixture was stirred for another 2 hours at room temperature. After concentration under reduced pressure, the residue was initially purified by silica gel chromatography, and then further purified by preparative TLC to obtain the title compound as a gray solid (12 mg, 20%).

[1028] 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 9.3 Hz, 1H), 7.08 (d, J = 9.4 Hz, 1H), 6.68 (s, 1H), 6.49 (s, 1H), 4.46-4.28 (m, 1H), 3.97-3.73 (m, 4H), 3.52-3.36 (m, 6H), 2.73 (t, J = 6.7 Hz, 2H), 2.62 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.11-1.61 (m, 8H).

[1029] MS m / z (ESI): 488.2 [M+H] + .

[1030] Example 101

[1031] 3-((3-exo)-3-((7-(3-methoxyacryl-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1032]

[1033] The preparation of 3-((3-exo)-3-((7-(3-methoxyacryl-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1034] MS m / z (ESI): 488.3 [M+H] + .

[1035] Example 102

[1036] 3-((3-exo)-3-((7-(4-methoxypiperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1037]

[1038] The preparation of 3-((3-exo)-3-((7-(4-methoxypiperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1039] MS m / z (ESI): 516.3 [M+H] + .

[1040] Example 103

[1041] 3-((3-exo)-3-((7-(4-(dimethylamino)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1042]

[1043] The preparation of 3-((3-exo)-3-((7-(4-(dimethylamino)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1044] MS m / z (ESI): 529.3 [M+H] + .

[1045] Example 104

[1046] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidone-1-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1047]

[1048] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidine-1-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1049] MS m / z (ESI): 472.3 [M+H] + .

[1050] Example 105

[1051] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(methylamino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1052]

[1053] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(methylamino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1054] MS m / z (ESI): 432.3 [M+H] + .

[1055] Example 106

[1056] 3-((3-exo)-3-((7-(methyl(oxobutylcyclo-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1057]

[1058] The preparation of 3-((3-exo)-3-((7-(methyl(oxobutylcyclo-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1059] MS m / z (ESI): 502.3 [M+H] + .

[1060] Example 107

[1061] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylacetidin-3-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1062]

[1063] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylacetidin-3-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 100.

[1064] MS m / z (ESI): 501.3 [M+H] + .

[1065] Example 108

[1066] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1067]

[1068] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(((tetrahydro-2H-pyran-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1069] MS m / z (ESI): 516.3 [M+H] + .

[1070] Example 109

[1071] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylpiperidin-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1072]

[1073] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylpiperidin-4-yl)methyl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1074] MS m / z (ESI): 529.3 [M+H] + .

[1075] Example 110

[1076] 3-((3-exo)-3-((7-(methyl(pyridin-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1077]

[1078] The preparation of 3-((3-exo)-3-((7-(methyl(pyridin-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1079] MS m / z (ESI): 523.3 [M+H] + .

[1080] Example 111

[1081] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1082]

[1083] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-morpholinoquinazolino-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out in accordance with Example 100.

[1084] MS m / z (ESI): 502.3 [M+H] + .

[1085] Example 112

[1086] 3-((3-exo)-3-((7-(1H-imidazol-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1087]

[1088] The preparation of 3-((3-exo)-3-((7-(1H-imidazol-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 100.

[1089] 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.64-7.26 (m, 2H), 7.19 (s, 1H), 6.62 (s, 0.8H), 5.93 (s, 0.2H), 4.47-4.22 (m, 1H), 3.41-3.36 (m, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.08-2.01 (m, 2H), 2.00-1.79 (m, 4H), 1.74-1.63 (m, 2H).

[1090] MS m / z (ESI): 469.2 [M+H] + .

[1091] Example 113

[1092] 3-((3-exo)-3-((7-(2-methoxyethoxy)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1093]

[1094] The preparation of 3-((3-exo)-3-((7-(2-methoxyethoxy)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[1095] MS m / z (ESI): 477.3 [M+H] + .

[1096] Example 114

[1097] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxobutylcyclo-3-ylmethoxy)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1098]

[1099] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxobutylcyclo-3-ylmethoxy)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 80.

[1100] MS m / z (ESI): 503.3 [M+H] + .

[1101] Example 115

[1102] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylacetidin-3-yl)methoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1103]

[1104] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylacetidin-3-yl)methoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[1105] MS m / z (ESI): 502.3 [M+H] + .

[1106] Example 116

[1107] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1108]

[1109] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[1110] MS m / z (ESI): 510.3 [M+H] + .

[1111] Example 117

[1112] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylacetidin-3-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1113]

[1114] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylacetidin-3-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[1115] MS m / z (ESI): 488.3 [M+H] + .

[1116] Example 118

[1117] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylpiperidin-4-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1118]

[1119] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-((1-methylpiperidin-4-yl)oxo)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out according to Example 80.

[1120] MS m / z (ESI): 516.3 [M+H] + .

[1121] Example 119

[1122] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1123]

[1124] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 80.

[1125] MS m / z (ESI): 516.3 [M+H] + .

[1126] Example 120

[1127] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methylacetidin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1128]

[1129] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methylacetidin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 80.

[1130] MS m / z (ESI): 486.3 [M+H] + .

[1131] Example 121

[1132] 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxobutyl-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1133]

[1134] The preparation of 3-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)-7-(oxobutane-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile was carried out according to Example 80.

[1135] MS m / z (ESI): 473.3 [M+H] + .

[1136] Example 122

[1137] 1-(((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1138]

[1139] 100 mg (0.222 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 10 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (0.73 mL, 4.44 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (44 mg, 0.244 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (59.3 mg, 54%).

[1140] 1 H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.50 (s, 1H), 7.29 (d, J = 44.1 Hz, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.36 (s, 1H), 4.12 (s, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.90 (t, J = 7.0 Hz, 2H), 3.69-3.57 (m, 1H), 2.20 (s, 3H), 2.10- 1.51 (m, 8H).

[1141] MS m / z (ESI): 494.2 [M+H] + .

[1142] Example 123

[1143] 1-(((3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1144]

[1145] 174 mg (0.36 mmol) of tert-butyl(3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 20 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (1.19 mL, 7.2 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (78 mg, 0.432 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (17.7 mg, 9%).

[1146] 1 H NMR (400 MHz, MeOD-d4) δ 8.02 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.57 (s, 1H), 4.51-4.40 (m, 1H), 4.27 (s, 2H), 4.17 (t, J = 8.5 Hz, 2H), 4.13-4.05 (m, 2H), 3.64-3.53 (m, 1H), 2.34 (s, 3H), 2.16 (s, 4H), 1.98 (d, J = 42.2 Hz, 2H), 1.76 (t, J =11.9 Hz, 2H).

[1147] MS m / z (ESI): 528.2 [M+H] + .

[1148] Example 124

[1149] 1-(((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1150]

[1151] The preparation of 1-(((3-exo)-3-((7-fluoro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile was carried out in accordance with Example 122.

[1152] 1 H NMR (400 MHz, CD3OD) δ 8.11 (dd, J = 9.1, 6.1 Hz, 1H), 7.21-6.82 (m, 2H), 6.56 (s, 0.8H), 5.88 (s, 0.2H), 4.58-4.34 (m, 1H), 4.29-4.19 (m, 2H), 4.17-4.08 (m, 2H), 4.06-3.96 (m, 2H), 3.72-3.58 (m, 1H), 2.31 (s, 3H), 2.18-1.85 (m, 6H), 1.82-1.66 (m, 2H).

[1153] MS m / z (ESI): 512.1 [M+H] + .

[1154] Example 125

[1155] 1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1156]

[1157] The preparation of 1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile was carried out in accordance with Example 122.

[1158] 1 H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.26-6.93 (m, 2H), 6.50 (s, 1H), 4.58-4.37 (m, 1H), 4.31-4.18 (m, 2H), 4.18-4.07 (m, 2H), 4.06-3.95 (m, 2H), 3.71-3.58 (m, 1H), 2.32 (s, 3H), 2.17-1.71 (m, 8H), 1.34-1.25 (m, 1H), 1.19-1.03 (m, 2H), 0.94-0.75 (m, 2H).

[1159] MS m / z (ESI): 534.1 [M+H] + .

[1160] Example 126

[1161] 3-((3-exo)-3-(((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azabicyclobutane-3-nitrile

[1162]

[1163] Step 1: Preparation of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[1164]

[1165] To a solution of 2-chloro-N-(5-methyl-1-hydropyrazole-3-yl)quinazolin-4-amine (200 mg, 0.77 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (222 mg, 0.92 mmol) and DIPEA (199 mg, 1.54 mmol) were added sequentially, followed by stirring at 170 °C under microwave conditions for 4 hours. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 mL x 3), washed with saturated sodium chloride aqueous solution (15 mL x 3), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a white solid (275 mg, 77%).

[1166] MS m / z (ESI): 464.2 [M+H] + .

[1167] Step 3: Preparation of 3-((3-exo)-3-(((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)azacyclobutane-3-nitrile

[1168]

[1169] 100 mg (0.21 mmol) of tert-butyl-(3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester was dissolved in 1,4-epoxyhexane hydrochloride solution (4.0 N, 5 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated. Then, it was dissolved in N,N-dimethylformamide (10 mL), and DIPEA (108 mg, 0.84 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and then 3-acrylazine-1-sulfonyl chloride (45 mg, 0.25 mmol) was added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the product was subjected to prep-HPLC to obtain the title compound as a white solid (30.5 mg, 29%).

[1170] 1 H NMR (400 MHz, DMSO) δ = 12.09 (s, 1H), 10.04 (s, 1H), 8.24 (s, 1H), 7.45 (s, 1H), 7.33-6.42 (m, 4H), 4.79 (s, 1H), 4.01-3.79 (m, 6H), 3.74-3.67 (m, 1H), 2.15 (s, 3H), 2.09-1.57 (m, 10H).

[1171] MS m / z (ESI): 508.2 [M+H] + .

[1172] Example 127

[1173] 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1174]

[1175] Step 1 reaction: Preparation of 2-chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazoline-4-amine

[1176]

[1177] 2,4-Dichloro-7-methoxyquinazoline (497 mg, 2.17 mmol), 5-methyl-1H-pyrazole-3-amine (221 mg, 2.28 mmol), and DIPEA (0.75 mL, 4.56 mmol) were added to anhydrous ethanol (10 mL), stirred at room temperature for 24 hours, and then heated to 50°C. o The reaction was carried out at C for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was washed with a mixed solvent of ethanol-water (v / v = 1:9, 20 mL). The filter residue was dried under reduced pressure to give the title compound (509 mg, 81%).

[1178] MS m / z (ESI): 290.0 [M+H] + .

[1179] Second step reaction: Preparation of tert-butyl(3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[1180]

[1181] 2-Chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (150 mg, 0.518 mmol), tert-butyl(3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (249 mg, 1.036 mmol), and DIPEA (0.43 mL, 2.59 mmol) were added to n-butanol (3 mL), and the mixture was heated to 170 °C using a microwave synthesizer. o The reaction was carried out at C for 6 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase column chromatography to give the title compound (193 mg, 75%).

[1182] MS m / z (ESI): 494.2 [M+H] + .

[1183] Third step reaction: Preparation of 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)sulfonyl)acetidine-3-carboxylonitrile

[1184]

[1185] 193 mg (0.39 mmol) of tert-butyl(3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 20 mL of 1,4-epoxyhexane in 4 M HCl. The mixture was stirred at room temperature for 60 minutes. The solvent was removed by concentration under reduced pressure. The remaining solid was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (1.93 mL, 11.7 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (71 mg, 0.39 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (97 mg, 46%).

[1186] 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.77 (s, 1H), 8.23 ​​(d, J = 8.9Hz, 1H), 6.72 (s, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 5.40-5.25 (m, 1H), 4.18 (s, 2H), 4.06 (t, J = 8.6 Hz, 2H), 4.01- 3.92 (m, 2H), 3.87-3.74 (m, 4H), 2.96 (s, 3H), 2.23 (s, 3H), 2.06-1.89 (m, 4H), 1.83 (d, J = 5.8 Hz, 2H), 1.61 (d, J = 11.2 Hz, 2H).

[1187] MS m / z (ESI): 538.2 [M+H] + .

[1188] Example 128

[1189] 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile

[1190]

[1191] Step 1 reaction: tert-butyl(3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester

[1192]

[1193] 2-Chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (50 mg, 0.173 mmol) and tert-butyl(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylic acid oxalate (171 mg, 0.518 mmol) were added to n-butanol (10 mL) and heated to 170 °C using a microwave synthesizer. o The reaction was carried out at C for 8 hours, the solvent was removed by concentration under reduced pressure, and the residue was separated by silica gel column chromatography to obtain the title compound (68 mg, 80%).

[1194] MS m / z (ESI): 494.2 [M+H] + .

[1195] Second step reaction: 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)sulfonyl)acetidine-3-carboxynitrile

[1196]

[1197] Tert-butyl(3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (68 mg, 0.138 mmol) was dissolved in 1,4-epoxyhexane (15 mL) in 4 M HCl and stirred at room temperature for 60 minutes. The solvent was removed by concentration under reduced pressure, and the remaining solid was dissolved in anhydrous N,N-dimethylformamide (10 mL) and cooled to 0 °C. o At C, DIPEA (0.68 mL, 4.14 mmol) and 3-cyanoacetidine-1-sulfonyl chloride (25 mg, 0.138 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (6.9 mg, 9%).

[1198] 1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.83 (s, 1H), 8.24 (d, J = 7.3Hz, 1H), 6.65 (dd, J = 29.7, 20.4 Hz, 4H), 4.83 (s, 1H), 4.02 (t, J = 8.5 Hz, 2H), 3.92 (dd, J = 14.9, 8.4 Hz, 4H), 3.87-3.73 (m, 4H), 2.21 (s, 3H), 2.04 (d, J = 4.3 Hz, 3H), 1.92-1.68 (m, 7H).

[1199] MS m / z (ESI): 538.2 [M+H] + .

[1200] Example 129

[1201] 1-((1R,3s,5S)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)-2-(dimethylamino)ethane-1-one

[1202]

[1203] tert-Butyl(3-exo)-3-((7-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dispersed in dichloromethane (2 mL), and a 1,4-epoxyhexane solution of 4 M HCl (20 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed by vacuum concentration, and the residue was dried under reduced pressure for 10 minutes on an oil pump. The obtained crude product was dissolved in anhydrous N,N-dimethylformamide (8 mL) and cooled to 0°C in an ice-water bath. o At C, under stirring, DIPEA (1.2 mL, 7.1 mmol), dimethylglycine (0.31 mL, 4.72 mmol), and HATU (118 mg, 0.31 mmol) were added sequentially. The resulting reaction mixture was then stirred at 0°C. o The reaction was stirred at C for 60 minutes. The solvent was removed by concentration under reduced pressure, and the crude product was separated by prep-HPLC to give the title compound as a white solid (20.7 mg, 21%).

[1204] 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.33 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.13-6.86 (m, 2H), 6.60 (s, 1H), 4.52 (s, 1H), 4.42 (d, J = 3.4 Hz, 2H), 3.16 (s, 2H), 2.38-2.12 (m, 9H), 2.05-1.94 (m, 2H), 1.93-1.73 (m, 4H), 1.63-1.46 (m, 2H).

[1205] MS m / z (ESI): 469.1 [M+H] + .

[1206] Example 130

[1207] 2-(dimethylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[1208]

[1209] The preparation of 2-(dimethylamino)-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one was carried out in accordance with Example 129.

[1210] 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.13 (s, 1H), 8.33 (s, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 30.8 Hz, 1H), 7.08 (s, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 4.56 (d, J = 6.1 Hz, 1H), 4.48 (s, 1H), 4.32 (d, J = 5.3 Hz, 1H), 3.65 (dd, J = 32.9, 14.8 Hz, 2H), 2.53 (s, 6H), 2.25 (s, 3H), 1.94 (ddd, J = 36.8, 20.0, 10.6 Hz, 6H), 1.56 (dd, J = 19.2, 9.5 Hz, 2H).

[1211] MS m / z (ESI): 435.2 [M+H]+ .

[1212] Example 131

[1213] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-2-yl)methyl ketone

[1214]

[1215] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-2-yl)methyl ketone was carried out in accordance with Example 129.

[1216] 1 H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.80 (s, 1H), 10.33 (s, 1H), 8.61 (d, J = 4.3 Hz, 1H), 8.52-8.24 (m, 1H), 7.96 (td, J = 7.8, 1.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.71-7.57 (m, 1H), 7.52 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.39 (d, J = 18.4Hz, 1H), 7.21 (d, J = 39.2 Hz, 1H), 6.60 (s,1H),4.74 (s, 1H), 4.69-4.44 (m, 2H), 2.27 (s, 3H), 2.12-1.69 (m, 8H).

[1217] MS m / z (ESI): 455.2 [M+H] + .

[1218] Example 132

[1219] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-3-yl)methyl ketone

[1220]

[1221] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-3-yl)methyl ketone was carried out in accordance with Example 129.

[1222] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.36 (s, 1H), 10.05 (s, 1H), 8.78-8.62 (m, 2H), 8.34 (d, J = 29.6 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.62-7.48 (m, 2H), 7.31 (dd, J = 19.3, 8.1 Hz, 1H), 7.12 (s, 1H), 6.60 (s, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 3.1 Hz, 1H), 2.25 (s, 3H), 2.16-1.48 (m, 8H).

[1223] MS m / z (ESI): 455.2 [M+H] + .

[1224] Example 133

[1225] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-4-yl)methyl ketone

[1226]

[1227] The preparation of ((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)(pyridin-4-yl)methyl ketone was carried out in accordance with Example 129.

[1228] 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.21 (s, 1H), 8.70 (d, J = 5.5Hz, 2H), 8.32 (dd, J = 28.3, 8.1 Hz, 1H), 7.59-7.51 (m, 1H), 7.45 (d, J = 1.8 Hz, 2H), 7.36-7.22 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.67 (d, J =4.9 Hz, 1H), 4.61-4.44 (m, 1H), 3.94 (d, J = 1.9 Hz, 1H), 2.24 (s, 3H), 2.09-1.53 ​​(m, 8H).

[1229] MS m / z (ESI): 455.2 [M+H] + .

[1230] Example 134

[1231] 2,2-Difluoro-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)ethane-1-one

[1232]

[1233] 100 mg (0.222 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 10 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o C. Add DIPEA (0.73 mL, 4.44 mmol), mix well, then add a mixture of difluoroacetic acid (0.023 mL, 0.233 mmol) and HATU (169 mg, 4.44 mmol) (pre-dissolved in 1 mL of dry N,N-dimethylformamide and reacted for 10 minutes). Continue the reaction mixture at 0°C. o The reaction was stirred at C for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (48.9 mg, 52%).

[1234] 1H NMR (400 MHz, MeOD-d4) δ 7.99 (d, J = 7.7 Hz, 1H), 7.56-7.44 (m, 1H), 7.40-7.19 (m, 1H), 7.13-7.03 (m, 1H), 6.55 (d, J = 4.7 Hz, 1H), 6.33 (t, J = 53.6 Hz, 1H), 4.57 (s, 2H), 4.46-4.40 (m, 1H), 2.18 (d, J = 33.6 Hz, 3H), 2.09-1.75 (m, 6H), 1.56 (t, J = 12.1 Hz, 2H).

[1235] MS m / z (ESI): 428.1 [M+H] + .

[1236] Example 135

[1237] N4-(5-methyl-1H-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-3-ylsulfonyl)-8-azabicyclo[3.2.1]octane-3-yl)quinazolin-2,4-diamine

[1238]

[1239] 100 mg (0.222 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 10 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (0.73 mL, 4.44 mmol) and 3-pyridinesulfonyl chloride hydrochloride (50 mg, 0.233 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (20.5 mg, 19%).

[1240] 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 4.8, 1.4Hz, 1H), 8.27-8.19 (m, 1H), 8.14-8.01 (m, 1H), 7.60-7.44 (m, 2H), 7.29 (ddd, J = 15.0, 9.9, 4.2 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.58-6.39 (m, 1H), 4.30 (dd, J = 6.0, 2.6Hz, 3H), 2.17 (s, 3H), 2.08-1.95 (m, 2H), 1.74 (dd, J = 16.7, 6.2 Hz, 2H), 1.64 (dd, J =17.3, 6.7 Hz, 2H), 1.43-1.32 (m, 2H).

[1241] MS m / z (ESI): 491.1 [M+H] + .

[1242] Example 136

[1243] N2-((3-exo)-8-((2-methoxyethyl)sulfonyl)-8-azabicyclo[3.2.1]octane-3-yl)-N4-(5-methyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine

[1244]

[1245] 100 mg (0.222 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 10 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in 10 mL of anhydrous N,N-dimethylformamide and cooled to 0 °C. o At C, DIPEA (0.73 mL, 4.44 mmol) and 2-methoxyethane-1-sulfonyl chloride (37 mg, 0.233 mmol) were added sequentially, and the reaction mixture was continued at 0°C. o The reaction was stirred at C for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (25.1 mg, 43%).

[1246] 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.24 (dd, J = 23.8, 8.5 Hz, 1H), 6.61 (s, 1H), 4.49-4.43 (m, 1H), 4.26 (s, 2H), 3.76 (t, J =6.2 Hz, 2H), 3.43-3.29 (m, 5H), 2.32 (s, 3H), 2.11-1.86 (m, 6H), 1.74 (t, J = 13.5 Hz, 2H).

[1247] MS m / z (ESI): 472.2 [M+H] + .

[1248] Example 137

[1249] N2-((3-exo)-8-(2-fluoroethyl)-8-azabicyclo[3.2.1]octane-3-yl)-N4-(5-methyl-1H-pyrazol-3-yl)quinazolin-2,4-diamine

[1250]

[1251] 100 mg (0.222 mmol) of tert-butyl(3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester was dissolved in 10 mL of 4 M HCl solution of 1,4-epoxyhexane and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in anhydrous N,N-dimethylformamide (5 mL). Anhydrous potassium carbonate (184 mg, 1.33 mmol) and 1-bromo-2-fluoroethane (50 mg, 0.233 mmol) were added sequentially. The reaction mixture was then heated at 40 °C. o The reaction was stirred at C for 19 hours. The solvent was removed by concentration under reduced pressure, and the residue was separated by reversed-phase HPLC to obtain the title compound (27.3 mg, 31%).

[1252] 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 17.8 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 44.5 Hz, 1H), 7.11 (s, 1H), 6.71 (s, 1H), 4.64-4.45 (m, 2H), 4.33-4.19 (m, 1H), 3.35 (s, 2H), 2.91-2.68 (m, 2H), 2.32 (s, 3H), 2.11-1.56 (m, 8H).

[1253] MS m / z (ESI): 396.2 [M+H] + .

[1254] Example 138

[1255] 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1256]

[1257] Step 1: Preparation of (3-((2,7-dichloroquinazoline-4-yl)amino)-1H-pyrazole-5-yl)methanol

[1258]

[1259] 2,4,7-Trichloroquinazoline (300 mg, 1.29 mmol), (3-amino-1H-pyrazole-5-yl)methanol (180 mg, 1.55 mmol), and DIPEA (500 mg, 3.87 mmol) were added to 1,4-dioxane (5 mL), mixed thoroughly, and reacted overnight at room temperature. The mixture was concentrated under reduced pressure, and methanol (5 mL) was added to the crude product. The mixture was filtered, and the solid was dried to give the title compound as a white solid (350 mg, 87%).

[1260] MS m / z (ESI): 310.0 [M+H] + .

[1261] Step 2: Preparation of tert-butyl(3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester

[1262]

[1263] (3-((2,7-dichloroquinazoline-4-yl)amino)-1H-pyrazol-5-yl)methanol (150 mg, 0.49 mmol), tert-butyl(3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylic acid ester (150 mg, 0.58 mmol), and DIPEA (190 mg, 1.47 mmol) were added to n-butanol (2 mL), mixed well, and then microwaved at 150 °C. o The reaction was carried out at C for 10 hours, cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by rapid silica gel column chromatography to obtain the target product as a white solid (140 mg, 55%).

[1264] MS m / z (ESI): 528.2 [M+H] + .

[1265] Step 3: Preparation of 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)propionitrile

[1266]

[1267] To a methanol (10 mL) solution of tert-butyl(3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ester (140 mg, 0.27 mmol), dioxane hydrochloride (4N, 2 mL) was slowly added dropwise. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in methanol (15 mL). DIPEA (0.5 mL) and acrylonitrile (25 mg, 0.46 mmol) were added separately at room temperature, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the title compound was purified by prep-HPLC to obtain a white solid (22 mg, 20%).

[1268] 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.02 (s, 1H), 8.35 (d, J = 8.4Hz, 1H), 7.28 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H), 5.25 (s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 3.31-2.87 (m, 7H), 2.66-2.59 (m, 2H), 2.08-1.87 (m, 5 H), 1.60-1.41 (m, 5H).

[1269] MS m / z (ESI): 481.2 [M+H] + .

[1270] Example 139

[1271] 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1272]

[1273] The preparation of 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile was carried out in accordance with Example 138.

[1274] H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.08 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.62-6.54 (m, 1H), 5.27-5.11 (m, 2H), 4.50 (d, J = 5.6 Hz, 2H), 3.31-2.27 (m, 2H), 2.94 (d, J = 16.0 Hz, 3H), 2.67-2.58 (m, 4H), 1.92-1.81 (m, 4H), 1.71-1.62 (m, 2H), 1.39-1.23 (m, 2H).

[1275] MS m / z (ESI): 467.2 [M+H] + .

[1276] Example 140

[1277] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propionitrile

[1278]

[1279] The preparation of 3-(4-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propionitrile was carried out according to Example 68.

[1280] 1 H NMR (400 MHz, CD3OD: CDCl3, v / v= 1:1) δ 8.03 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.63 (s, 1H), 5.92 (s, 1H), 4.01-3.87 (m, 1H), 2.98 (d, J = 11.6 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.64 (t, J =6.9 Hz, 2H), 2.45-2.22 (m, 5H), 2.19-2.07 (m, 2H), 1.65 (td, J = 14.0, 3.4 Hz, 2H).

[1281] MS m / z (ESI): 377.1 [M+H] + .

[1282] Example 141

[1283] 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile

[1284]

[1285] The preparation of 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)sulfonyl)acetidine-3-carboxynitrile was carried out in accordance with Example 122.

[1286] 1H NMR (400 MHz, CD3OD: CDCl3, v / v= 1:1) δ 8.04 (d, J = 8.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.31 (s, 1H), 4.17 (t, J = 8.3 Hz, 2H), 4.12-4.01 (m, 3H), 3.74 (d, J = 12.7 Hz, 2H), 3.61 (ddd, J =15.1, 8.7, 6.4 Hz, 1H), 3.06 (t, J = 11.3 Hz, 2H), 2.32 (s, 3H), 2.21-2.11 (m, 2H), 1.64 (td, J = 13.6, 3.3 Hz, 2H).

[1287] MS m / z (ESI): 468.1 [M+H] + .

[1288] Example 142

[1289] 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile

[1290]

[1291] The preparation of 3-(endo-6-((4-(((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-3-azabicyclo[3.1.0]hexane-3-yl)propionitrile was carried out according to Example 79.

[1292] MS m / z (ESI): 375.2 [M+H] + .

[1293] II. Biological Testing Evaluation

[1294] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[1295] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on JAK kinase activity

[1296] Experimental objective: The purpose of this test case is to test the inhibitory activity of the compound on JAK kinase activity.

[1297] Experimental instruments: Centrifuge (5702R) purchased from Eppendorf, pipettes purchased from Eppendorf or Rainin, and microplate reader purchased from BioTek, USA, model SynergyH1 full-function microplate reader.

[1298] Experimental Methods: This experiment used fluorescence resonance energy transfer (TR-FRET) to test the inhibitory effect of the compound on JAK kinase activity and determined the half-maximal inhibitory concentration (IC50) of the compound on JAK kinase activity. 50 .

[1299] The specific experimental procedure is as follows:

[1300] The kinase reaction was carried out in white 384-well plates (PerkinElmer). 1-5 μL of different concentrations of the compound diluted with DMSO and ddH2O were added to each well. For positive control wells, 1-5 μL of the corresponding solvent was added. Then, 1-5 μL of 0.1-20 nM JAK kinase solution diluted with kinase buffer (HEPES 50-250 mM, MgCl2 5-20 mM, etc.) was added to each well. For negative control wells, 1-5 μL of kinase buffer was added. 1-5 μL of substrate mixture containing peptide substrate and ATP was added, and the plates were incubated at room temperature for 0.5-5 hours. 10 μL of EDTA and detection solution containing labeled antibody were added, and the plates were incubated at room temperature for 1-24 hours. The fluorescence signal values ​​at approximately 620 nm and 665 nm were measured using a BioTek Synergy H1 microplate reader. The inhibition rate was calculated based on the fluorescence signal values. The IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[1301] Experimental data processing methods:

[1302] The percentage inhibition data for wells treated with the compound was calculated using positive control wells (DMSO control wells) and negative control wells (no kinase added) on a plate: {% inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[1303] Experimental conclusion:

[1304] Based on the above methods, the compounds of the embodiments shown in this invention exhibited the biological activities shown in Table 15 below in the JAK1 / 2 / 3 / TYK2 kinase activity assay.

[1305] Table 15

[1306]

[1307]

[1308]

[1309] As shown in the table above, the compounds in the above examples can significantly inhibit the enzymatic activity of JAK1 / 2 / 3 / TYK2 kinases, and some compounds show strong inhibitory effects on JAK1 / 2 / 3 / TYK2 kinases (NA indicates not detected).

[1310] Test Example 2: Determination of the inhibitory effect of the compound of the present invention on the cellular JAK-STAT signaling pathway.

[1311] Experimental objective:

[1312] The purpose of this test case is to test the activity of the compound in inhibiting the cellular JAK-STAT signaling pathway.

[1313] Experimental apparatus:

[1314] Microplate oscillator (88880024) purchased from Thermo Scientific™

[1315] Centrifuge (5702R) was purchased from Eppendorf.

[1316] The pipette was purchased from Eppendorf.

[1317] The microplate reader was purchased from BioTek Inc. in the United States, model SynergyH1 full-function microplate reader.

[1318] Experimental methods:

[1319] This experiment used the U266 cell line to activate the JAK-STAT signaling pathway via INF-α stimulation. The inhibitory activity of the compound on downstream STAT3 phosphorylation was detected, and the half-maximal inhibitory concentration (IC50) of the compound on the JAK-STAT signaling pathway activity was determined. 50 .

[1320] The specific experimental procedure is as follows:

[1321] 3-12 μL of U266 cells were seeded into each well of a 384-well plate (100-300 cells per well). 2 μL of a serially diluted compound solution was added, and the plate was incubated at 350 rpm for 2 hours at room temperature. After 2 hours, 2 μL of INF-α (final concentration 1000 U / mL) was added, and the plate was incubated at room temperature for 15 minutes. 2-5 μL of (5X) LANCE Ultra Lysis Buffer 2 solution was added, and the plate was incubated at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) solution (final concentration 0.5 nM) and LANCE Ultra U Light-labeled Anti-STAT3 Antibody (PerkinElmer) solution (final concentration 5 nM) were added, and the plate was incubated overnight at room temperature. The fluorescence signal value at 665 nm was measured using a microplate reader. The inhibition rate was calculated from the fluorescence signal value, and the IC50 of the compound was obtained by curve fitting based on the inhibition rate at different concentrations. 50 .

[1322] Experimental data processing methods:

[1323] The percentage inhibition data for the wells treated with the compound were calculated using positive control wells (DMSO control wells) and negative control wells (no cells) on a plate: {%inhibition rate = 100 - [(test compound value - negative control value)] / (positive control value - negative control value) × 100}. The IC50 was calculated using a GraphPad Prism approximation to fit different concentrations and corresponding percentage inhibition rate data to a 4-parameter nonlinear logic formula. 50 value.

[1324] Experimental conclusion:

[1325] Based on the above scheme, the compounds of the embodiments of the present invention showed the following biological activities in the JAK-STAT signaling pathway of U266 cells, as shown in Table 16.

[1326] Table 16

[1327]

[1328]

[1329] As shown in the table above, the compounds in the above examples have a significant inhibitory effect on the JAK-STAT signaling pathway activity of human myeloma cells U266.

[1330] Test 3: Pharmacokinetic assay in Balb / C mice

[1331] 1. Research Objective:

[1332] Using Balb / C mice as test animals, the pharmacokinetic behaviors of Compound Examples 1, 8, 9, 15, 17, 18, 28, 31, 33, 34, 38, 48, 49, 59, 67, 68, 80, 81, 82, 88, 100, 122, and 123 in mice (plasma, colon, and ileum tissues) after oral administration at a dose of 5 mg / kg were studied. By analyzing the drug concentrations in the colon and ileum, as well as the ratios of colon / ileum drug concentration and colon / plasma drug concentration, compounds with excellent PK were screened for further research.

[1333] 2. Test Protocol

[1334] 2.1 Test Drugs:

[1335] Compound Examples 1, 8, 9, 15, 17, 18, 28, 31, 33, 34, 38, 48, 49, 59, 67, 68, 80, 81, 82, 88, 100, 122, and 123 of the present invention were self-made.

[1336] 2.2 Test Animals:

[1337] 12 male Balb / C mice in each group, from Shanghai Jiesijie Laboratory Animal Co., Ltd., with the animal production license number (SCXK (Shanghai) 2013 - 0006 N0.311620400001794).

[1338] 2.3 Drug Administration:

[1339] 12 male Balb / C mice in each group; after fasting overnight, they were given drugs p.o. at a dose of 5 mg / kg and a dosing volume of 10 mL / kg.

[1340] 2.4 Sample Collection:

[1341] Before and after drug administration in mice, at 0, 0.5, 1, 2, 3, 5, and 7 hours, they were sacrificed by CO2, 0.2 mL of blood was collected from the heart and placed in an EDTA-K2 tube, centrifuged at 6000 rpm for 6 minutes at 4 °C to separate plasma, and stored at -80 °C; for the ileum, the part near the cecum with a length of about 4 - 5 cm was taken; for the colon, the part near the cecum with a length of about 2 - 3 cm was taken, weighed after removal, placed in a 2 mL centrifuge tube, and stored at -80 °C.

[1342] 2.5 Sample preparation:

[1343] 1) Add 40 μL of plasma sample to 160 μL of acetonitrile to precipitate, mix, and centrifuge at 3500 × g for 5-20 minutes.

[1344] 2) Add 90 µL of acetonitrile containing internal standard (100 ng / mL) to 30 µL of plasma and intestinal homogenate samples, mix, and centrifuge at 13000 rpm for 8 minutes.

[1345] 3) Take 70 μL of the treated supernatant and add it to 70 µL of water. Vortex mix for 10 minutes, then take 20 µL for LC / MS / MS analysis of the concentration of the analyte. LC / MS / MS analyzer: AB Sciex API 4000 Qtrap.

[1346] 2.6 Liquid Phase Analysis

[1347] Liquid phase conditions: Shimadzu LC-20AD pump

[1348] Chromatographic column: Agilent ZORBAX XDB-C18 (50×2.1 mm, 3.5 μm); Mobile phase: Solution A was 0.1% formic acid aqueous solution, Solution B was acetonitrile.

[1349] Flow rate: 0.4 mL / min

[1350] Elution time: 0-4.0 minutes, eluent as follows:

[1351]

[1352] 3. Experimental Results and Analysis

[1353] The main pharmacokinetic parameters were calculated using WinNonlin 6.1. The results of the mouse pharmacokinetic experiment are shown in Table 17.

[1354] Table 17

[1355]

[1356]

[1357]

[1358] NA indicates not detected or not tested (the limit of quantitation for blood drug concentration is 1 ng / ml; when C is detected in the blood...). maxWhen NA is present, NA in a blood test indicates that it was not detected; when C is present in a blood test... max When the concentration is 1 ng / ml above the limit of quantitation, NA in blood tests indicates undetected; NA in tissues (colon and ileum) also indicates undetected.

[1359] Experimental conclusion:

[1360] The results of the mouse pharmacokinetic (PK) experiment in the table show that the compounds in the embodiments of this invention exhibit good exposure levels in the colon and ileum, with low area under the plasma concentration-time curve (AUC) and low peak plasma concentration (C). max All compounds met the screening criteria; and the colon / ileum drug concentration and colon / plasma drug concentration ratio were high, demonstrating good selectivity.

[1361] Test 4: In vivo efficacy test procedures and results

[1362] 4.1 Experimental Objective:

[1363] The efficacy of the compounds in the examples was evaluated in a DSS (dextran sulfate sodium)-induced C57BL / 6 mouse colitis model.

[1364] 4.2. Main Experimental Materials

[1365] 4.2.1 Instruments

[1366] 1. Balance Mettler toledo AL104

[1367] 2. Balance TP-602

[1368] 4.2.2 Reagents

[1369] 1. Sodium Dextran Sulfate (DSS): MP Biomedicals, LLC, Solon, Ohio, Catalog No.: 160110

[1370] 2. Cyclosporine (CsA): Novartis, Switzerland, Lot No.: S0033A

[1371] 3. Sodium carboxymethyl cellulose: Sinopharm Chemical Reagent Co., Ltd.

[1372] 4. Tween 80: Sigma, Part Number: 8CBM 513V

[1373] 4.2.3 Details of the experimental animals are shown in Table 18 below:

[1374] Table 18 Details of Laboratory Animals

[1375]

[1376] 4.3. Experimental Procedure

[1377] 4.3.1 Grouping

[1378] Based on animal weight, on day 1, the animals were randomly grouped using BioBook software to ensure that the weight values ​​of each group were similar, thereby reducing bias. The grouping and dosing regimens are shown in Table 19 below.

[1379] Table 19 Grouping and Dosing Regimen

[1380]

[1381] a: The solvent is 0.5% CMC-Na + 1% Tween 80

[1382] b: 8-hour interval

[1383] 4.3.2 Experimental Procedure

[1384] 1. Reagent preparation

[1385] DSS-containing drinking water: Dissolve an appropriate amount of DSS powder in autoclaved drinking water to prepare a 2% DSS solution.

[1386] 2. Induction of enteritis

[1387] On day -1, the animals were divided into 12 groups of 10 each. (See Table 19 for the specific grouping scheme.)

[1388] From 9:00 AM on Day 0 to 9:00 AM on Day 6, mice in groups 2 through 9 drank a 2% DSS solution for 6 days (from Day 0 to Day 6). Afterward, mice had free access to normal water for 3 days (from 9:00 AM on Day 6 to before necropsy on Day 9). The day of model initiation was counted as Day 0. The DSS solution was wrapped in aluminum foil to protect it from light. The DSS solution was changed every 2 days.

[1389] Group 1 mice had free access to normal water for 9 days (from 9:00 on day 0 to before necropsy on day 9).

[1390] 3. Administration

[1391] For specific dosage, route of administration and time of administration, please refer to Table 19 above.

[1392] 4.4 Measurement

[1393] 1) Weight

[1394] The recording frequency is once a day.

[1395] 2) Daily Illness Index (DAI)

[1396] Records are recorded once a day and graded into four levels according to the following criteria:

[1397] Weight change (0, ≤1%; 1, 1-5%; 2, 5-10%; 3, 10-15%; 4, >15%)

[1398] Blood in stool (0, negative; 4, positive);

[1399] Stool score (0, normal; 2, loose stool; 4, diarrhea)

[1400] The scores from the above three parts are added together and divided by 3 to obtain the Daily Disease Index (DAI). A DAI-time (day) curve is plotted based on the daily DAI score, and the area under the curve (AUC) is calculated. The percentage decrease in DAI AUC is calculated by comparing the drug-treated group with the vehicle group, using the formula: (DAI AUC...) 给药组 -DAI AUC Vehicle ) / DAI AUC Vehicle ×100%

[1401] 4.5. Experimental results are shown in Table 20:

[1402] Table 20 Experimental Results

[1403]

[1404] 4.6. Experimental Conclusions

[1405] In a DSS-induced C57BL / 6 mouse colitis model, the compounds in the above examples significantly reduced the Daily Disease Index (DAI), demonstrating significant efficacy.

[1406] III. Study on the salts and crystal forms of compounds

[1407] As is well known to those skilled in the art, when the compounds of the above embodiments are shown to have significant pharmacological and pharmacodynamic activity against JAK1 / 2 / 3 / TYK2 kinases, their pharmaceutically acceptable salts often possess the same pharmacological and pharmacodynamic activity. Based on this, the inventors further investigated the physicochemical properties of the salt forms and crystal forms of the corresponding compounds. However, the specific preparation and characterization of the salt forms or crystal forms described below do not constitute a limitation on the scope of protection of this invention. Those skilled in the art can use this invention as a basis to obtain more salt forms and crystals of the compounds of this invention through conventional salt-forming or crystallization methods. These salt forms and crystals are all protected by this invention. Specifically, as follows:

[1408] 1. Experimental apparatus

[1409] 1.1 Some parameters of the physicochemical testing instruments are shown in Table 21:

[1410] Table 21

[1411]

[1412] 1.2 Instruments and Liquid Chromatography Analysis Conditions

[1413] 1.2.1 Instruments and equipment are listed in Table 22:

[1414] Table 22

[1415]

[1416] 1.2.2 Chromatographic conditions

[1417] Column: ZORBAX (SB-C8, 3.5μm, 4.6*75 mm)

[1418] Flow rate: 1.5 mL / min

[1419] Column temperature: 40 ℃

[1420] Detection wavelength: 242 nm

[1421] Injection volume: 5.0 μL

[1422] Runtime: 15 min

[1423] Diluent: ACN-water (v / v, 1:1)

[1424] Mobile phase: A: Water (0.05% trifluoroacetic acid); B: Acetonitrile (0.05% trifluoroacetic acid)

[1425] The gradient of the mobile phase is shown in Table 23:

[1426] Table 23

[1427]

[1428] 2. Research on the salt forms of compounds

[1429] The preparation method of the salt form of the compound is as follows:

[1430] Method 1 for preparing the acid salt of the compound shown in general formula (I) specifically includes the following steps:

[1431] 1) Weigh an appropriate amount of free base and dissolve it in a good solvent;

[1432] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent;

[1433] 3) Combine the two solutions mentioned above and stir to precipitate, or add a poor solvent and stir to precipitate;

[1434] 4) Rapid centrifugation or static drying to obtain the target product;

[1435] in:

[1436] The beneficial solvent is selected from 2-butanol, methanol, isopropanol, 2-butanone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, or N-methylpyrrolidone; preferably one or more of 2-butanol, methanol, or dimethyl sulfoxide.

[1437] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably one or more of methanol, ethanol, or acetonitrile.

[1438] The unsuitable solvent is selected from one or more of heptane, water, methyl tert-butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone, or acetonitrile; preferably one or more of water, methyl tert-butyl ether, or isopropyl ether.

[1439] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, and glucose. Acids, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2 - Sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenediol. Sulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid; more preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid; even more preferably phosphoric acid, maleic acid, or benzenesulfonic acid.

[1440] Method 2 for preparing the acid salt of the compound shown in general formula (I) specifically includes the following steps:

[1441] 1) Weigh an appropriate amount of free base and suspend it in a poor solvent;

[1442] 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent;

[1443] 3) Add the above solution to the above suspension and stir;

[1444] 4) Rapid centrifugation or static drying yields the salt of the compound;

[1445] in:

[1446] The undesirable solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, 3-pentanone, isopropyl acetate, ethyl formate, 1,4-dioxane, chlorobenzene, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, n-propanol, tert-butanol, or 2-butanone; preferably one or more of dichloromethane, toluene, acetonitrile, acetone, methanol, or ethyl acetate.

[1447] The organic solvent is selected from methanol, ethanol, ethyl acetate, dichloromethane, acetone, n-hexane, petroleum ether, benzene, toluene, chloroform, acetonitrile, carbon tetrachloride, dichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol, or N,N-dimethylformamide; preferably one or more of methanol, ethanol, or acetonitrile.

[1448] The aforementioned counterionic acid is selected from hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, 2,5-dihydroxybenzoic acid, 1-hydroxy-2-naphtholic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxyxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, 4-aminobenzoic acid, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, camphorsulfonic acid, aspartic acid, camphoric acid, and glucose. Acids, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecyl sulfate, dibenzoyl tartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactobionic acid, gentian acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, hydroxyethyl sulfonic acid, lactobionic acid, ascorbic acid, aspartic acid, lauric acid, camphoric acid, maleic acid, malonic acid, methanesulfonic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2 - Sulfonic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthyl acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanate, pamoic acid, formic acid, undecanoic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid; preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, hydroxyethylsulfonic acid, 1,5-naphthalenediol. Sulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid, stearic acid; more preferably phosphoric acid, succinic acid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid; even more preferably phosphoric acid, maleic acid, or benzenesulfonic acid.

[1449] 2.1 Salt Form Study of Compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one

[1450] 2.1.1 Experimental Objective:

[1451] Different counterionic acids were selected to detect which counterionic acids could form compound salts.

[1452] 2.1.2 Experimental Procedure:

[1453] 1) Instruments and equipment are listed in Table 24:

[1454] Table 24

[1455]

[1456] 2) Operating Procedures:

[1457] Weigh 10 mg of free base and add 200 μL of methanol solvent. Heat and stir at 50 °C. Add different counterionic acids (base:acid = 1:1.2 molar ratio, each counterionic acid was dissolved in the following organic solutions before addition). Stir to react. If a solid precipitates after the reaction, centrifuge quickly or let it stand to dry to obtain the salt of the compound. If no solid precipitates, add the antisolvent to the reaction solution, stir to precipitate, and then centrifuge quickly or let it stand to dry to obtain the salt of the compound. The results are shown in Table 25 below.

[1458] Table 25

[1459]

[1460]

[1461] 2.1.3 Experimental Results

[1462] Salt type screening experiments showed that the salt types that can form salts with the free base of the compound are maleate, benzenesulfonate, sulfate, hydroxyethylsulfonate, adipate, p-toluenesulfonate, fumarate, oxalate, hydrobromide, 1,5-naphthalenedisulfonate, and tartrate.

[1463] 2.2 Salt type screening of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1464] 2.2.1 Experimental Objective:

[1465] Different counterionic acids were selected to detect which counterionic acids could form compound salts.

[1466] 2.2.2 Experimental Procedure:

[1467] 1) The instruments and equipment are listed in Table 26:

[1468] Table 26

[1469]

[1470] 2) Operating Procedures

[1471] Salt formation by natural evaporation using methanol as solvent:

[1472] Weigh an appropriate amount of free base and prepare a 20 mg / mL solution with methanol as a stock solution. Take 0.5 mL or 1 mL of the stock solution and add different counterion acid solutions (base:acid molar ratio of 1:1.2 or base:acid molar ratio of 1:2.2) to carry out the reaction. Then, allow the solvent to evaporate at room temperature. The results are shown in Table 27 below.

[1473] Table 27

[1474]

[1475]

[1476]

[1477] 2.2.3 Experimental Results

[1478] Through salt type research experiments of the present invention, phosphates, succinates, acetates, hydrochlorides, benzenesulfonates, hydrobromates, oxalates, adipates, ethanesulfonates, benzoates, 1,5-naphthalenedisulfonates, pamoate, hippurate, sulfates, malonates, p-toluenesulfonates, maleates, malates, tartrates, and fumarates of the corresponding compounds were obtained. As described above, those skilled in the art can obtain more pharmaceutically usable salts based on the present invention using conventional methods.

[1479] 3. Study on the crystal form of compound salts

[1480] 3.1 Study on the crystal forms of salts of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one

[1481] 3.1.1 Experimental Objective:

[1482] By selecting different counterionic acids and using appropriate crystallization methods, we can determine which counterionic acids can form the crystal form of compound salts.

[1483] 3.1.2 Experimental Procedure:

[1484] 3) Instruments and equipment are listed in Table 28:

[1485] Table 28

[1486]

[1487] 4) Operating Procedures

[1488] I. Salt crystallization by natural evaporation using methanol as solvent

[1489] Weigh 10 mg of free base and add 200 μL of methanol solvent. Add different counterionic acids (base:acid molar ratio = 1:1.2) to each mixture and allow the solvent to evaporate at room temperature. For amorphous or poorly crystalline forms, add 200 μL of ethyl acetate and slurry. The results are shown in Table 29 below.

[1490] Table 29

[1491]

[1492] II. The results of salt crystallization by dissolution or suspension in different solvents are shown in Table 30 below:

[1493] Table 30

[1494]

[1495]

[1496] III. Pulping with different solvents

[1497] 10 mg of different salt-type crystalline solids obtained with methanol as solvent were added to 200 μL of organic solvent and slurried at 50 °C. The results are shown in Table 31 below:

[1498] Table 31

[1499]

[1500] 3.1.3 Experimental Results

[1501] Through experiments studying the crystal forms of the salts of this compound, it has been determined that crystals of maleate, benzenesulfonate, sulfate, hydroxyethylsulfonate, adipate, p-toluenesulfonate, fumarate, oxalate, hydrobromide, 1,5-naphthalenedisulfonate, and tartrate can be obtained. Among them, the crystals of maleate, benzenesulfonate, sulfate, hydroxyethylsulfonate, and adipate have good crystallinity. All of the above salt forms exhibit polymorphism and have a greater advantage in crystallization compared with other salt forms.

[1502] 3.2 Study on the salt crystal form of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1503] 3.2.1 Experimental Objective:

[1504] By selecting different counterionic acids and using appropriate crystallization methods, we can determine which counterionic acids can form compound salt crystals.

[1505] 3.2.2 Experimental Procedure:

[1506] 1) The instruments and equipment are listed in Table 32:

[1507] Table 32

[1508]

[1509] 2) Operating Procedures

[1510] I. Salt crystallization by dissolution or suspension in different solvents

[1511] Weigh out 10 mg or 20 mg of free base, and add different counterion acid solutions (base:acid = 1:1.2 molar ratio or base:acid = 1:2.2 molar ratio) to different solvents as reaction solvents. The results are shown in Table 33 below.

[1512] Table 33

[1513]

[1514]

[1515] 3.2.3 Experimental Results

[1516] Through experiments studying the crystal forms of the salts of this compound, it was found that phosphate, succinate, acetate, hydrochloride, benzenesulfonate, hydrobromide, oxalate, adipate, ethanesulfonate, benzoate, 1,5-naphthalenedisulfonate, pamoate, hippurate, sulfate, malonate, p-toluenesulfonate, maleate, malate, tartrate, and fumarate were observed. Among these, phosphate, succinate, and acetate showed good crystallization effects, and the corresponding crystal forms exhibited good reproducibility, demonstrating that the above salts and their crystal forms have good pharmaceutical advantages.

[1517] 3.3 Study on the crystal form of salts of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one

[1518] 3.3.1 Experimental Objective:

[1519] Based on the results of salt type studies, appropriate crystallization methods are selected to obtain different crystal forms of salt.

[1520] 3.3.2 Experimental Procedure:

[1521] 1) Instruments and equipment are listed in Table 34

[1522] Table 34

[1523]

[1524] 2) Operating Procedures

[1525] I. Preparation of maleate crystal form A

[1526] Weigh 500 mg of free base, add 10 mL of methanol, heat and stir at 50 °C, then slowly add 1367 μL of 1.0 M maleic acid methanol solution to the system. After dissolution, a large amount of solid precipitates. Filter and vacuum dry to obtain maleate crystal form A. Analysis shows that it has the following properties: Figure 1 The XRPD diagram shown is as follows: Figure 2 The DSC diagram shown and as follows Figure 3 The TGA diagram shown.

[1527] II. Preparation of maleate crystal form B

[1528] Weigh 10 mg of free base, add 200 μL of dichloromethane, heat and stir at 50 °C, then slowly add 27 μL of 1.0 M maleic acid in methanol solution. After dissolution, a large amount of solid precipitates. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain maleate crystal form B. Analysis shows that it has the following properties: Figure 4 The XRPD diagram shown is as follows: Figure 5 The DSC diagram shown and as follows Figure 6 The TGA diagram shown.

[1529] III. Preparation of Hydroxyethyl Sulfonate Crystal Form C

[1530] Weigh 10 mg of free base, add 200 μL of tetrahydrofuran, heat and stir at 50 °C, then slowly add 28 μL of a 1.0 M hydroxyethyl sulfonic acid methanol solution to the system. Stir overnight until insoluble, centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain hydroxyethyl sulfonate crystal form C. Analysis revealed the following properties: Figure 7 The XRPD diagram shown is as follows: Figure 8 The DSC diagram shown.

[1531] IV. Preparation of p-Toluenesulfonate crystal form A

[1532] Weigh 10 mg of free base, add 200 μL of methanol, heat and stir at 50 °C, then slowly add 28 μL of 1.0 M adipic acid methanol solution to the system. After dissolving completely, the precipitate forms. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain p-toluenesulfonate crystal form A. Analysis revealed the following properties: Figure 9 The XRPD diagram shown is as follows: Figure 10 The DSC diagram shown and as follows Figure 11 The TGA diagram shown.

[1533] V. Preparation of fumarate crystal form A

[1534] Weigh 100 mg of free base, add 2 mL of methanol, heat and stir at 50 °C, then slowly add 1120 μL of 0.25 M fumaric acid ethanol solution to the system. If insoluble, stir overnight at room temperature, filter, and dry the solid in a vacuum drying oven at 50 °C to constant weight to obtain fumarate crystal form A. Analysis revealed the following properties: Figure 12 The XRPD diagram shown is as follows: Figure 13 The DSC diagram shown and as follows Figure 14 The TGA diagram shown.

[1535] VI. Preparation of fumarate crystal form B

[1536] Weigh 10 mg of fumarate crystal form A, add 200 μL of methanol, and slurry at 50°C for 1 day. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50°C until constant weight to obtain fumarate crystal form B. Analysis revealed the following properties: Figure 15 The XRPD diagram shown is as follows: Figure 16 The DSC diagram shown.

[1537] VII. Preparation of fumarate crystal form C

[1538] Weigh 10 mg of fumarate crystal form A, add 200 μL of acetone, and homogenize at 50°C for 1 day. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50°C until constant weight to obtain fumarate crystal form C. Analysis revealed the following properties: Figure 17 The XRPD diagram shown.

[1539] VIII. Preparation of Oxalate Crystal Form A

[1540] Weigh 100 mg of free base, add 2 mL of methanol, heat and stir at 50 °C, then slowly add 280 μL of 1.0 M oxalic acid ethanol solution to the system. If insoluble, continue stirring overnight. Filter, and dry the solid in a vacuum drying oven at 50 °C to constant weight to obtain oxalate crystal form A. Analysis revealed the following properties: Figure 18 The XRPD diagram shown is as follows: Figure 19 The DSC diagram shown and as follows Figure 20 The TGA diagram shown.

[1541] Preparation of IX, hydrobromide crystal form A

[1542] Weigh 10 mg of free base, add 200 μL of methanol, heat and stir at 50 °C, then slowly add 28 μL of 1.0 M hydrobromic acid in ethanol solution. After dissolving completely, precipitate forms. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain hydrobromide crystal form A. Analysis revealed the following properties: Figure 21 The XRPD diagram shown is as follows: Figure 22 The DSC diagram shown and as follows Figure 23 The TGA diagram shown.

[1543] Preparation of X, 1,5-naphthalenedisulfonate crystal form A

[1544] Weigh 10 mg of free base, add 200 μL of methanol, heat and stir at 50 °C, then slowly add 224 μL of 0.125 M 1,5-naphthalenedisulfonic acid ethanol solution to the system. After stirring and precipitating, an oil forms. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain 1,5-naphthalenedisulfonic acid crystalline form A. Analysis revealed the following properties: Figure 24 The XRPD diagram shown is as follows: Figure 25 The DSC diagram shown and as follows Figure 26 The TGA diagram shown.

[1545] XI. Preparation of tartrate crystal form A

[1546] Weigh 10 mg of free base, add 200 μL of methanol, heat and stir at 50 °C, then slowly add 56 μL of 0.5 M tartaric acid ethanol solution to the system. After dissolving completely, precipitate forms. Centrifuge to remove the supernatant, and dry the remaining solid in a vacuum drying oven at 50 °C to constant weight to obtain tartrate crystal form A. Analysis revealed the following properties: Figure 27 The XRPD diagram shown is as follows: Figure 28 The DSC diagram shown and as follows Figure 29 The TGA diagram shown.

[1547] XII. Preparation of Free Alkali Crystal Form A

[1548] Weigh 1000 mg of the hydrochloride salt of the free base into a 40 mL glass bottle, add 7 mL of methanol, heat and stir at 50 °C, add 1 M HCl hydrochloric acid solution to dissolve it completely, filter, add 1 M NaOH solution until a precipitate forms (pH around 10), stir overnight at room temperature, filter, wash with water, and dry the solid under vacuum at 50 °C to obtain free base crystal form A. Analysis shows that it has the following properties: Figure 30 The XRPD diagram shown.

[1549] 3.4 Study on the crystal form of salts of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1550] 3.4.1 Experimental Objective:

[1551] Based on the results of salt type screening, a suitable crystallization method was selected to study different crystal forms of maleate.

[1552] 3.4.2 Experimental Procedure:

[1553] 1) The instruments and equipment are listed in Table 35:

[1554] Table 35

[1555]

[1556] 2) Operating Procedures

[1557] I. Preparation of Phosphate Crystal Form A

[1558] Weigh an appropriate amount of free base and prepare a stock solution with a concentration of 20 mg / mL using methanol; weigh 12.12 mg of phosphoric acid, add 200 μL of methanol, dissolve completely, then add 1 mL of the stock solution, evaporate to dryness at room temperature in an open container, and then vacuum dry to obtain phosphate crystal form A. Analysis showed that it possessed the following properties: Figure 31 The XRPD diagram shown is as follows: Figure 32 The DSC diagram shown and as follows Figure 33The TGA diagram shown.

[1559] II. Preparation of Phosphate Crystal Form B

[1560] Weigh an appropriate amount of free base and prepare a stock solution with a concentration of 20 mg / mL using methanol; weigh 5.77 mg of phosphoric acid, add 200 μL of methanol, dissolve completely, then add 1 mL of the stock solution, evaporate to dryness at room temperature in an open container, and then vacuum dry to obtain phosphate crystal form B. Analysis showed that it possessed the following properties: Figure 34 The XRPD diagram shown.

[1561] III. Preparation of Succinate Crystal Form A

[1562] Weigh an appropriate amount of free base and prepare a stock solution with a concentration of 20 mg / mL in methanol; weigh 7.96 mg of phosphoric acid, add 200 μL of methanol, dissolve completely, then add 1 mL of the stock solution, evaporate to dryness at room temperature in an open container, and then vacuum dry to obtain succinate crystal form A. Analysis showed that it possessed the following properties: Figure 35 The XRPD diagram shown.

[1563] IV. Preparation of Free Base Crystal Form A

[1564] Weigh 9.4 g of (3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and dissolve it in methanol (47 mL). Add 1,4-dioxane (94 mL) of 4M HCl while stirring at 10-20℃. Stir the reaction at 20-30℃ for 1-2 hours. After the reaction is complete, filter the reaction solution. Wash the filter cake with methanol (20 mL) and use the solid directly in the next reaction. Dissolve the solid in methanol (56 mL). Add DIPEA (10 g, 0.0784 mol) dropwise at 10-20℃. After the addition is complete, adjust the reaction solution temperature to 20-30℃ and add acrylonitrile (3.1 g, 0.0588 mol). Add mol) to the reaction solution and react at 20-30℃ for 2 hours. Filter the reaction solution, wash the filter cake with 15 mL of methanol, and dry to obtain a white solid (7.6 g) of compound IV. Analysis revealed the following properties: Figure 36 The XRPD diagram shown.

[1565] 4. Confirmation of crystal structure

[1566] 4.1 Experimental Objective:

[1567] Elemental analysis, nuclear magnetic resonance spectroscopy (NMR), TGA, and acid content detection are used to examine whether candidate compounds form salts or their crystal forms, providing a basis for product qualitative or quantitative analysis.

[1568] 4.2 Experimental Procedure: Crystallographic samples of different salts were taken, and their nuclear magnetic resonance (NMR), TGA, and acid content were detected respectively. The results were then analyzed.

[1569] 4.3 Experimental Results:

[1570] 1) The structural confirmation results of the salt crystal form of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one:

[1571] 4.1. The elemental analysis results are shown in Table 36 below.

[1572] Table 36 Elemental analysis data of maleate crystal form A sample

[1573]

[1574] Note: Calculated values ​​are based on the maleate molecular formula C 21 H 28 N8OS·C4H4O4 is used.

[1575] 4.2. Nuclear Magnetic Resonance Spectroscopy (NMR)

[1576] The nuclear magnetic resonance spectrum of maleate form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one is shown in the appendix. Figure 37 The hydrogen spectrum data of the sample is consistent with its maleate crystal form A structure.

[1577] 4.3.TGA

[1578] TGA of maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one showed almost no weight loss from room temperature to 200 °C, indicating that the sample does not contain water of crystallization or adsorbed solvent. Subsequently, the sample began to lose weight slowly, with a sharp weight loss at 230 °C, and a weight loss of about 14% at about 350 °C.

[1579] 4.4. The acid content test results are shown in Table 37 below:

[1580] Table 37 Acid content detection results of maleate crystal form A sample

[1581]

[1582] The results for the maleic acid content in maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one are in line with expectations.

[1583] 4.4 Experimental Conclusions:

[1584] In summary, the maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one contains a single maleate crystal, consistent with its maleate crystal form A.

[1585] 5. Crystal form stability experiment

[1586] 5.1 Study on crystal form stability before and after experiments with different influencing factors

[1587] 5.1.1 Experimental Objective:

[1588] The physicochemical stability of the salts or crystal forms of the candidate compounds was investigated under the conditions of 5000 lx light, 60 °C high temperature, 92.5% RH high humidity, and 50 °C 75% RH high temperature and high humidity, so as to provide a basis for product storage.

[1589] 5.1.2 Experimental Procedure:

[1590] Approximately 2 mg of different salt crystal forms were taken and subjected to 5000 lx light, 60°C high temperature, 92.5% RH high humidity, and 50°C high temperature and 75% RH high temperature conditions for 5 and 10 days. The salt content was determined by HPLC using the external standard method, and the changes in related substances were calculated using the chromatographic peak area normalization method.

[1591] 5.1.3 Experimental Results:

[1592] 1) The physicochemical stability results of the salt crystal forms of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one are shown in Table 38:

[1593] Table 38

[1594]

[1595] Stability results showed that different salts of the compound had different crystal forms with varying stability. The fumarate crystal form was unstable under high temperature and high humidity conditions and needed to be stored in a dry environment at room temperature. Maleate crystal form A showed the best stability under light conditions and also exhibited excellent stability under high temperature and high humidity conditions. Hydroxyethyl sulfonate crystal form C, 1,5-naphthalene disulfonate crystal form A, and tartrate crystal form A showed good stability under high temperature and high humidity conditions.

[1596] 2) The physicochemical stability results of the salts of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile are shown in Table 39:

[1597] Table 39

[1598]

[1599] The stability results showed that the crystal forms of the compounds had different stability after salt formation, with phosphate crystal form A showing better stability.

[1600] 5.1.4 Experimental Conclusions

[1601] Based on the stability studies of both salt forms and crystal forms, the maleate salt and crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one, and 1,5-naphthalene disulfonate and crystal form A; and the phosphate salt and crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile exhibited excellent stability.

[1602] 5.2 Comparative Study of Crystal Forms Before and After Experiments with Different Influencing Factors

[1603] 5.2.1 Comparative Study of Crystal Forms of Different Batch Samples

[1604] 1) Experimental objective:

[1605] The process reproducibility of the compound salt or its crystal form was investigated.

[1606] 2) Experimental design:

[1607] Take different batches of the same salt or its crystal form of the compound and analyze its X-ray powder diffraction data.

[1608] 3) Experimental results:

[1609] The statistical data of multiple batches of salt crystal forms of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one are shown in Table 40 below.

[1610] Table 40 X-ray powder diffraction data (2θ values) of maleate crystal form A samples from different production batches

[1611]

[1612] 5) Experimental conclusions:

[1613] X-ray diffraction data confirmed that all five batches of samples were maleate crystal form A. The process for obtaining maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one showed good reproducibility.

[1614] 5.2.2 Study on Crystal Form Before and After Sample Influencing Factors

[1615] 1) Experimental objective:

[1616] Investigate the salts or crystal forms of the compounds under light irradiation (total ultraviolet irradiance not less than 200 W·hr / m²). 2, Total illuminance not less than 1.2 × 10⁻⁶ 6 The stability of the crystal structure under conditions of lux·hr, high temperature (60℃) and high humidity (90%RH) provides a basis for product storage.

[1617] 2) Experimental design:

[1618] Take approximately 2 mg of different salt crystal forms and expose them to light (total ultraviolet irradiance not less than 200 W·hr / m²). 2, Total illuminance not less than 1.2 × 10⁻⁶ 6 The X-ray powder diffraction data were collected after 10 and 14 days under conditions of lux·hr, high temperature 60℃ and high humidity 90%RH.

[1619] 3) Experimental results:

[1620] The X-ray powder diffraction data of the salt crystal forms of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one are compared in Table 41 below.

[1621] Table 41 Comparison of -2θ values ​​of maleate crystal form A before and after the experiment under different influencing factors

[1622]

[1623] 4) Experimental conclusions:

[1624] After 10 days of light exposure and 14 days of high temperature and high humidity, the X-ray powder diffraction data of different batches of samples were consistent with the initial data, indicating that the maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one was stable under the influence of light exposure, 60℃, 25℃RH90%.

[1625] 5.3 Study on crystal form stability during long-term testing

[1626] 1) Experimental objective: To investigate the physicochemical stability of the crystal form of the compound under conditions of 2~8℃, so as to provide a basis for product storage.

[1627] 2) Experimental design:

[1628] Approximately 2 mg of different salt crystals were taken and observed under light conditions of 2–8 °C for 3 months. The salt content was determined by HPLC using the external standard method, and the changes in related substances were calculated using the chromatographic peak area normalization method.

[1629] 3) Experimental results:

[1630] The X-ray powder diffraction data of the salt crystal forms of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one are compared in Table 42 below.

[1631] Table 42

[1632]

[1633] 4) Experimental conclusions:

[1634] The maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one exhibits excellent stability under long-term storage conditions.

[1635] 6. Hygroscopicity test

[1636] 6.1 Experimental Objective

[1637] The hygroscopicity of different salts or crystal forms of the compound under different relative humidity conditions was investigated.

[1638] 6.2 Experimental Procedure:

[1639] The crystal form of the compound salt was placed in saturated water vapor with different relative humidities to allow the compound to reach dynamic equilibrium with the water vapor, and the percentage of the compound's weight gain due to moisture absorption after equilibrium was calculated.

[1640] 6.3 Experimental Results:

[1641] 6.3.1 The hygroscopic properties of different salts of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one are shown below:

[1642] 1) Maleate crystal form A gains 0.673% weight upon moisture absorption at 80% RH, indicating slight hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of maleate crystal form A remained unchanged, indicating that the crystal form did not change.

[1643] 2) p-Toluenesulfonate crystal form A gains 3.228% weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of p-toluenesulfonate crystal form A remained unchanged, indicating no crystal form transformation.

[1644] 3) Oxalate crystal form A gains 1.488% weight upon moisture absorption at 80% RH, indicating slight hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of oxalate crystal form A remained unchanged, indicating that the crystal form did not transform.

[1645] 4) Hydrobromide crystal form A gains 2.421% in weight upon moisture absorption at 80% RH, indicating hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of hydrobromide crystal form A remained unchanged, meaning the crystal form did not transform.

[1646] 5) After two cycles of moisture absorption and desorption under 0-95% relative humidity, the XRPD spectrum of 1,5-naphthalene disulfonate crystal form A changed and transformed into crystal form D.

[1647] 6.3.2 Hygroscopicity of different salts of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile

[1648] 1) Phosphate crystal form A gains 0.5482% weight by absorbing moisture under RH 80% conditions, indicating slight hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, the XRPD spectrum of phosphate crystal form A did not change, meaning the crystal form did not transform.

[1649] 2) Succinate crystal form A gains 10.770% weight by absorbing moisture under RH 80% conditions, indicating hygroscopicity. Furthermore, after two cycles of moisture absorption and desorption under 0-95% relative humidity conditions, the XRPD spectrum of succinate crystal form A did not change, meaning the crystal form did not transform.

[1650] 6.4 Experimental Conclusions

[1651] Compound 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one has the least hygroscopicity in its maleate crystal form A; compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile has the least hygroscopicity in its phosphate crystal form A.

[1652] 7. Solubility experiments in different media

[1653] 7.1 Experimental Objective

[1654] Compare the free base crystal form A with the maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one and compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazole The solubility of phosphate crystal form A of lin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile in different pH buffers, simulated gastric juice (FaSSGF), fasting simulated intestinal juice (FaSSIF), non-fasting simulated intestinal juice (FeSSIF), fasting simulated colonic juice (FaSSCoF), non-fasting simulated colonic juice (FeSSCoF), and pure water provides a basis for evaluating the druggability of the salt.

[1655] 7.2 Experimental Procedure:

[1656] Approximately 1 mg of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one free base crystal form A and maleate crystal form A were suspended in different media for 6 hours. The thermodynamic solubility of the compound at 37 °C was determined by HPLC using the external standard method.

[1657] Approximately 1 mg of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile free base crystal form A and phosphate crystal form A were suspended in different media for 3 hours, and the thermodynamic solubility of the compound was determined by HPLC using the external standard method.

[1658] 7.3 Experimental Results:

[1659] The solubility data of the free base crystal form A and maleate crystal form A of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)ethane-1-one are shown in Table 43 below:

[1660] Table 43

[1661]

[1662] The solubility data of the free base crystal form A and phosphate crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile are shown below:

[1663] 7.4 The experimental conclusions are shown in Table 44 below:

[1664] Table 44

[1665]

[1666] The results showed that the solubility of maleate form A, the free base of compound 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one, was increased in water due to changes in ambient pH. Similarly, the solubility of phosphate form A, the free base of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile form A, was increased in water, FeSSIF, and FeSSCoF due to changes in ambient pH.

[1667] 8. Experiment on the thermodynamic stability of crystal form

[1668] 8.1 Experimental Objective:

[1669] Through polycrystalline screening and crystal form competition experiments, a thermodynamically stable salt crystal form was found.

[1670] 8.2 Experimental Procedure:

[1671] Select an organic solvent and water with a certain solubility, suspend the compound in the solvent system, stir and slurry at room temperature and 50°C for 1 week respectively, centrifuge, discard the supernatant, and dry the solid under vacuum at 50°C (-0.1 MPa) overnight. Measure the XRPD of the solid and compare it with the XRPD of the raw material compound salt.

[1672] 8.3 Experimental Results:

[1673] Different crystal forms of different salts were obtained by pulping and changing the crystallization solvent and crystallization method. Based on the crystal form competition test and DSC results, it can be determined that the maleate crystal form A and maleate crystal form B of compound 1-((3-exo)-3-((4-(((5-methyl-1H-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one, and the phosphate crystal form A of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile are all thermodynamically stable crystal forms.

Claims

1. An acidic salt of a compound, characterized in that, It is an acid salt of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one, wherein the acid salt is selected from hydrochloride, maleate, benzenesulfonate, hydroxyethylsulfonate, 1,5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate or stearate; Alternatively, it may be an acid salt of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile, wherein the acid salt is selected from phosphates, succinates, acetates, hydrochlorides, benzenesulfonates, hydrobromates, oxalates, adipates, ethanesulfonates, benzoates, 1,5-naphthalenedisulfonates, pamoate, hippurate, sulfates, malonates, p-toluenesulfonates, maleates, malates, tartrates, and fumarates.

2. The acid salt according to claim 1, characterized in that, The acid salt is a maleate salt, and the number of acids is 1 or 2.

3. The acid salt according to claim 1, characterized in that, The acid salt of compound 1-((3-exo)-3-((4-(((5-methyl-1-hydro-pyrazol-3-yl)amino)thiopheno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-yl)-2-(methylamino)-ethane-1-one is a crystalline form, wherein the crystalline form of the acid salt is selected from: Maleate crystal form A, with an acid number of 1, has X-ray powder diffraction patterns with diffraction peaks at 2θ of 22.9±0.2°, 12.9±0.2°, 27.9±0.2°, 8.9±0.2°, 13.7±0.2°, 20.7±0.2°, 23.1±0.2°, 13.5±0.2°, 14.9±0.2°, 16.4±0.2°, 17.4±0.2°, 18.9±0.2°, 21.4±0.2°, 21.8±0.2°, and 28.2±0.2°. Maleate crystal form B, with an acid number of 1, exhibits X-ray powder diffraction peaks at 2θ of 4.4±0.2°, 6.2±0.2°, 8.8±0.2°, 14.0±0.2°, 16.4±0.2°, 18.9±0.2°, 19.7±0.2°, 8.5±0.2°, 9.9±0.2°, 13.3±0.2°, 14.9±0.2°, 16.0±0.2°, 17.8±0.2°, 20.3±0.2°, and 20.7±0.2°. Hydroxyethyl sulfonate crystal form C has X-ray powder diffraction patterns with diffraction peaks at 2θ of 20.0±0.2°, 18.5±0.2°, 21.4±0.2°, 15.7±0.2°, 18.7±0.2°, 19.7±0.2°, 23.4±0.2°, 6.6±0.2°, 11.3±0.2°, 12.8±0.2°, 14.6±0.2°, 17.7±0.2°, 20.3±0.2°, 20.6±0.2°, and 23.0±0.2°. The X-ray powder diffraction patterns of p-toluenesulfonate crystal form A are as follows: 2θ = 9.3±0.2°, 14.7±0.2°, 17.8±0.2°, 10.7±0.2°, 13.3±0.2°, 21.1±0.2°, 25.1±0.2°, 8.6±0.2°, 14.4±0.2°, 14.9±0.2°, 18.5±0.2°, 21.7±0.2°, 22.2±0.2°, 22.8±0.2°, and 28.7±0.2°. Fumarate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 20.1±0.2°, 12.1±0.2°, 17.6±0.2°, 14.4±0.2°, 15.5±0.2°, 17.8±0.2°, 21.6±0.2°, 8.8±0.2°, 11.2±0.2°, 20.9±0.2°, 22.7±0.2°, 24.4±0.2°, 24.7±0.2°, 25.1±0.2°, and 26.4±0.2°. Fumarate crystal form B has X-ray powder diffraction patterns with diffraction peaks at 2θ of 10.7±0.2°, 15.5±0.2°, 19.8±0.2°, 11.8±0.2°, 19.1±0.2°, 20.1±0.2°, 21.3±0.2°, 6.6±0.2°, 11.3±0.2°, 12.2±0.2°, 14.1±0.2°, 17.2±0.2°, 23.9±0.2°, 24.5±0.2°, and 24.8±0.2°. The fumarate crystal form C exhibits X-ray powder diffraction peaks at 2θ values ​​of 6.1±0.2°, 15.5±0.2°, 19.3±0.2°, 10.8±0.2°, 19.9±0.2°, 20.4±0.2°, 21.6±0.2°, 6.8±0.2°, 8.6±0.2°, 12.8±0.2°, 13.6±0.2°, 16.6±0.2°, 17.0±0.2°, 18.0±0.2°, and 23.2±0.2°. Oxalate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 19.3±0.2°, 9.0±0.2°, 22.4±0.2°, 24.6±0.2°, 25.8±0.2°, 7.0±0.2°, 9.6±0.2°, 13.0±0.2°, 14.8±0.2°, 17.7±0.2°, 18.8±0.2°, 20.3±0.2°, and 23.6±0.2°. Hydrobromide crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 11.9±0.2°, 22.4±0.2°, 27.1±0.2°, 14.9±0.2°, 18.6±0.2°, 20.5±0.2°, 24.4±0.2°, 20.8±0.2°, and 21.6±0.2°. 1,5-Naphthalenedisulfonate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 16.4±0.2°, 11.5±0.2°, 24.3±0.2°, 10.3±0.2°, 14.6±0.2°, 19.7±0.2°, 21.5±0.2°, 6.1±0.2°, 12.1±0.2°, 12.8±0.2°, 15.0±0.2°, 19.0±0.2°, 20.5±0.2°, 21.1±0.2°, and 23.9±0.2°. Tartrate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 21.6±0.2°, 16.0±0.2°, 17.7±0.2°, 17.1±0.2°, 19.8±0.2°, 20.7±0.2°, 22.5±0.2°, 13.1±0.2°, 14.2±0.2°, and 20.1±0.2°.

4. The acid salt according to claim 3, characterized in that, Maleate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 17.7±0.2°, 18.0±0.2°, 19.6±0.2°, 24.9±0.2° and 25.6±0.2°. Maleate crystal form B has X-ray powder diffraction patterns with diffraction peaks at 2θ of 22.4±0.2° and 24.5±0.2°; Hydroxyethyl sulfonate crystal form C has X-ray powder diffraction patterns with diffraction peaks at 2θ of 23.8±0.2°, 26.2±0.2°, 26.6±0.2°, 27.1±0.2°, 30.2±0.2° and 32.1±0.2°. p-Toluenesulfonate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 14.4±0.2°, 14.9±0.2°, 18.5±0.2°, 21.7±0.2°, 22.2±0.2°, 22.8±0.2° and 28.7±0.2°. Fumarate crystal form A has a diffraction peak at 2θ of 26.8 ± 0.2° in its X-ray powder diffraction pattern; Fumarate crystal form B has X-ray powder diffraction patterns with diffraction peaks at 2θ of 16.5±0.2°, 17.6±0.2°, 18.0±0.2° and 22.0±0.2°. The fumarate crystal form C has X-ray powder diffraction patterns with diffraction peaks at 2θ of 24.2±0.2° and 24.6±0.2°. Oxalate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 14.3±0.2°, 15.6±0.2°, 16.3±0.2°, 20.6±0.2°, 20.9±0.2° and 24.0±0.2°. Hydrobromate crystal form A has a diffraction peak at 2θ = 25.2 ± 0.2° in its X-ray powder diffraction pattern; 1,5-Naphthalene disulfonate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 22.0±0.2°, 25.1±0.2° and 27.6±0.2°; Tartrate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 14.5±0.2° and 28.6±0.2°.

5. The acid salt according to claim 3, characterized in that, Maleate crystal form A, its X-ray powder diffraction pattern is basically shown in Figure 1, its DSC pattern is basically shown in Figure 2, or its TGA pattern is basically shown in Figure 3. Maleate crystal form B, its X-ray powder diffraction pattern is basically shown in Figure 4, its DSC pattern is basically shown in Figure 5, or its TGA pattern is basically shown in Figure 6. The X-ray powder diffraction pattern of hydroxyethyl sulfonate crystal form C is basically shown in Figure 7, or its DSC pattern is basically shown in Figure 8. The X-ray powder diffraction pattern of p-toluenesulfonate crystal form A is basically shown in Figure 9, or its DSC pattern is basically shown in Figure 10, or its TGA pattern is basically shown in Figure 11. The fumarate crystal form A has an X-ray powder diffraction pattern as shown in Figure 12, or a DSC pattern as shown in Figure 13, or a TGA pattern as shown in Figure 14. The X-ray powder diffraction pattern of fumarate crystal form B is basically shown in Figure 15, or its DSC pattern is basically shown in Figure 16. The X-ray powder diffraction pattern of fumarate crystal form C is shown in Figure 17. The X-ray powder diffraction pattern of oxalate crystal form A is basically shown in Figure 18, or its DSC pattern is basically shown in Figure 19, or its TGA pattern is basically shown in Figure 20. The basic X-ray powder diffraction pattern of hydrobromide crystal form A is shown in Figure 21, or its DSC pattern is shown in Figure 22, or its TGA pattern is shown in Figure 23. The X-ray powder diffraction pattern of 1,5-naphthalene disulfonate crystal form A is shown in Figure 24, or its DSC pattern is shown in Figure 25, or its TGA pattern is shown in Figure 26. The X-ray powder diffraction pattern of tartrate crystal form A is basically shown in Figure 27, or its DSC pattern is basically shown in Figure 28, or its TGA pattern is basically shown in Figure 29.

6. The acid salt according to claim 1, characterized in that, The acid salt of compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-yl)propionitrile is a crystalline form, wherein the crystalline form of the acid salt is selected from: Phosphate crystal form A, with 2 acid atoms, exhibits X-ray powder diffraction peaks at 2θ values ​​of 21.7±0.2°, 21.2±0.2°, 23.0±0.2°, 7.5±0.2°, 16.6±0.2°, 23.4±0.2°, 26.0±0.2°, 6.9±0.2°, 9.5±0.2°, 12.3±0.2°, 13.7±0.2°, 19.5±0.2°, 20.3±0.2°, 24.9±0.2°, and 27.6±0.2°. Phosphate crystal form B exhibits X-ray powder diffraction peaks at 2θ of 5.9±0.2°, 5.1±0.2°, 17.7±0.2°, 14.7±0.2°, 21.8±0.2°, 25.6±0.2°, 27.0±0.2°, 8.6±0.2°, 13.7±0.2°, 14.4±0.2°, 20.0±0.2°, 20.9±0.2°, and 21.4±0.2°. Succinate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 6.8±0.2°, 5.8±0.2°, 22.1±0.2°, 12.4±0.2°, 17.8±0.2°, 19.0±0.2°, 26.4±0.2°, 9.0±0.2°, 11.7±0.2°, 13.7±0.2°, 14.8±0.2°, 16.7±0.2°, 18.6±0.2°, 20.6±0.2°, and 23.5±0.2°.

7. The acid salt according to claim 6, characterized in that, Phosphate crystal form A has a diffraction peak at 2θ = 28.4 ± 0.2° in its X-ray powder diffraction pattern; Phosphate crystal form B has a diffraction peak at 2θ = 23.4 ± 0.2° in its X-ray powder diffraction pattern; Succinate crystal form A has X-ray powder diffraction patterns with diffraction peaks at 2θ of 20.1±0.2°, 25.0±0.2° and 27.0±0.2°.

8. The acid salt according to claim 6, characterized in that... Phosphate crystal form A has an X-ray powder diffraction pattern as shown in Figure 31, a DSC pattern as shown in Figure 32, and a TGA pattern as shown in Figure 33. The X-ray powder diffraction pattern of phosphate crystal form B is shown in Figure 34. The X-ray powder diffraction pattern of succinate crystal form A is shown in Figure 35.

9. A method for preparing the acid salt according to any one of claims 1-8, comprising the following steps: 1) Weigh an appropriate amount of free base and dissolve it in a good solvent; 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; 3) Combine the two solutions above, stir to precipitate or add a poor solvent and then stir to precipitate; 4) Obtain the target product by rapid centrifugation or by allowing it to stand; The benign solvent is selected from one or more of 2-butanol, methanol, or dimethyl sulfoxide; The organic solvent is selected from one or more of methanol, ethanol, or acetonitrile; The unsuitable solvent is selected from one or more of water, methyl tert-butyl ether, or isopropyl ether; Alternatively, it may include the following steps: 1) Weigh an appropriate amount of free base and suspend it in a poor solvent; 2) Weigh an appropriate amount of the counterionic acid and dissolve it in an organic solvent; 3) Add the solution from step 2) to the suspension from step 1) and stir; 4) Obtain the target product by rapid centrifugation or by allowing it to stand; The undesirable solvent is selected from one or more of dichloromethane, acetonitrile, acetone, methanol, or ethyl acetate; The organic solvent is selected from one or more of methanol or ethanol; Alternatively, it may include the following steps: 1) Weigh an appropriate amount of the acid salt of the compound, suspend it in a poor solvent, and shake it. 2) Centrifuge the above suspension, remove the supernatant, and dry to obtain the target product; The undesirable solvent is selected from one or more of methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate, 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, tert-butanol, or 2-butanone; The counterionic acid is selected from phosphoric acid, succinic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, hydroxyethylsulfonic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid, or hydrobromic acid.

10. The preparation method according to claim 9, wherein, The counterionic acid is selected from phosphoric acid, maleic acid, or benzenesulfonic acid.

11. A pharmaceutical composition comprising a therapeutically effective amount of the acid salt of any one of claims 1-8 and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. The use of the acid salt according to any one of claims 1-8 and the pharmaceutical composition according to claim 11 in the preparation of a medicament for the prevention and / or treatment of diseases related to JAK kinase.

13. The application according to claim 12, characterized in that, The JAK kinase-related diseases mentioned are inflammatory diseases and / or neoplastic diseases.

14. The application according to claim 12, characterized in that, The inflammatory diseases mentioned are selected from rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease; The tumor diseases mentioned are selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myelocytic leukemia, acute lymphoblastic leukemia, ductal carcinoma of the breast and non-small cell lung cancer.

15. The application according to claim 14, characterized in that, Inflammatory bowel disease is a chronic inflammatory bowel disease.

16. The application according to claim 14, characterized in that, Inflammatory bowel disease is selected from ulcerative colitis and Crohn's disease.

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