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CN113717194A - Salts of heteroaromatic derivatives and process for preparing the same - Google Patents

Salts of heteroaromatic derivatives and process for preparing the same Download PDF

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CN113717194A
CN113717194A CN202110572325.7A CN202110572325A CN113717194A CN 113717194 A CN113717194 A CN 113717194A CN 202110572325 A CN202110572325 A CN 202110572325A CN 113717194 A CN113717194 A CN 113717194A
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李媛媛
呙临松
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

本发明涉及一种含杂芳类衍生物的盐及其制备方法。具体涉及一种具有通式(I)化合物盐及晶型、制备方法和含有治疗有效量的该晶型的药物组合物，及其作为JAK激酶抑制剂，在治疗类风湿性关节炎、皮炎、银屑病、炎症性肠病等炎症性疾病及结肠癌、非小细胞肺癌等肿瘤疾病的用途。

Figure DDA0003083170720000011

Figure 202110572325

The present invention relates to a salt containing heteroaromatic derivatives and a preparation method thereof. Specifically, it relates to a compound salt and crystal form of the general formula (I), a preparation method and a pharmaceutical composition containing the crystal form in a therapeutically effective amount, and as a JAK kinase inhibitor, it is used in the treatment of rheumatoid arthritis, dermatitis, Psoriasis, inflammatory bowel disease and other inflammatory diseases and colon cancer, non-small cell lung cancer and other tumor diseases.

Figure DDA0003083170720000011

Figure 202110572325

Description

Salts of heteroaromatic derivatives and process for preparing the same
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a salt and a crystal form of a heteroaromatic derivative, and a preparation method and application thereof.
Background
Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signaling and activation of various cytokines. The JAK kinase family contains four subfamily members of JAK1, JAK2, JAK3 and TYK2, each of which mediates different types of cytokine signaling pathways, JAK1, JAK2 and TYK2 are expressed in each tissue cell of human body, and JAK3 is mainly expressed in each hematopoietic tissue cell. A common feature of cytokine receptors is that the receptor itself has no kinase activity, but the intracellular segment of the receptor has a binding site for the tyrosine kinase JAK. After the cell factor receptor is combined with a ligand thereof, JAKs coupled with the receptor are activated, so that the receptor is phosphorylated, a phosphorylated tyrosine site can be combined with STAT protein containing an SH2 structural domain, STAT is recruited to the receptor and is phosphorylated through JAKs, then phosphotyrosine mediates STAT dimerization, and the activated STAT dimer is transferred to a cell nucleus and activates target gene transcription of the cell nucleus, so that multiple functions of growth, activation, differentiation and the like of multiple cells are regulated.
The JAK/STAT signal pathway mediates the signal transduction of most of intracellular cytokines and plays a key role in the biological processes of immune regulation, immune cell proliferation and the like. The JAK/STAT signal channel has wide functions, participates in a plurality of important biological processes such as proliferation, differentiation, apoptosis, immunoregulation and the like of cells, and is closely related to a plurality of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and the like; meanwhile, the JAK/STAT signal pathway is closely related to neoplastic diseases such as myelofibrosis, polycythemia vera and essential thrombocythemia, and the mutation of JAK molecules can also cause Acute Myelocytic Leukemia (AML), Acute Lymphocytic Leukemia (ALL), ductal breast cancer, non-small cell lung cancer (NSCLC) and other neoplastic diseases.
Inflammatory bowel disease is a chronic inflammatory disease of the intestinal tract, including Ulcerative Colitis (UC) and Crohn's Disease (CD). The existing medicines for treating inflammatory bowel diseases mainly comprise aminosalicylic acid preparations, glucocorticoids, immunosuppressive agents, antibiotics and the like. The treatment of UC mainly comprises the regulation of immune response and the inhibition of inflammation. Currently, sulfasalazine is mainly used for treating mild to moderate UC in clinic. While the drugs commonly used for the treatment of moderate to severe UC include glucocorticoids, they are not considered as long-term treatments because of the greater risk than benefit. The monoclonal antibody has the problems of high cost, influence on the safety and effectiveness of the drug due to the generation of the drug antibody, inconvenience in intravenous administration mode and the like, and still has a far-unmet medical requirement in the field. Many patients receiving treatment have not been alleviated, and up to 80% of patients with crohn's disease and 30% of patients with UC eventually require surgical treatment.
Tofacitinib (Xeljanz) is the first oral JAK inhibitor for treating moderate-to-severe active adult patients with UC, has obvious inhibitory activity on JAK1, subtypes 2 and 3, increases the curative effect of the tofacitinib, and brings more serious side effects. Adverse reactions include infection, tuberculosis, tumors, anemia, liver damage, increased cholesterol, and the like. The specification for Tofacitinib is indicated by a number of black boxes: severe infections (tuberculosis, bacteria, fungi, viruses) and malignancies (lymphomas, etc.). Due to the wide range of functions mediated by each JAK, these side effects are caused by the simultaneous inhibition of multiple JAKs by the drug. Since JAKs are widely involved in the regulation of immune cells, JAK inhibitors inevitably cause side effects associated with immunosuppression, such as severe infection, even tumorigenesis, and the like. Even with the numerous highly selective inhibitors currently under investigation, such side effects caused by the inhibitory target are unavoidable.
In view of the good curative effect and the relevant serious side effect of multiple targets of the JAK inhibitor, the problem to be solved urgently at present is to develop a JAK inhibitor medicine with higher safety. Since inflammatory bowel disease occurs on the luminal surface of the gastrointestinal tract and acts without the need for drugs to enter the blood system, the development of a drug that reduces systemic exposure of the drug in the blood circulation and increases the local exposure of the drug at the site of inflammation is a good strategy to increase safety. International application WO2016191524a1 reports that Theravance corporation synthesizes a series of compounds that have very low systemic exposure and form enrichment at intestinal inflammatory sites, and can effectively treat intestinal inflammation without causing serious side effects, indicating that the strategy has great feasibility and may generate great clinical application value.
The invention discloses a series of structures of heteroaromatic derivative inhibitors in PCT patent (application number: PCT/CN2019/121944), and comprehensively researches free base crystal forms of the compounds in subsequent development for the purposes of easy product treatment, filtration and drying, and searching for suitable crystals which are convenient to store, stable for a long time and high in bioavailability.
Disclosure of Invention
All that is referred to in patent PCT/CN2019/121944 is added to the present invention by way of reference.
The invention aims to provide an acid salt of a compound shown in a general formula (I), which has the following structure:
Figure BDA0003083170700000031
wherein:
L1selected from the group consisting of a bond, - (CH)2)r-、-(CH2)rS(O)2-、-S(O)2(CH2)r-、-(CH2)rS(O)2NRa-、-(CH2)rNRa-、-C(O)(CH2)r-、-C(O)(CH2)rNRa-、-C(O)(CH2)rNRa(CH2)s-、-(CH2)rC (O) -or- (CH)2)rC(O)NRa-；
RaSelected from hydrogen, C1-6Alkyl radical, C1-6Hydroxyalkyl or C1-6An alkoxy group;
R1selected from hydrogen, cyano, halogen, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C3-8Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-10 membered heteroaryl, optionally further substituted by cyano, halogen, C1-6Alkyl radical, C1-6Alkoxy or C1-6Substituted by one or more substituents of hydroxyalkyl, preferably hydrogen, cyano, halogen, C1-3Alkyl radical, C3-6Cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered nitrogen-containing heteroaryl, optionally further oneStep (5) by cyano, halogen, C1-3Alkyl radical, C 1-3Alkoxy or C1-3Substituted with one or more substituents in hydroxyalkyl;
R2selected from hydrogen or C1-6An alkyl group;
R3selected from hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C1-6Alkoxy radical, C1-6Alkyl monosubstituted amino, C1-6Alkyl disubstituted amino, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C1-6Alkyl monosubstituted amino, C1-6Alkyl disubstituted amino, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-12Aryl or 5-to 10-membered heteroaryl, preferably hydrogen, hydroxy, halogen, amino, C1-3Alkyl radical, C3-6Cycloalkyl, 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, phenyl or 5-6 membered nitrogen containing heteroaryl, optionally further substituted by halogen, amino, cyano, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Alkyl monosubstituted amino, C1-3Alkyl disubstituted amino, C3-6Cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered nitrogen containing heteroaryl;
R4selected from hydrogen, C1-6Alkyl radical, C1-6Hydroxyalkyl or C1-6An alkoxy group;
ring A is selected from aryl, five-membered sulfur-containing heterocyclic group, preferably phenyl,
Figure BDA0003083170700000032
Figure BDA0003083170700000041
Ring B is selected from 5-10 membered nitrogen-containing heterocyclic group, preferably
Figure BDA0003083170700000042
Figure BDA0003083170700000043
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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy-hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic acid, lactobionic acid, lactic acid, tartaric acid, citric acid, tartaric acid, citric acid, tartaric acid, citric acid, tartaric acid, citric acid, tartaric acid, citric 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, or L-malic acid;
m is 1, 2 or 3;
r is 0, 1, 2 or 3;
s is 1, 2 or 3.
In a further preferred embodiment of the present invention, the compound has the structure represented by general formula (II):
Figure BDA0003083170700000051
wherein n is 1 or 2.
In a further preferred embodiment of the inventionIn (1), the R1Selected from hydrogen, cyano, halogen, C1-3Alkyl, phenyl,
Figure BDA0003083170700000052
Optionally further substituted by cyano, halogen, C1-3Alkyl radical, C1-3Substituted with one or more substituents in the alkoxy group.
In a further preferred embodiment of the invention, R is3Selected from the group consisting of hydrogen, hydroxy, halofluoro, chloro, bromo, amino, methylamino, ethylamino, dimethylamino, methyl, ethyl, hydroxymethyl, methoxy, ethoxy, phenyl, methyl, ethyl, methyl, ethyl, propyl, isopropyl, and the isopropyl, and the like,
Figure BDA0003083170700000053
Figure BDA0003083170700000054
Optionally further substituted by halogen, amino, C1-3Alkyl monosubstituted amino, C1-3Alkyl disubstituted amino, C1-3Alkyl radical, C1-3Hydroxyalkyl radical, C1-3Alkoxy, phenyl, or a salt thereof,
Figure BDA0003083170700000055
Figure BDA0003083170700000056
Is substituted with one or more substituents.
In a further preferred embodiment of the 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, isethionic 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, 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, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; further preferred is phosphoric acid, maleic acid or benzenesulfonic acid.
In a further preferred embodiment of the invention, the general formula (I) is selected from the following compounds:
Figure BDA0003083170700000061
Figure BDA0003083170700000071
Figure BDA0003083170700000081
Figure BDA0003083170700000091
Figure BDA0003083170700000101
Figure BDA0003083170700000111
Figure BDA0003083170700000121
Figure BDA0003083170700000131
Figure BDA0003083170700000141
the specific structures of the compounds corresponding to the corresponding numbers are as follows:
Figure BDA0003083170700000142
Figure BDA0003083170700000151
Figure BDA0003083170700000161
Figure BDA0003083170700000171
Figure BDA0003083170700000181
Figure BDA0003083170700000191
in a further preferred embodiment of the invention, the general formula (I) is selected from the following compounds:
Figure BDA0003083170700000192
Figure BDA0003083170700000201
Figure BDA0003083170700000211
the acid is selected from phosphoric acid, succinic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, malonic acid, pamoic acid, ethanesulfonic acid, benzoic acid, malic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid or stearic acid, preferably phosphoric acid, succinic acid, maleic acid, isethionic acid, 1, 5-naphthalenedisulfonic acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid or fumaric acid.
In a further preferred embodiment of the invention, the acid salt of compound 1- ((3-exo) -3- ((4- ((5-methyl-1 h-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethan-1-one, wherein the acid is selected from hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic 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.
In a further preferred embodiment of the invention, the 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) -8-azabicyclo [3.2.1] octan-8-yl) -2-morpholinoethan-1-one, wherein the acid salt is selected from hydrochloride, maleate, benzenesulfonate, isethionate, 1, 5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate or stearate.
In a further preferred embodiment of the invention, the compound 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) ethan-1-one is an acid salt, wherein the acid salt is selected from the group consisting of hydrochloride, maleate, benzenesulfonate, isethionate, 1, 5-naphthalenedisulfonate, tartrate, adipate, sulfate, p-toluenesulfonate, hydrobromide, oxalate, fumarate, formate, hippurate, laurate and stearate. ,
in a further preferred embodiment of the 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] octan-8-yl) propionitrile, wherein the acid is selected from phosphoric acid, succinic acid, acetic acid, hydrochloric acid, benzenesulfonic acid, hydrobromic acid, oxalic acid, adipic acid, ethanesulfonic acid, benzoic acid, 1, 5-naphthalenedisulfonic acid, pamoic acid, hippuric acid, sulfuric acid, malonic acid, p-toluenesulfonic acid, maleic acid, malic acid, tartaric acid, fumaric acid, preferably phosphoric acid.
In a further preferred embodiment of the invention, the number of acids is from 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
In a further preferred embodiment of the invention, the acid salt is a hydrate or an anhydrate, and when the acid salt is a hydrate, the number of water ranges from 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, 1- ((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] octan-8-yl) -2-morpholinoethan-1-one and 2- (ethylamino) ) An acid salt of-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) ethan-1-one, wherein the acid salt is a maleate salt and the number of acids is 1 or 2.
In a further preferred embodiment of the invention, the compound is an acid salt of 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile, wherein the acid salt is a phosphate and the number of acids is 1 or 2.
In a further preferred embodiment of the invention, the compound 1- ((3-exo) -3- ((4- ((5-methyl-1 h-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethan-1-one in the form of its acid salt in crystalline form, wherein the acid is selected from the group consisting of hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic 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.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile in its acid salt crystalline form, wherein the acid is selected from phosphoric acid, succinic acid, acetic acid, hydrochloric acid, benzenesulfonic acid, hydrobromic acid, oxalic acid, adipic acid, ethanesulfonic acid, benzoic acid, 1, 5-naphthalenedisulfonic acid, pamoic acid, hippuric acid, sulfuric acid, malonic acid, p-toluenesulfonic acid, maleic acid, malic acid, tartaric acid, fumaric acid, preferably phosphoric acid.
In a further preferred embodiment of the invention, the number of acids is from 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form a has an X-ray powder diffraction pattern having a diffraction peak at 9.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 13.4 ± 0.2 ° and 22.7 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 11.0 ± 0.2 °, 14.9 ± 0.2 °, 18.2 ± 0.2 ° and 22.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 17.4 ± 0.2 °, 17.8 ± 0.2 °, 18.4 ± 0.2 °, 19.1 ± 0.2 °, 19.7 ± 0.2 °, 20.2 ± 0.2 °, 21.1 ± 0.2 ° and 25.7 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 24.1 ± 0.2 °, 24.7 ± 0.2 °, 25.9 ± 0.2 °, 27.7 ± 0.2 ° and 29.1 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 16.9 ± 0.2 °, 23.1 ± 0.2 °, 24.3 ± 0.2 °, 26.5 ± 0.2 °, 28.3 ± 0.2 ° and 29.7 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 1.
TABLE 1
Figure BDA0003083170700000231
Figure BDA0003083170700000241
Figure BDA0003083170700000251
Crystalline form a of the benzenesulfonate salt of the 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] nonan-9-yl) -2- (methylamino) -ethane-1-one according to the present invention has an X-ray powder diffraction pattern substantially as shown in fig. 1, a DSC pattern substantially as shown in fig. 2, and a TGA pattern substantially as shown in fig. 3.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form B has an X-ray powder diffraction pattern with a diffraction peak at 13.6 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 21.4 ± 0.2 ° and 23.7 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.7 ± 0.2 °, 9.2 ± 0.2 °, 18.4 ± 0.2 ° and 23.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 10.9 ± 0.2 °, 13.0 ± 0.2 °, 14.3 ± 0.2 °, 14.8 ± 0.2 °, 15.8 ± 0.2 °, 18.0 ± 0.2 °, 19.2 ± 0.2 ° and 19.5 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, the optical film further comprises diffraction peaks at 21.7 ± 0.2 °, 22.3 ± 0.2 ° and 24.4 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2 theta angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 2.
TABLE 2
Figure BDA0003083170700000252
Figure BDA0003083170700000261
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one besylate crystal form B has an X-ray powder diffraction pattern basically shown in figure 4.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form C has an X-ray powder diffraction pattern with a diffraction peak at 14.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 21.5 ± 0.2 ° and 22.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.1 ± 0.2 °, 13.6 ± 0.2 °, 18.3 ± 0.2 ° and 18.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 22.5 ± 0.2 °, 23.4 ± 0.2 °, 23.7 ± 0.2 ° and 24.5 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 3.
TABLE 3
Figure BDA0003083170700000271
Figure BDA0003083170700000281
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a benzenesulfonate crystalline form C, an X-ray powder diffraction pattern of which is substantially as shown in figure 5, a DSC pattern of which is substantially as shown in figure 6, and a TGA pattern of which is substantially as shown in figure 7.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form D has an X-ray powder diffraction pattern having a diffraction peak at 18.2 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 11.0 ± 0.2 ° and 22.2 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.6 ± 0.2 °, 21.2 ± 0.2 °, 21.5 ± 0.2 ° and 25.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.7 ± 0.2 °, 13.5 ± 0.2 °, 14.9 ± 0.2 °, 15.3 ± 0.2 °, 17.4 ± 0.2 °, 18.6 ± 0.2 °, 19.1 ± 0.2 ° and 19.8 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 22.7 ± 0.2 °, 24.7 ± 0.2 °, 25.8 ± 0.2 ° and 27.6 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 16.9 ± 0.2 °, 19.4 ± 0.2 °, 20.4 ± 0.2 °, 23.1 ± 0.2 °, 26.3 ± 0.2 °, 28.2 ± 0.2 ° and 29.1 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 4.
TABLE 4
Figure BDA0003083170700000282
Figure BDA0003083170700000291
Figure BDA0003083170700000301
The compound of the invention, 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-D ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a benzenesulfonate crystal form D, and an X-ray powder diffraction pattern is substantially as shown in figure 8.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form E has an X-ray powder diffraction pattern having a diffraction peak at 21.4 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 11.9 ± 0.2 ° and 21.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.8 ± 0.2 °, 8.7 ± 0.2 °, 14.3 ± 0.2 ° and 25.0 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 10.6 ± 0.2 °, 12.1 ± 0.2 °, 15.7 ± 0.2 °, 16.1 ± 0.2 °, 16.8 ± 0.2 °, 22.5 ± 0.2 °, 26.4 ± 0.2 ° and 27.2 ± 0.2 ° of 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 5.
TABLE 5
Figure BDA0003083170700000311
Figure BDA0003083170700000321
Crystalline form E of the benzenesulfonate 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] nonan-9-yl) -2- (methylamino) -ethane-1-one according to the invention has an X-ray powder diffraction pattern substantially as shown in FIG. 9, a DSC pattern substantially as shown in FIG. 10, and a TGA pattern substantially as shown in FIG. 11.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form F having an X-ray powder diffraction pattern with a diffraction peak at 18.2 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 13.4 ± 0.2 ° and 24.6 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 15.2 ± 0.2 °, 16.8 ± 0.2 °, 20.9 ± 0.2 ° and 25.0 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, the optical element further comprises diffraction peaks at 6.8 ± 0.2 °, 9.4 ± 0.2 °, 18.2 ± 0.2 °, 19.5 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 °, 23.11 ± 0.2 °, 24.6 ± 0.2 ° and 29.7 ± 0.2 ° of 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 6.
TABLE 6
Figure BDA0003083170700000322
Figure BDA0003083170700000331
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a benzenesulfonate crystalline form F, the X-ray powder diffraction pattern of which is substantially as shown in figure 12.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form G having an X-ray powder diffraction pattern with a diffraction peak at 20.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 17.8 ± 0.2 ° and 21.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 15.9 ± 0.2 °, 17.1 ± 0.2 °, 20.8 ± 0.2 ° and 22.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 12.4 ± 0.2 °, 13.1 ± 0.2 °, 18.7 ± 0.2 °, 19.7 ± 0.2 ° and 25.7 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 7.
TABLE 7
Figure BDA0003083170700000341
Figure BDA0003083170700000351
The compound of the invention, 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a benzenesulfonate crystal form G, and the X-ray powder diffraction pattern thereof is substantially as shown in figure 13.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one besylate crystalline form H has an X-ray powder diffraction pattern with a diffraction peak at 21.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 11.9 ± 0.2 ° and 20.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.9 ± 0.2 °, 14.2 ± 0.2 °, 17.5 ± 0.2 ° and 26.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.7 ± 0.2 °, 10.5 ± 0.2 °, 16.0 ± 0.2 °, 17.8 ± 0.2 °, 22.0 ± 0.2 °, 22.4 ± 0.2 °, 25.0 ± 0.2 ° and 25.3 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, the optical film further comprises diffraction peaks at 17.3 ± 0.2 °, 18.4 ± 0.2 ° and 28.0 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 8.
TABLE 8
Figure BDA0003083170700000361
Figure BDA0003083170700000371
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one besylate crystal form H has an X-ray powder diffraction pattern basically shown in figure 14.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one is present in the form of the sulfate salt form a having a diffraction peak at 14.0 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising having diffraction peaks at 16.0 ± 0.2 ° and 22.0 ± 0.2 ° 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 13.3 ± 0.2 °, 19.3 ± 0.2 °, 21.8 ± 0.2 ° and 22.7 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 7.4 ± 0.2 °, 11.0 ± 0.2 °, 11.5 ± 0.2 °, 12.8 ± 0.2 °, 15.0 ± 0.2 °, 17.4 ± 0.2 °, 21.5 ± 0.2 ° and 27.4 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, it further comprises diffraction peaks at 8.8 + -0.2 °, 10.0 + -0.2 °, 15.4 + -0.2 °, 16.9 + -0.2 °, 19.7 + -0.2 °, 20.8 + -0.2 °, 22.5 + -0.2 °, 23.1 + -0.2 °, 23.9 + -0.2 °, 24.2 + -0.2 °, 27.0 + -0.2 °, 28.0 + -0.2 ° and 28.2 + -0.2 ° of 2 θ (+ -0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 9.
TABLE 9
Figure BDA0003083170700000372
Figure BDA0003083170700000381
Figure BDA0003083170700000391
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, has a crystalline form A of the sulfate salt with an X-ray powder diffraction pattern substantially as shown in figure 15, a DSC pattern substantially as shown in figure 16 and a TGA pattern substantially as shown in figure 17.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one isethionate salt crystalline form a having an X-ray powder diffraction pattern with diffraction peaks at 10.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 17.0 ± 0.2 ° and 22.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 7.0 ± 0.2 °, 19.1 ± 0.2 °, 20.1 ± 0.2 ° and 20.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 14.2 ± 0.2 °, 14.7 ± 0.2 °, 16.3 ± 0.2 °, 21.4 ± 0.2 °, 21.8 ± 0.2 °, 22.2 ± 0.2 °, 24.6 ± 0.2 ° and 26.0 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, the optical film further comprises diffraction peaks at 9.3 ± 0.2 °, 18.8 ± 0.2 °, 23.8 ± 0.2 ° and 25.4 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 10.
Watch 10
Figure BDA0003083170700000392
Figure BDA0003083170700000401
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in crystal form a, and has an X-ray powder diffraction pattern substantially as shown in figure 18; a DSC profile substantially as shown in figure 19; the TGA profile is substantially as shown in figure 20.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one isethionate salt form B having an X-ray powder diffraction pattern with diffraction peaks at 11.4 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 18.4 ± 0.2 ° and 20.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.1 ± 0.2 °, 11.4 ± 0.2 °, 17.4 ± 0.2 ° and 26.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 15.8 ± 0.2 °, 17.1 ± 0.2 °, 21.5 ± 0.2 °, 22.6 ± 0.2 °, 23.0 ± 0.2 °, 23.6 ± 0.2 °, 24.9 ± 0.2 ° and 25.2 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, diffraction peaks at 9.8 ± 0.2 °, 13.9 ± 0.2 °, 14.9 ± 0.2 °, 22.9 ± 0.2 °, 26.1 ± 0.2 ° and 28.6 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 11.
TABLE 11
Figure BDA0003083170700000411
Figure BDA0003083170700000421
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in crystal form B, and has an X-ray powder diffraction pattern substantially as shown in figure 21; a DSC profile substantially as shown in figure 22; the TGA profile is substantially as shown in figure 23.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one isethionate salt crystalline form C has an X-ray powder diffraction pattern with a diffraction peak at 20.0 ± 0.2 ° 2 Θ (± 0.2 °); more preferably, further comprising diffraction peaks at 18.5 ± 0.2 ° and 21.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 15.7 ± 0.2 °, 18.7 ± 0.2 °, 19.7 ± 0.2 ° and 23.4 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 6.6 ± 0.2 °, 11.3 ± 0.2 °, 12.8 ± 0.2 °, 14.6 ± 0.2 °, 20.3 ± 0.2 °, 20.6 ± 0.2 °, 26.6 ± 0.2 ° and 27.1 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 17.7 ± 0.2 °, 23.0 ± 0.2 °, 23.8 ± 0.2 °, 26.2 ± 0.2 °, 30.2 ± 0.2 ° and 32.1 ± 0.2 ° in 2 θ (± 0.2 °); most preferably, further comprising diffraction peaks at 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 ° in 2 θ (+ -0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 12.
TABLE 12
Figure BDA0003083170700000422
Figure BDA0003083170700000431
Figure BDA0003083170700000441
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one of the invention has a crystal form C of isethionate, and an X-ray powder diffraction pattern substantially as shown in figure 24; the DSC pattern is basically shown in figure 25.
In a further preferred embodiment of the invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, adipate crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 19.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 16.6 ± 0.2 ° and 20.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 18.0 ± 0.2 °, 18.4 ± 0.2 °, 18.6 ± 0.2 ° and 22.9 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.1 ± 0.2 °, 9.8 ± 0.2 °, 12.6 ± 0.2 °, 13.0 ± 0.2 °, 13.3 ± 0.2 °, 17.8 ± 0.2 °, 21.1 ± 0.2 ° and 26.4 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, the composition further comprises diffraction peaks at 24.2 ± 0.2 ° and 29.5 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 13.
Watch 13
Figure BDA0003083170700000442
Figure BDA0003083170700000451
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-ketone adipate crystal form A has an X-ray powder diffraction pattern basically shown in a figure 26; a DSC profile substantially as shown in figure 27; the TGA profile is substantially as shown in figure 28.
In a further preferred embodiment of the invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, adipate crystalline form B, has an X-ray powder diffraction pattern with a diffraction peak at 20.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 16.5 ± 0.2 ° and 19.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 13.2 ± 0.2 °, 17.8 ± 0.2 °, 21.3 ± 0.2 ° and 27.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 10.6 ± 0.2 °, 11.0 ± 0.2 °, 14.5 ± 0.2 °, 16.1 ± 0.2 °, 16.7 ± 0.2 °, 21.9 ± 0.2 °, 22.2 ± 0.2 ° and 23.5 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 17.5 ± 0.2 °, 19.2 ± 0.2 °, 23.3 ± 0.2 °, 24.2 ± 0.2 ° and 29.4 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 14.
TABLE 14
Figure BDA0003083170700000461
Figure BDA0003083170700000471
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one of the invention has the adipate crystal form B, and the X-ray powder diffraction pattern is basically shown in figure 29; a DSC profile substantially as shown in figure 30; the TGA profile is substantially as shown in figure 31.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, crystalline form a of the p-toluenesulfonate has an X-ray powder diffraction pattern having a diffraction peak at 9.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 14.7 ± 0.2 ° and 17.8 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 10.7 ± 0.2 °, 13.3 ± 0.2 °, 21.1 ± 0.2 ° and 25.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.6 ± 0.2 °, 14.9 ± 0.2 °, 18.5 ± 0.2 °, 19.8 ± 0.2 °, 21.7 ± 0.2 °, 22.2 ± 0.2 °, 22.8 ± 0.2 ° and 28.7 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 14.4 ± 0.2 °, 16.6 ± 0.2 °, 19.5 ± 0.2 °, 20.3 ± 0.2 °, 24.2 ± 0.2 °, 24.5 ± 0.2 °, and 25.5 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 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 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 15.
Watch 15
Figure BDA0003083170700000481
Figure BDA0003083170700000491
Crystalline form a of the p-toluenesulfonate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one of the present invention has an X-ray powder diffraction pattern substantially as shown in figure 32; a DSC profile substantially as shown in figure 33; the TGA profile is substantially as shown in figure 34.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, crystalline form B of the p-toluenesulfonate has an X-ray powder diffraction pattern having a diffraction peak at 20.9 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 7.0 ± 0.2 ° and 19.6 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.3 ± 0.2 °, 10.3 ± 0.2 °, 11.6 ± 0.2 ° and 25.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 12.4 ± 0.2 °, 13.2 ± 0.2 °, 14.6 ± 0.2 °, 16.3 ± 0.2 °, 18.2 ± 0.2 °, 19.0 ± 0.2 °, 20.3 ± 0.2 °, 21.6 ± 0.2 ° and 23.0 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 16.
TABLE 16
Figure BDA0003083170700000501
Figure BDA0003083170700000511
The p-toluenesulfonate crystalline form B of the 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] nonan-9-yl) -2- (methylamino) -ethane-1-one of the present invention has an X-ray powder diffraction pattern substantially as shown in FIG. 35; a DSC profile substantially as shown in figure 36; the TGA profile is substantially as shown in figure 37.
In a further preferred embodiment of the present invention, the fumarate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, form a, has an X-ray powder diffraction pattern with a diffraction peak at 20.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 12.1 ± 0.2 ° and 17.6 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 15.5 ± 0.2 °, 17.8 ± 0.2 °, 21.6 ± 0.2 ° and 25.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, the optical element further comprises diffraction peaks at 8.8 ± 0.2 °, 11.2 ± 0.2 °, 14.4 ± 0.2 °, 20.9 ± 0.2 °, 22.7 ± 0.2 °, 24.4 ± 0.2 °, 24.7 ± 0.2 °, 26.4 ± 0.2 ° and 26.8 ± 0.2 ° of 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 17.
TABLE 17
Figure BDA0003083170700000512
Figure BDA0003083170700000521
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in the fumarate crystalline form a, having an X-ray powder diffraction pattern substantially as shown in figure 38; a DSC profile substantially as shown in figure 39; its TGA profile is substantially as shown in figure 40.
In a further preferred embodiment of the present invention, the fumarate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, form B, has an X-ray powder diffraction pattern with a diffraction peak at 10.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 15.5 ± 0.2 ° and 19.8 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 11.8 ± 0.2 °, 19.1 ± 0.2 °, 20.1 ± 0.2 ° and 21.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 6.6 ± 0.2 °, 14.1 ± 0.2 °, 16.5 ± 0.2 °, 17.2 ± 0.2 °, 18.0 ± 0.2 °, 23.9 ± 0.2 °, 24.5 ± 0.2 ° and 24.8 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 11.3 ± 0.2 °, 12.2 ± 0.2 °, 17.6 ± 0.2 ° and 22.0 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 18.
Watch 18
Figure BDA0003083170700000522
Figure BDA0003083170700000531
The fumarate salt crystal form B of the compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one has an X-ray powder diffraction pattern substantially as shown in figure 41; the DSC pattern is basically shown in figure 42.
In a further preferred embodiment of the present invention, the fumarate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, form C, has an X-ray powder diffraction pattern with a diffraction peak at 6.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 15.5 ± 0.2 ° and 19.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 10.8 ± 0.2 °, 19.9 ± 0.2 °, 20.4 ± 0.2 ° and 21.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 6.8 ± 0.2 °, 12.8 ± 0.2 °, 8.6 ± 0.2 °, 13.6 ± 0.2 °, 16.6 ± 0.2 °, 17.0 ± 0.2 °, 18.0 ± 0.2 ° and 23.2 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, the composition further comprises diffraction peaks at 24.2 ± 0.2 ° and 24.6 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 19.
Watch 19
Figure BDA0003083170700000541
Figure BDA0003083170700000551
The fumarate salt crystal form C of the compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one has an X-ray powder diffraction pattern basically shown in figure 43.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one has the oxalate crystalline form a with an X-ray powder diffraction pattern having a diffraction peak at 19.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 11.2 ± 0.2 ° and 18.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 2 θ (± 0.2 °) and 9.0 ± 0.2 °, 22.4 ± 0.2 °, 24.6 ± 0.2 ° and 25.8 ± 0.2 °; further preferably, it further comprises diffraction peaks at 9.6 ± 0.2 °, 14.8 ± 0.2 °, 17.7 ± 0.2 °, 18.8 ± 0.2 °, 20.3 ± 0.2 °, 20.6 ± 0.2 °, 23.6 ± 0.2 ° and 24.0 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, diffraction peaks at 7.0 ± 0.2 °, 13.0 ± 0.2 °, 14.3 ± 0.2 °, 15.6 ± 0.2 °, 16.3 ± 0.2 ° and 20.9 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 20.
Watch 20
Figure BDA0003083170700000552
Figure BDA0003083170700000561
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-ketone has oxalate crystal form A, and an X-ray powder diffraction pattern is basically shown in figure 44; a DSC profile substantially as shown in figure 45; the TGA profile is substantially as shown in figure 46.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one is crystalline form a of the hydrobromide salt having an X-ray powder diffraction pattern with a diffraction peak at 11.9 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 22.4 ± 0.2 ° and 27.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 14.9 ± 0.2 °, 18.6 ± 0.2 °, 20.5 ± 0.2 ° and 24.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 20.8 ± 0.2 °, 21.6 ± 0.2 ° and 25.2 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 21.
TABLE 21
Figure BDA0003083170700000571
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in the hydrobromide crystal form a, and has an X-ray powder diffraction pattern substantially as shown in figure 47; a DSC profile substantially as shown in figure 48; the TGA profile is substantially as shown in figure 49.
In a further preferred embodiment of the invention, 1, 5-naphthalenedisulfonate crystal form B 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] nonan-9-yl) -2- (methylamino) -ethan-1-one having a diffraction peak at 16.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 10.4 ± 0.2 ° and 18.4 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 ° and 26.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 11.5 ± 0.2 °, 12.4 ± 0.2 °, 14.5 ± 0.2 °, 17.5 ± 0.2 °, 19.0 ± 0.2 °, 22.0 ± 0.2 °, 23.8 ± 0.2 ° and 24.3 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 6.7 ± 0.2 °, 10.1 ± 0.2 °, 11.7 ± 0.2 °, 13.0 ± 0.2 °, 15.5 ± 0.2 ° and 25.1 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 22.
TABLE 22
Figure BDA0003083170700000581
Figure BDA0003083170700000591
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidine-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-yl) -2- (methylamino) -ethane-1-ketone has the crystal form B of 1, 5-naphthalenedisulfonate, and the X-ray powder diffraction pattern of the crystal form B is basically shown as the graph 50.
In a further preferred embodiment of the invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, form C of the 1, 5-naphthalenedisulfonate crystal, having a diffraction peak at 8.8 ± 0.2 ° 2 θ (± 0.2 °); preferably, further comprising diffraction peaks at 15.1 ± 0.2 ° and 24.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 13.4 ± 0.2 °, 13.9 ± 0.2 °, 15.5 ± 0.2 ° and 18.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 14.8 ± 0.2 °, 17.0 ± 0.2 °, 18.9 ± 0.2 °, 19.8 ± 0.2 °, 20.3 ± 0.2 °, 21.0 ± 0.2 °, 21.4 ± 0.2 ° and 24.1 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 23.
TABLE 23
Figure BDA0003083170700000592
Figure BDA0003083170700000601
1, 5-naphthalenedisulfonate crystal form C of compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one, wherein an X-ray powder diffraction pattern is substantially shown in figure 51; a DSC profile substantially as shown in figure 52; the TGA profile is substantially as shown in figure 53.
In a further preferred embodiment of the invention, 1, 5-naphthalenedisulfonate crystal form D 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] nonan-9-yl) -2- (methylamino) -ethan-1-one having a diffraction peak at 20.4 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 10.4 ± 0.2 ° and 20.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 12.6 ± 0.2 °, 14.4 ± 0.2 °, 22.5 ± 0.2 ° and 24.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 7.2 ± 0.2 °, 10.9 ± 0.2 °, 15.2 ± 0.2 °, 16.9 ± 0.2 °, 18.5 ± 0.2 °, 24.7 ± 0.2 °, 25.1 ± 0.2 ° and 26.5 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 9.2 ± 0.2 °, 14.6 ± 0.2 °, 16.0 ± 0.2 °, 19.4 ± 0.2 °, 21.9 ± 0.2 °, 27.5 ± 0.2 °, 28.1 ± 0.2 ° and 33.2 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 24.
Watch 24
Figure BDA0003083170700000611
Figure BDA0003083170700000621
1, 5-naphthalenedisulfonate crystal form D 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] nonan-9-yl) -2- (methylamino) -ethane-1-one according to the invention having an X-ray powder diffraction pattern substantially as shown in FIG. 54; a DSC profile substantially as shown in figure 55; the TGA profile is substantially as shown in figure 56.
In a further preferred embodiment of the invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one is crystalline form a of the tartrate salt having a diffraction peak at 21.6 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 16.0 ± 0.2 ° and 17.7 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 17.1 ± 0.2 °, 19.8 ± 0.2 °, 20.7 ± 0.2 ° and 22.5 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 13.1 ± 0.2 °, 14.2 ± 0.2 °, 14.5 ± 0.2 °, 20.1 ± 0.2 ° and 28.6 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 25.
TABLE 25
Figure BDA0003083170700000631
The compound of the invention 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one in the form of tartrate crystal form a, the X-ray powder diffraction pattern of which is substantially as shown in figure 57; a DSC profile substantially as shown in figure 58; the TGA profile is substantially as shown in figure 59.
In a further preferred embodiment of the present invention, 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, form a formate salt, has an X-ray powder diffraction pattern with a diffraction peak at 18.0 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 17.6 ± 0.2 ° and 23.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 12.8 ± 0.2 °, 14.5 ± 0.2 °, 21.0 ± 0.2 ° and 24.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 8.4 ± 0.2 °, 13.1 ± 0.2 °, 19.9 ± 0.2 °, 22.9 ± 0.2 °, 25.3 ± 0.2 °, 28.8 ± 0.2 ° and 31.0 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 26.
Watch 26
Figure BDA0003083170700000641
Figure BDA0003083170700000651
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-yl) -2- (methylamino) -ethane-1-ketone has a formate crystal form A, and an X-ray powder diffraction pattern of the formate crystal form A is basically shown in a figure 60.
Crystalline hippurate form a of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one having an X-ray powder diffraction pattern with a diffraction peak at 19.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 18.0 ± 0.2 ° and 19.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 17.6 ± 0.2 °, 21.3 ± 0.2 °, 21.8 ± 0.2 ° and 23.0 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 5.8 ± 0.2 °, 8.8 ± 0.2 °, 13.7 ± 0.2 °, 16.6 ± 0.2 °, 18.5 ± 0.2 °, 20.3 ± 0.2 °, 23.4 ± 0.2 ° and 25.3 ± 0.2 ° of 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 27.
Watch 27
Figure BDA0003083170700000652
Figure BDA0003083170700000661
The compound of the invention, 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a hippurate crystal form A, and the X-ray powder diffraction pattern is basically shown in figure 61.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, crystalline form a of the laurate salt having a diffraction peak at 2 Θ (± 0.2 °)9.6 ± 0.2 ° in an X-ray powder diffraction pattern; preferably, further comprising having diffraction peaks at 21.3 ± 0.2 ° and 23.0 ± 0.2 ° 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 2 θ (± 0.2 °)8.6 ± 0.2 °, 21.6 ± 0.2 °, 22.8 ± 0.2 ° and 25.4 ± 0.2 °; further preferably, it further comprises diffraction peaks at 12.7 ± 0.2 °, 15.0 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 17.9 ± 0.2 °, 20.0 ± 0.2 °, 22.3 ± 0.2 ° and 24.2 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, the optical film further comprises diffraction peaks at 14.8 ± 0.2 °, 18.4 ± 0.2 ° and 26.2 ± 0.2 ° in 2 θ (± 0.2 °).
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 28.
Watch 28
Figure BDA0003083170700000671
Figure BDA0003083170700000681
The compound of the invention, 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] nonan-9-yl) -2- (methylamino) -ethane-1-one, is in a laurate crystalline form a having an X-ray powder diffraction pattern substantially as shown in figure 62; a DSC profile substantially as shown in figure 63; the TGA profile is substantially as shown in figure 64.
In a further preferred embodiment of the present invention, the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, stearate in crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 20.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 17.5 ± 0.2 ° and 22.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 16.1 ± 0.2 °, 20.1 ± 0.2 °, 21.0 ± 0.2 ° and 23.7 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, diffraction peaks at 5.8 ± 0.2 °, 7.3 ± 0.2 °, 18.0 ± 0.2 °, 19.6 ± 0.2 °, 22.0 ± 0.2 ° and 23.2 ± 0.2 ° in 2 θ (± 0.2 °) are also included.
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 29.
Watch 29
Figure BDA0003083170700000691
Figure BDA0003083170700000701
The compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) -ethane-1-one of the invention has a stearate crystal form A, and an X-ray powder diffraction pattern is basically shown in a figure 65.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, succinate crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 6.8 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 5.8 ± 0.2 ° and 22.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 12.4 ± 0.2 °, 17.8 ± 0.2 °, 19.0 ± 0.2 ° and 26.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.0 ± 0.2 °, 11.7 ± 0.2 °, 13.7 ± 0.2 °, 14.8 ± 0.2 °, 18.6 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 ° and 23.5 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 16.7 ± 0.2 °, 25.0 ± 0.2 ° and 27.0 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 30.
Watch 30
Figure BDA0003083170700000702
Figure BDA0003083170700000711
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 has an X-ray powder diffraction pattern basically shown in figure 67.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, succinate crystalline form B, has an X-ray powder diffraction pattern with a diffraction peak at 21.6 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.4 ± 0.2 ° and 19.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 10.7 ± 0.2 °, 16.5 ± 0.2 °, 18.7 ± 0.2 ° and 19.7 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.9 ± 0.2 °, 15.5 ± 0.2 °, 17.0 ± 0.2 °, 17.3 ± 0.2 °, 20.3 ± 0.2 °, 21.1 ± 0.2 °, 25.7 ± 0.2 ° and 27.1 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 8.1 ± 0.2 °, 17.9 ± 0.2 ° and 23.1 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 31.
Watch 31
Figure BDA0003083170700000721
Figure BDA0003083170700000731
The compound of the invention, 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile, is in the succinate crystal form B, and has an X-ray powder diffraction pattern which is basically shown in a figure 68, a DSC pattern which is basically shown in a figure 69 and a TGA pattern which is basically shown in a figure 70;
in a further preferred embodiment of the 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] octan-8-yl) propionitrile acetate form a has an X-ray powder diffraction pattern with a diffraction peak at 20.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.3 ± 0.2 ° and 20.4 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.8 ± 0.2 °, 10.2 ± 0.2 °, 21.6 ± 0.2 ° and 23.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.9 ± 0.2 °, 16.9 ± 0.2 °, 19.2 ± 0.2 °, 26.7 ± 0.2 ° and 27.2 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 32.
Watch 32
Figure BDA0003083170700000741
Figure BDA0003083170700000751
The compound of the invention, namely 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 in acetate crystal form A, and the X-ray powder diffraction spectrum of the acetate crystal form A is basically shown in figure 71.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile acetate form B has an X-ray powder diffraction pattern with a diffraction peak at 8.1 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 9.6 ± 0.2 ° and 26.5 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 17.0 ± 0.2 °, 17.2 ± 0.2 °, 20.2 ± 0.2 ° and 22.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.6 ± 0.2 °, 10.2 ± 0.2 °, 14.0 ± 0.2 °, 15.2 ± 0.2 °, 16.3 ± 0.2 °, 16.6 ± 0.2 °, 19.8 ± 0.2 ° and 26.9 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 21.0 ± 0.2 ° and 23.6 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 33.
Watch 33
Figure BDA0003083170700000761
Figure BDA0003083170700000771
The compound of the invention, namely 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 in acetate crystal form B, and the X-ray powder diffraction spectrum of the acetate crystal form B is basically shown in figure 72.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile acetate form C has an X-ray powder diffraction pattern with a diffraction peak at 5.4 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 10.3 ± 0.2 ° and 21.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 2 θ (± 0.2 °) and at 15.7 ± 0.2 °, 19.5 ± 0.2 °, 22.9 ± 0.2 ° and 25.1 ± 0.2 °; further preferably, it further comprises diffraction peaks at 10.8 ± 0.2 °, 16.7 ± 0.2 °, 17.6 ± 0.2 °, 18.8 ± 0.2 °, 20.4 ± 0.2 °, 24.1 ± 0.2 °, 25.3 ± 0.2 ° and 29.0 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 34.
Watch 34
Figure BDA0003083170700000772
Figure BDA0003083170700000781
Figure BDA0003083170700000791
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 acetate crystal form C has an X-ray powder diffraction pattern basically shown in figure 73.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile acetate form D has an X-ray powder diffraction pattern with a diffraction peak at 4.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.1 ± 0.2 ° and 27.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 10.9 ± 0.2 °, 13.4 ± 0.2 °, 17.6 ± 0.2 ° and 18.9 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 10.3 ± 0.2 °, 13.9 ± 0.2 °, 14.4 ± 0.2 °, 15.2 ± 0.2 °, 20.3 ± 0.2 °, 23.2 ± 0.2 °, 25.8 ± 0.2 ° and 26.7 ± 0.2 ° of 2 θ (± 0.2 °); still further preferably, further comprising having diffraction peaks at 17.2 ± 0.2 °, 20.7 ± 0.2 °, 22.0 ± 0.2 ° and 22.6 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 35.
Watch 35
Figure BDA0003083170700000792
Figure BDA0003083170700000801
The compound of the invention, namely 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 in acetate crystal form D, and the X-ray powder diffraction spectrum of the acetate crystal form D is basically shown in figure 74.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile acetate form E has an X-ray powder diffraction pattern with a diffraction peak at 6.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 19.8 ± 0.2 ° and 20.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.0 ± 0.2 °, 10.3 ± 0.2 °, 22.3 ± 0.2 ° and 25.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 15.1 ± 0.2 °, 26.9 ± 0.2 °, 28.0 ± 0.2 ° and 29.5 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 36.
Watch 36
Figure BDA0003083170700000811
Figure BDA0003083170700000821
The compound of the invention, 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile, is in acetate crystal form E, and the X-ray powder diffraction spectrum is basically shown in figure 75.
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] octan-8-yl) propionitrile hydrochloride form a having a diffraction peak at 5.5 ± 0.2 ° 2 Θ (± 0.2 °) in its X-ray powder diffraction pattern; preferably, further comprising diffraction peaks at 9.1 ± 0.2 ° and 20.5 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.3 ± 0.2 °, 14.2 ± 0.2 °, 16.2 ± 0.2 ° and 27.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.7 ± 0.2 °, 10.3 ± 0.2 °, 19.0 ± 0.2 °, 25.1 ± 0.2 ° and 26.3 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 37.
Watch 37
Figure BDA0003083170700000822
Figure BDA0003083170700000831
The hydrochloride 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 has an X-ray powder diffraction pattern basically shown in a figure 76.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, hydrochloride form B, has an X-ray powder diffraction pattern with a diffraction peak at 10.2 ± 0.2 ° 2 θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.9 ± 0.2 ° and 20.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.5 ± 0.2 °, 17.9 ± 0.2 °, 22.2 ± 0.2 ° and 25.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 5.3 ± 0.2 °, 15.0 ± 0.2 °, 21.3 ± 0.2 °, 26.1 ± 0.2 °, 26.7 ± 0.2 ° and 29.5 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 38.
Watch 38
Figure BDA0003083170700000841
Figure BDA0003083170700000851
The hydrochloride 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 is shown in the figure 77 basically, and the X-ray powder diffraction spectrum of the hydrochloride crystal form B is shown in the figure 77.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile hydrochloride form C has an X-ray powder diffraction pattern with a diffraction peak at 6.3 ± 0.2 ° 2 θ (± 0.2 °); preferably, further comprising diffraction peaks at 18.9 ± 0.2 ° and 24.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 13.8 ± 0.2 °, 18.0 ± 0.2 °, 21.8 ± 0.2 ° and 27.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.4 ± 0.2 °, 11.3 ± 0.2 °, 16.0 ± 0.2 °, 21.5 ± 0.2 °, 23.0 ± 0.2 °, 27.3 ± 0.2 ° and 29.4 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 39.
Watch 39
Figure BDA0003083170700000852
Figure BDA0003083170700000861
The hydrochloride crystal form C 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 has an X-ray powder diffraction pattern basically shown in a figure 78.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile hydrochloride form D has an X-ray powder diffraction pattern with a diffraction peak at 5.2 ± 0.2 ° 2 θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.8 ± 0.2 ° and 26.3 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.8 ± 0.2 °, 13.8 ± 0.2 °, 19.8 ± 0.2 ° and 25.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 6.3 ± 0.2 °, 14.2 ± 0.2 °, 15.8 ± 0.2 °, 17.3 ± 0.2 °, 18.5 ± 0.2 ° and 23.3 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 40.
Watch 40
Figure BDA0003083170700000871
Figure BDA0003083170700000881
The hydrochloride crystal form D 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 has an X-ray powder diffraction pattern basically shown in a figure 79.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 6.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 12.1 ± 0.2 ° and 15.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 7.5 ± 0.2 °, 21.2 ± 0.2 °, 26.6 ± 0.2 ° and 27.0 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 14.8 ± 0.2 °, 15.3 ± 0.2 °, 16.2 ± 0.2 °, 20.0 ± 0.2 °, 20.5 ± 0.2 °, 21.8 ± 0.2 °, 23.8 ± 0.2 ° and 29.0 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 41.
Table 41
Figure BDA0003083170700000882
Figure BDA0003083170700000891
Figure BDA0003083170700000901
The X-ray powder diffraction spectrum of the benzenesulfonate 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 is basically shown in figure 80.
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] octan-8-yl) propionitrile, in crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 5.2 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.8 ± 0.2 ° and 19.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.8 ± 0.2 °, 9.6 ± 0.2 °, 18.5 ± 0.2 ° and 19.7 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.4 ± 0.2 °, 9.8 ± 0.2 °, 12.4 ± 0.2 °, 17.2 ± 0.2 °, 22.6 ± 0.2 °, 24.6 ± 0.2 °, 24.9 ± 0.2 °, 25.9 ± 0.2 ° and 27.0 ± 0.2 ° of 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 42.
Watch 42
Figure BDA0003083170700000902
Figure BDA0003083170700000911
The compound of the invention, namely the hydrobromide crystal form A 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, has an X-ray powder diffraction pattern basically as shown in a figure 81.
In a further preferred embodiment of the invention, the oxalate 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] octan-8-yl) propionitrile, form a, has an X-ray powder diffraction pattern with a diffraction peak at 5.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 8.4 ± 0.2 ° and 24.6 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.6 ± 0.2 °, 13.1 ± 0.2 °, 14.7 ± 0.2 ° and 27.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 7.2 ± 0.2 °, 12.4 ± 0.2 °, 16.9 ± 0.2 °, 20.0 ± 0.2 °, 20.9 ± 0.2 °, 24.4 ± 0.2 ° and 25.4 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 43.
Watch 43
Figure BDA0003083170700000921
Figure BDA0003083170700000931
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 of the invention has an oxalate crystal form A, and an X-ray powder diffraction spectrum is basically shown in figure 82.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, adipate form a, has an X-ray powder diffraction pattern with a diffraction peak at 7.9 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 21.3 ± 0.2 ° and 23.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 7.7 ± 0.2 °, 11.1 ± 0.2 °, 24.7 ± 0.2 ° and 27.4 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 13.1 ± 0.2 °, 16.5 ± 0.2 °, 20.1 ± 0.2 °, 25.1 ± 0.2 ° and 29.7 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 44.
Watch 44
Figure BDA0003083170700000932
Figure BDA0003083170700000941
Figure BDA0003083170700000951
The adipate 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 has an X-ray powder diffraction pattern basically shown in a figure 83.
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] octan-8-yl) propionitrile, ethanesulfonate form a, has an X-ray powder diffraction pattern with a diffraction peak at 6.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 5.5 ± 0.2 ° and 13.1 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.5 ± 0.2 °, 16.4 ± 0.2 °, 20.0 ± 0.2 ° and 22.0 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, the composition further comprises diffraction peaks at 12.9 ± 0.2 ° and 16.0 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 45.
TABLE 45
Figure BDA0003083170700000952
Figure BDA0003083170700000961
The ethanesulfonate 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 has an X-ray powder diffraction pattern basically shown in a figure 84.
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] octan-8-yl) propionitrile, form a benzoate, has an X-ray powder diffraction pattern having a diffraction peak at 21.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 9.5 ± 0.2 ° and 15.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 5.9 ± 0.2 °, 14.0 ± 0.2 °, 15.5 ± 0.2 ° and 25.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 6.8 ± 0.2 °, 9.1 ± 0.2 °, 12.2 ± 0.2 °, 19.7 ± 0.2 °, 20.8 ± 0.2 °, 23.7 ± 0.2 °, 26.0 ± 0.2 ° and 28.1 ± 0.2 ° of 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 46.
TABLE 46
Figure BDA0003083170700000971
Figure BDA0003083170700000981
The benzoate 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 provided by the invention has an X-ray powder diffraction spectrum basically as shown in figure 85.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, 1, 5-naphthalenedisulfonate form a, has an X-ray powder diffraction pattern with a diffraction peak at 9.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 4.7 ± 0.2 ° and 16.5 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 18.4 ± 0.2 °, 20.6 ± 0.2 °, 21.9 ± 0.2 ° and 23.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 13.0 ± 0.2 °, 14.1 ± 0.2 °, 17.6 ± 0.2 °, 21.6 ± 0.2 °, 22.5 ± 0.2 °, 24.7 ± 0.2 °, 25.1 ± 0.2 °, 26.2 ± 0.2 ° and 27.6 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 47.
Watch 47
Figure BDA0003083170700000982
Figure BDA0003083170700000991
Figure BDA0003083170700001001
The crystal form A of the 1, 5-naphthalenedisulfonate 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 is shown as a graph 86 basically in an X-ray powder diffraction pattern.
In a further preferred embodiment of the invention, the pamoate 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] octan-8-yl) propionitrile has an X-ray powder diffraction pattern with a diffraction peak at 21.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 7.9 ± 0.2 ° and 17.8 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 9.9 ± 0.2 °, 10.7 ± 0.2 °, 20.8 ± 0.2 ° and 23.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 6.7 ± 0.2 °, 11.2 ± 0.2 °, 14.6 ± 0.2 °, 16.4 ± 0.2 °, 16.9 ± 0.2 °, 18.3 ± 0.2 °, 20.4 ± 0.2 ° and 23.0 ± 0.2 ° in 2 θ (± 0.2 °); still further preferably, further comprising diffraction peaks at 12.7 ± 0.2 °, 19.4 ± 0.2 ° and 22.4 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 48.
Watch 48
Figure BDA0003083170700001002
Figure BDA0003083170700001011
Figure BDA0003083170700001021
Pamoate 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 provided by the invention has an X-ray powder diffraction pattern basically shown in a figure 87.
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] octan-8-yl) propionitrile, crystalline form a of its hippurate, has an X-ray powder diffraction pattern having a diffraction peak at 5.7 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 16.1 ± 0.2 ° and 23.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.1 ± 0.2 °, 11.6 ± 0.2 °, 21.7 ± 0.2 ° and 25.5 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 11.0 ± 0.2 °, 16.4 ± 0.2 °, 17.4 ± 0.2 ° and 24.6 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 49.
Watch 49
Figure BDA0003083170700001022
Figure BDA0003083170700001031
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 of the invention has a crystal form A of hippurate, and an X-ray powder diffraction pattern is basically shown in a figure 88.
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] octan-8-yl) propionitrile, sulfate crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 6.6 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 26.1 ± 0.2 ° and 29.55 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 12.1 ± 0.2 °, 16.9 ± 0.2 °, 17.8 ± 0.2 ° and 26.6 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.3 ± 0.2 °, 13.8 ± 0.2 °, 16.6 ± 0.2 °, 21.9 ± 0.2 °, 22.9 ± 0.2 °, 23.9 ± 0.2 °, 27.2 ± 0.2 ° and 27.7 ± 0.2 ° of 2 θ (± 0.2 °); still more preferably, further comprising diffraction peaks at 18.6 ± 0.2 °, 19.6 ± 0.2 ° and 25.1 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 50.
Watch 50
Figure BDA0003083170700001041
Figure BDA0003083170700001051
The compound of the invention, namely the sulfate crystal form A 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, has an X-ray powder diffraction pattern basically as shown in figure 89.
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] octan-8-yl) propionitrile, sulfate crystalline form B, has an X-ray powder diffraction pattern with a diffraction peak at 5.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 18.9 ± 0.2 ° and 25.5 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.5 ± 0.2 °, 14.1 ± 0.2 °, 17.1 ± 0.2 ° and 22.1 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 16.8 ± 0.2 °, 18.5 ± 0.2 °, 24.2 ± 0.2 ° and 25.3 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 51.
Watch 51
Figure BDA0003083170700001052
Figure BDA0003083170700001061
The compound of the invention, namely the sulfate crystal form B 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, has an X-ray powder diffraction pattern basically as shown in a figure 90.
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] octan-8-yl) propionitrile malonate salt form a having an X-ray powder diffraction pattern with a diffraction peak at 5.2 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 10.3 ± 0.2 ° and 10.8 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 4.8 ± 0.2 ° and 16.4 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 52.
Table 52
Figure BDA0003083170700001071
Figure BDA0003083170700001081
The malonate 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 has an X-ray powder diffraction pattern basically shown in a figure 91.
In a further preferred embodiment of the present invention, compound 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile, crystalline form a, p-toluenesulfonate has an X-ray powder diffraction pattern having a diffraction peak at 6.9 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 7.2 ± 0.2 ° and 25.6 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 14.3 ± 0.2 °, 15.4 ± 0.2 °, 19.8 ± 0.2 ° and 27.3 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.8 ± 0.2 °, 16.4 ± 0.2 ° and 20.3 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 53.
Watch 53
Figure BDA0003083170700001082
Figure BDA0003083170700001091
The p-toluenesulfonate 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 provided by the invention has an X-ray powder diffraction pattern basically shown in a figure 92.
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] octan-8-yl) propionitrile, in crystalline maleate form a, has an X-ray powder diffraction pattern having a diffraction peak at 4.3 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 6.8 ± 0.2 ° and 26.2 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 6.1 ± 0.2 °, 9.7 ± 0.2 °, 15.5 ± 0.2 ° and 27.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 12.2 ± 0.2 °, 12.6 ± 0.2 °, 13.6 ± 0.2 °, 16.4 ± 0.2 °, 17.2 ± 0.2 °, 18.0 ± 0.2 °, 20.2 ± 0.2 ° and 25.7 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 54.
Watch 54
Figure BDA0003083170700001101
Figure BDA0003083170700001111
The compound of the invention, 3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile, is in a maleate crystal form A, and an X-ray powder diffraction spectrum is basically shown in figure 93.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, malate salt form a, has an X-ray powder diffraction pattern having a diffraction peak at 7.7 ± 0.2 ° 2 θ (± 0.2 °); preferably, further comprising diffraction peaks at 19.6 ± 0.2 ° and 23.9 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 16.2 ± 0.2 °, 17.3 ± 0.2 °, 18.5 ± 0.2 ° and 24.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 9.5 ± 0.2 °, 10.8 ± 0.2 °, 19.1 ± 0.2 °, 22.0 ± 0.2 ° and 26.5 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 55.
Watch 55
Figure BDA0003083170700001112
Figure BDA0003083170700001121
Figure BDA0003083170700001131
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 of the invention has a malate crystal form A, and an X-ray powder diffraction spectrum is basically shown in figure 94.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, in crystalline form a, has an X-ray powder diffraction pattern with a diffraction peak at 5.5 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 9.5 ± 0.2 ° and 19.0 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 8.2 ± 0.2 °, 15.0 ± 0.2 °, 19.9 ± 0.2 ° and 25.8 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 10.9 ± 0.2 °, 13.9 ± 0.2 °, 16.4 ± 0.2 °, 18.6 ± 0.2 ° and 24.6 ± 0.2 ° in 2 θ (± 0.2 °);
Characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 56.
Watch 56
Figure BDA0003083170700001132
Figure BDA0003083170700001141
The X-ray powder diffraction spectrum of the tartrate 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 is basically shown in figure 95.
In a further preferred embodiment of the 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] octan-8-yl) propionitrile, in crystalline form a, has an X-ray powder diffraction pattern having a diffraction peak at 6.2 ± 0.2 ° 2 Θ (± 0.2 °); preferably, further comprising diffraction peaks at 6.9 ± 0.2 ° and 25.2 ± 0.2 ° in 2 θ (± 0.2 °); more preferably, further comprising diffraction peaks at 15.8 ± 0.2 °, 16.6 ± 0.2 °, 18.7 ± 0.2 ° and 25.2 ± 0.2 ° in 2 θ (± 0.2 °); further preferably, it further comprises diffraction peaks at 8.7 ± 0.2 °, 11.1 ± 0.2 °, 14.3 ± 0.2 °, 25.9 ± 0.2 ° and 26.7 ± 0.2 ° in 2 θ (± 0.2 °);
characteristic diffraction peaks of X-rays expressed in terms of 2. theta. angle and interplanar spacing d using Cu-K.alpha.radiation are shown in Table 57.
Watch 57
Figure BDA0003083170700001151
The fumarate 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 provided by the invention has an X-ray powder diffraction pattern basically as shown in a figure 96.
In a further preferred embodiment of the invention, the acid salt form is a hydrate or an anhydrate, and when the acid salt form is a hydrate, the number of water ranges from 0.2 to 3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3.
The invention also provides a method for preparing the acid salt of the compound shown in the general formula (I), which comprises the following steps:
1) weighing a proper amount of free alkali, and dissolving the free alkali by using a benign solvent;
2) weighing a proper amount of counter ion acid, and dissolving the counter ion acid by using an organic solvent;
3) mixing the two solutions, stirring to separate out or dripping a poor solvent and stirring to separate out;
4) quickly centrifuging or standing and drying to obtain a target product;
wherein:
the benign solvent is selected from 2-butanol, methanol, isopropanol, 2-butanone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; preferably one or more of 2-butanol, methanol or dimethyl sulfoxide;
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-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably one or more of methanol, ethanol or acetonitrile;
the poor 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;
the counter-ionic 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, fumaric acid, and the like, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic 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, isethionic 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, 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, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; further preferred is phosphoric acid, maleic acid or benzenesulfonic acid.
The invention also provides a method for preparing the acid salt of the compound shown in the general formula (I), which comprises the following steps:
1) weighing a proper amount of free alkali, and suspending with an adverse solvent;
2) weighing a proper amount of counter ion acid, and dissolving the counter ion acid by using an organic solvent;
3) adding the solution into the suspension, and stirring;
4) quickly centrifuging or standing and drying to obtain a salt of the compound;
wherein:
the poor solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 3-pentanone, isopropyl acetate, ethyl formate, 1, 4-dioxane, chlorobenzene, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol, tert-butanol or 2-butanone; preferably one or more of dichloromethane, toluene, acetonitrile, acetone, methanol or ethyl acetate;
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-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably one or more of methanol, ethanol or acetonitrile;
The counter-ionic 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, fumaric acid, and the like, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic 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, isethionic 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, 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, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; further preferred is phosphoric acid, maleic acid or benzenesulfonic acid.
The invention also provides a method for preparing the crystal form of the acid salt of the compound shown in the general formula (I), which comprises the following steps:
1) weighing a proper amount of compound salt, and suspending with a poor solvent;
2) shaking the suspension;
3) quickly centrifuging the suspension, removing supernatant, and drying the residual solid to constant weight to obtain a target product;
wherein:
the poor 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.
It is also an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of an acid salt or crystal form of an acid salt of the above-mentioned compound and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention also aims to provide application of the acid salt or the acid salt crystal form and the pharmaceutical composition in preparation of drugs for preventing and/or treating diseases related to JAK kinase, wherein the diseases related to JAK kinase are preferably inflammatory diseases and/or tumor diseases.
Wherein the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis and inflammatory bowel disease; wherein the inflammatory bowel disease is preferably chronic intestinal inflammatory disease, further preferably ulcerative colitis and Crohn's disease;
the tumor disease is selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myeloid leukemia, acute lymphocytic leukemia, ductal carcinoma of breast and non-small cell lung cancer.
Drawings
Figures 1-3 are XRPD, DSC, TGA graphic representations of besylate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 4 is an XRPD pattern of besylate crystalline form B 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 5-7 are XRPD, DSC, TGA graphic representations 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] nonan-9-yl) -2- (methylamino) -ethan-1-one as besylate salt form C.
Figure 8 is an XRPD pattern of besylate crystalline form D 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 9-11 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] nonan-9-yl) -2- (methylamino) -ethane-1-one is an XRPD, DSC, TGA graphic representation of besylate crystalline form E.
Figure 12 is an XRPD representation of besylate crystalline form F 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 13 is an XRPD pattern of benzenesulfonate salt form G 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 14 is an XRPD pattern of besylate form H 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 15-17 are XRPD, DSC, TGA graphic representations of the sulfate crystalline 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 18-20 are XRPD, DSC, TGA graphic representations of isethionate salt crystalline 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 21-23 are XRPD, DSC, TGA graphic representations of isethionate salt crystalline form B 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Fig. 24-25 are XRPD, DSC diagrams of isethionate salt form C 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 26-28 are XRPD, DSC, TGA graphic representations of adipate crystalline 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] nonan-9-yl) -2- (methylamino) -ethane-1-one.
Fig. 29-31 are XRPD, DSC, TGA graphic representations of adipate crystalline form B 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] nonan-9-yl) -2- (methylamino) -ethane-1-one.
FIGS. 32-34 are XRPD, DSC, TGA representations of crystalline form A of the p-toluenesulfonate salt of 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 35-37 are XRPD, DSC, TGA graphic representations of crystalline form B of the p-toluenesulfonate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 38-40 are XRPD, DSC, TGA graphic representations of fumarate salt 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 41-42 are XRPD, DSC diagrams of fumarate salt form B 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 43 is a graphical representation of the XRPD of fumarate salt form C 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 44-46 are XRPD, DSC, TGA graphic representations of oxalate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 47-49 are XRPD, DSC, TGA graphic representations of hydrobromide crystalline 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 50 is an XRPD pattern of 1, 5-naphthalenedisulfonate crystal form B 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 51-53 are XRPD, DSC, TGA graphic representations of 1, 5-naphthalenedisulfonate crystal form C 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 54-56 are XRPD, DSC, TGA graphic representations of 1, 5-naphthalenedisulfonate crystal form D 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
FIGS. 57-59 are XRPD, DSC, TGA graphic representations of tartrate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 60 is an XRPD pattern of formate salt 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 61 is an XRPD pattern of hippurate crystalline 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figures 62-64 are XRPD, DSC, TGA graphic representations of the laurate salt 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] nonan-9-yl) -2- (methylamino) -ethane-1-one.
Figure 65 is an XRPD pattern of stearate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 66 is an XRPD pattern of free base crystalline 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] nonan-9-yl) -2- (methylamino) -ethan-1-one.
Figure 67 is an XRPD pattern 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] octan-8-yl) propionitrile.
Figures 68-70 are XRPD, DSC, TGA graphic representations of succinate 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] octan-8-yl) propionitrile.
Figure 71 is an XRPD pattern of acetate 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] octan-8-yl) propionitrile.
Figure 72 is an XRPD pattern of acetate 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] octan-8-yl) propionitrile.
Figure 73 is an XRPD pattern of acetate form C 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] octan-8-yl) propionitrile.
Figure 74 is an XRPD pattern of acetate form D 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] octan-8-yl) propionitrile.
Figure 75 is an XRPD pattern of acetate form E 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] octan-8-yl) propionitrile.
Figure 76 is an XRPD pattern of hydrochloride 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] octan-8-yl) propionitrile.
Figure 77 is an XRPD pattern of hydrochloride 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] octan-8-yl) propionitrile.
Figure 78 is an XRPD pattern of hydrochloride form C 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] octan-8-yl) propionitrile.
Figure 79 is an XRPD pattern of hydrochloride form D 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] octan-8-yl) propionitrile.
Figure 80 is an XRPD pattern of benzenesulfonate 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] octan-8-yl) propionitrile.
Figure 81 is an XRPD pattern of hydrobromide 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] octan-8-yl) propionitrile.
Figure 82 is an XRPD pattern of oxalate 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] octan-8-yl) propionitrile.
Figure 83 is an XRPD pattern of adipate 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] octan-8-yl) propionitrile.
Figure 84 is an XRPD pattern of ethanesulfonate salt 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] octan-8-yl) propionitrile.
Figure 85 is an XRPD pattern of benzoate 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] octan-8-yl) propionitrile.
FIG. 86 is a graphical representation of the XRPD of 1, 5-naphthalenedisulfonate 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] octan-8-yl) propionitrile.
FIG. 87 is an XRPD pattern for pamoate 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] octan-8-yl) propionitrile.
Figure 88 is an XRPD pattern of hippurate 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] octan-8-yl) propionitrile.
Figure 89 is an XRPD pattern of sulfate 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] octan-8-yl) propionitrile.
Figure 90 is an XRPD pattern of sulfate 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] octan-8-yl) propionitrile.
Figure 91 is an XRPD pattern of malonate salt 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] octan-8-yl) propionitrile.
Figure 92 is an XRPD pattern of crystalline form a of the p-toluenesulfonate 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] octan-8-yl) propionitrile.
Figure 93 is an XRPD pattern of maleate 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] octan-8-yl) propionitrile.
Figure 94 is an XRPD pattern of malate salt 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] octan-8-yl) propionitrile.
Figure 95 is an XRPD pattern of tartrate 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] octan-8-yl) propionitrile.
Figure 96 is an XRPD pattern of fumarate salt 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] octan-8-yl) propionitrile.
Figure 97 is an XRPD pattern of free base crystalline 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] octan-8-yl) propionitrile.
Detailed Description
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, hydroxy-substituted alkyl and cyano-substituted alkyl.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl. The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably containing from 3 to 12 ring atoms,wherein 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, pyrrolidinonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring. The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl and the like, preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl or thiazolyl; more preferred are oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, pyridyl, thiazolyl, and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more 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 carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Alkoxy groups having 1 to 8 carbon atoms are preferred, alkoxy groups having 1 to 6 carbon atoms are more preferred, and alkoxy groups having 1 to 3 carbon atoms are most preferred. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"DMSO" refers to dimethyl sulfoxide.
"LDA" refers to lithium diisopropylamide.
"DMAP" refers to 4-dimethylaminopyridine.
"EtMgBr" refers to ethyl magnesium bromide.
"HOSu" refers to N-hydroxysuccinimide.
"EDCl" refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
"IPA" refers to isopropanol.
"MeOH" refers to methanol.
"EtOH" refers to ethanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to N, N-diisopropylethylamine.
"HEPES" means 4-hydroxyethylpiperazine ethanesulfonic acid.
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", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"stereoisomerism" encompasses geometric isomerism (cis-trans isomerism), optical isomerism, conformational isomerism, and the like.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
X-ray powder diffraction pattern (XRPD), which refers to the experimentally observed diffraction pattern or parameters derived therefrom, is characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that the experimental error therein will depend on the conditions of the instrument, the sample preparation and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns will generally vary with the conditions of the instrument, and those skilled in the art will appreciate that a suitable error tolerance for XRPD may be: 2 theta +/-0.5 degrees; 2 theta +/-0.4 degrees; 2 theta +/-0.3 degrees; 2 theta +/-0.2 deg. It is particularly noted that the relative intensities of the X-ray diffraction patterns may also vary with the experimental conditions, so that the order of the peak intensities cannot be considered as the sole or determining factor. In addition, due to the influence of experimental factors such as sample height, an overall shift in peak angle is caused, and a certain shift is usually allowed. Thus, it will be understood by those skilled in the art that any crystalline form having the same or similar characteristic peaks as the inventive profile is within the scope of the invention.
"TGA" refers to a thermogravimetric analysis (TGA) experiment.
"DSC" refers to a Differential Scanning Calorimetry (DSC) experiment.
"HPLC" refers to High Performance Liquid Chromatography (HPLC) experiments.
"PK" refers to Pharmacokinetic (PK) experiments.
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Preparation of compounds
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was measured using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C)18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001271
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine
Figure BDA0003083170700001272
To a solution of 2, 4-dichlorothieno [3,2-d ] pyrimidine (205mg,1mmol) in N-methylpyrrolidone (10mL) were added 3-amino-5-methylpyrazole (116mg,1.2mmol), DIPEA (258mg,2mmol) in this order, followed by stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50mL) was added to the reaction mixture, and the precipitated solid was filtered and slurried with ethyl acetate to give the title compound as a pale yellow solid (135mg, 51%).
MS m/z(ESI):266.0[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700001281
To a solution of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (135mg,0.51mmol) in N-butanol (5mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (138mg,0.61mmol), DIPEA (129mg,1mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 98:2) to give the title compound as a pale yellow solid (146mg, 63%).
MS m/z(ESI):456.2[M+H]+.
The third step: preparation of 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] octan-8-yl) propionitrile
Figure BDA0003083170700001282
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-carboxylate (146mg,0.32mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N,5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; methanol (10mL) was then added to dissolve it, DIPEA (166mg, 1.28mmol) was added slowly dropwise, stirring at room temperature for 10 minutes, acrylonitrile (25mg,0.48mmol) was added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (14.4mg, 11%).
1H NMR(400MHz,DMSO)δ12.02(s,1H),9.70(s,1H),7.89(s,1H),6.99(s,1H),6.44(d,J＝59.6Hz,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＝47.8,17.6Hz,6H).
MS m/z(ESI):409.2[M+H]+.
Example 2
3- ((3-exo) -3- ((7-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001291
Preparation of 3- ((3-exo) -3- ((7-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 1.
MS m/z(ESI):423.2[M+H]+.
Example 3
3- ((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) propionitrile
Figure BDA0003083170700001292
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine
Figure BDA0003083170700001301
To a solution of 2, 4-dichlorothieno [2,3-d ] pyrimidine (205mg,1mmol) in N-methylpyrrolidone (10mL) were added 3-amino-5-methylpyrazole (116mg,1.2mmol), DIPEA (258mg,2mmol) in this order, followed by stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (250mg, 94%).
MS m/z(ESI):266.0[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700001302
To a solution of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (250mg,0.94mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (256mg,1.13mmol), DIPEA (242mg,1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 98:2) to give the title compound as a pale yellow solid (200mg, 47%).
MS m/z(ESI):456.1[M+H]+.
The third step: preparation of 3- ((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] octan-8-yl) propionitrile
Figure BDA0003083170700001311
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-carboxylate (200mg,0.44mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N,5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; methanol (10mL) was then added to dissolve it, DIPEA (227mg, 1.76mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (35mg,0.66mmol) was added followed by stirring for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (31.6mg, 18%).
1H NMR(400MHz,DMSO)δ12.13(s,1H),9.93(s,1H),7.73(s,1H),6.88(d,J＝117.2Hz,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).
MS m/z(ESI):409.2[M+H]+.
Example 4
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001312
Preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [4,5-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 1.
MS m/z(ESI):410.2[M+H]+.
Example 5
3- ((3-exo) -3- ((7- ((5-methyl-1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001321
The first step is as follows: preparation of 5-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine
Figure BDA0003083170700001322
To a solution of 5, 7-dichlorothiazolo [5,4-d ] pyrimidine (206mg,1mmol) in dimethylsulfoxide (10mL) was added 3-amino-5-methylpyrazole (116mg,1.2mmol), DIPEA (258mg,2mmol) in this order, followed by stirring at 70 ℃ for 1 hour. After completion of the reaction, water (50mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (200mg, 75%).
MS m/z(ESI):267.0[M+H]+.
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0003083170700001323
To a solution of 5-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine (200mg,0.75mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (204mg,0.9mmol), DIPEA (193mg,1.5mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to give the title compound as a pale yellow solid (74mg, 22%).
MS m/z(ESI):457.1[M+H]+.
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001331
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (74mg,0.16mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N,2mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; methanol (10mL) was then added to dissolve it, DIPEA (83mg, 0.64mmol) was added slowly dropwise, stirring was carried out at room temperature for 10 minutes, and acrylonitrile (9mg,0.24mmol) was added followed by stirring for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (16.3mg, 25%).
1H NMR(400MHz,DMSO)δ12.07(s,1H),9.33(s,1H),8.76(d,J＝20.4Hz,1H),6.96(s,1H),6.55(d,J＝12.0Hz,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).
Example 6
1- (((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] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001332
The first step is as follows: preparation of (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0003083170700001341
2, 4-dichlorothieno [2,3-d ] pyrimidine (100mg, 0.49mmol), (3-amino-1H-pyrazol-5-yl) methanol (55mg, 0.49mmol), DIPEA (190mg, 1.47mmol) and the reaction mixture were added to N' N-dimethylformamide (2mL), and the reaction mixture was stirred at 70 ℃ overnight. Concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (100mg, 73%).
MS m/z(ESI):282.0[M+H]+.
The second step is that: preparation 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-carboxylate
Figure BDA0003083170700001342
Adding (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg,0.36mmol), tert-butyl (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (135mg,0.53mmol) and DIPEA (140mg,1.08mmol) into n-butanol (2.5mL), uniformly mixing, reacting at the temperature of 150 ℃ for 10 hours by using a microwave, cooling to room temperature, concentrating the reaction liquid under reduced pressure, and separating and purifying the obtained crude product by using a flash silica gel column chromatography to obtain a white solid (70mg, 39%).
MS m/z(ESI):500.1[M+H]+.
The third step: preparation of 1- (((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] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001343
Dioxane hydrochloride (4N,2.5mL) was slowly added dropwise to a methanol (10mL) 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-carboxylate (70mg, 0.14mmol), the mixture was reacted at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the crude product was dissolved in DMF (5mL), DIPEA (0.3mL) and 3-cyanoazetidine-1-sulfonyl chloride (22mg,0.12mmol) were added in an ice-water bath at 0 ℃ and the mixture was reacted at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to give the title compound as a white solid (9.7mg, 13%)
1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),7.68(d,J＝4.4Hz,1H),7.04(d,J＝6.0Hz,1H),6.52-6.54(m,1H),5.53-5.55(m,1H),5.33-5.35(m,1H),4.44(d,J＝5.2Hz,2H),4.05-4.01(m,4H),3.94-3.90(m,2H),382-3.79(m,1H),2.89(d,J＝8.4Hz,3H),2.08-1.68(m,11H).
MS m/z(ESI):544.1[M+H]+.
Example 7
1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001351
Preparation of 1- (((3-exo) -3- ((7- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 6.
MS m/z(ESI):545.2[M+H]+.
Example 8
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) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001352
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-carboxylate (200mg, 0.439mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (20mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (1.45mL, 8.78mmol) and 3-cyanoazetidine-1-sulfonyl chloride (95mg, 0.527mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (70mg, 32%).
1H NMR(400MHz，MeOD-d4)δ7.37(d，J＝6.0Hz，1H)，6.94(d，J＝6.0Hz，1H)，6.25(s，1H)，4.44-4.34(m，1H)，4.26(s，2H)，4.16(t，J＝8.5Hz，2H)，4.12-4.05(m，2H)，3.57(ddd，J＝15.3，8.7，6.5Hz，1H)，2.31(s，3H)，2.23-2.10(m，4H)，2.01(d，J＝7.4Hz，2H)，1.73(dd，J＝18.2，7.1Hz，2H).
MS m/z(ESI):500.1[M+H]+.
Example 9
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] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001361
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, and after addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring at room temperature was continued overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (14.4mg, 13%).
1H NMR(400MHz，DMSO)δ＝12.02(s，1H)，9.81(s，1H)，7.61(s，1H)，6.90(s，1H)，6.59(d，J＝57.6Hz，2H)，4.74(s，1H)，3.96(t，J＝8.4Hz，2H)，3.85(dd，J＝16.8Hz，6.4，4H)，3.75-3.67(m，1H)，2.14(s，3H)，2.00(d，J＝8.4Hz，2H)，1.87-1.60(m，8H).
MS m/z(ESI):514.1[M+H]+.
Example 10
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] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001371
The first step is as follows: 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-carboxylate
Figure BDA0003083170700001372
To a solution of 2-chloro-N- (5-methyl-1 h-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (250mg, 0.94mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (287mg, 1.13mmol), DIPEA (242mg, 1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol 98:2) to give the title compound as a pale white solid (228mg, 50%).
MS m/z(ESI):484.2[M+H]+.
The second step is that: 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] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001381
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, and after addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring at room temperature was continued overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (46.0mg, 42%).
1H NMR(400MHz，DMSO)δ＝12.09(s，1H)，9.79(s，1H)，7.68(d，J＝6.0Hz，1H)，7.02(d，J＝6.0Hz，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).
MS m/z(ESI):528.2[M+H]+.
Example 11
1- (((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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001391
The first step of 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-carboxylate
Figure BDA0003083170700001392
2-chloro-6-methyl-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (150mg, 0.536mmol) and tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (257mg, 1.072mmol) were added to N-butanol (10mL) and heated to 170 ℃ with a microwave synthesizer for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was dissolved in methylene chloride, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and isolated by silica gel column chromatography to give the title compound (73mg, 28%).
MS m/z(ESI):484.2[M+H]+.
The second step of reaction: preparation of 1- (((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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001393
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-carboxylate (73mg, 0.151mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic ring (20mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (0.75mL, 4.53mmol) and 3-cyanoazetidine-1-sulfonyl chloride (30mg, 0.166mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 4.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (31.5mg, 40%).
1H NMR(400MHz，DMSO-d6)δ12.06(s，1H)，9.66(s，1H)，7.35(s，1H)，6.48(s，1H)，5.31-5.15(m，1H)，4.18(d，J＝1.0Hz，2H)，4.06(t，J＝8.6Hz，2H)，4.00-3.91(m，2H)，3.80(ddd，J＝12.8，8.9，6.5Hz，1H)，2.90(s，3H)，2.40(s，3H)，2.22(s，3H)，2.07-1.99(m，2H)，1.95(dd，J＝18.2，7.0Hz，2H)，1.88-1.79(m，2H)，1.62(dd，J＝11.8，4.1Hz，2H).
MS m/z(ESI):528.2[M+H]+.
Example 12
1- (((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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001401
The first step of 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-carboxylate
Figure BDA0003083170700001402
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376mmol) and tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (181mg, 0.752mmol) were added to N-butanol (3mL), and heated to 170 ℃ with a microwave synthesizer for 18 hours. The solvent was removed by concentration under reduced pressure, and the residue was used directly in the next reaction.
MS m/z(ESI):470.2[M+H]+.
The second step of reaction: preparation of 1- (((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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001411
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-carboxylate was dissolved in 4M HCl in 1, 4-epoxyhexacyclic compound (20mL), the reaction was stirred at room temperature for 30 minutes, the solvent was removed by concentration under reduced pressure, and the residue was chromatographically separated by a reverse phase column to give 117mg of a white solid.
The above white solid was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 deg.C, DIPEA (0.14mL, 0.632mmol) and 3-cyanoazetidine-1-sulfonyl chloride (57mg, 0.316mmol) were added sequentially, and the reaction mixture was stirred at 0 deg.C for 17 hours. The solvent was removed by concentration under reduced pressure and the residue was isolated by prep-HPLC to give the title compound (16.4mg, 10%).
1H NMR(400MHz，MeOD-d4)δ7.37(d，J＝5.9Hz，1H)，6.98(d，J＝5.7Hz，1H)，6.40(s，1H)，5.40-5.28(m，1H)，4.31-4.24(m，2H)，4.17(t，J＝8.5Hz，2H)，4.11-4.04(m，2H)，3.57(ddd，J＝15.4，8.9，6.7Hz，1H)，3.04(s，3H)，2.31(s，3H)，2.17(dd，J＝8.6，3.3Hz，2H)，2.11-2.01(m，2H)，2.00-1.92(m，2H)，1.75(ddd，J＝10.8，4.3，2.7Hz，2H).
MS m/z(ESI):514.1[M+H]+.
Example 13
2- (dimethylamino) -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] nonan-9-yl) ethan-1-one
Figure BDA0003083170700001412
Figure BDA0003083170700001421
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.32mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, dimethylglycine (24mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (17.1mg, 18%).
1H NMR(400MHz，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).
MS m/z(ESI):455.2[M+H]+.
Example 14
2- (dimethylamino) -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) ethan-1-one
Figure BDA0003083170700001422
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-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (46mg, 0.36mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, dimethylglycine (10mg, 0.1mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (4.4mg, 11%).
1H NMR(400MHz，DMSO)δ＝12.08(s，1H)，9.88(s，1H)，7.65(s，1H)，7.11-6.46(m，3H)，4.47(d，J＝30.0Hz，3H)，3.06(s，2H)，2.21(s，9H)，2.04-1.66(m，6H)，1.62-1.44(m，2H).
MS m/z(ESI):441.2[M+H]+.
Example 15
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) -2-morpholinoethan-1-one
Figure BDA0003083170700001431
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-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; 2- (7-Benzotolyltriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (51mg, 0.13mmol) was then added and dissolved in N, N-dimethylformamide (5mL), DIPEA (46mg, 0.36mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (14.5mg, 0.1mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (7.8mg, 18%).
1H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.88(s，1H)，7.66(s，1H)，7.11-6.49(m，3H)，4.48(d，J＝26.4Hz，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).
MS m/z(ESI):483.2[M+H]+.
Example 16
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] octan-8-yl) -2-morpholinoethan-1-one
Figure BDA0003083170700001441
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] octan-8-yl) -2-morpholinoethan-1-one refers to example 244.
1H NMR(400MHz,DMSO-d6)δ＝9.85(s,1H),8.22(s,1H),7.68(d,J＝6.0Hz,1H),7.02(d,J＝6.0Hz,1H),6.53(s,1H),5.37(s,1H),4.54(d,J＝16.4Hz,2H),3.58(d,J＝4.0Hz,4H),3.04(d,J＝13.2Hz,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).
MS m/z(ESI):497.2[M+H]+.
Example 17
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] nonan-9-yl) -2-morpholinoethane-1-one
Figure BDA0003083170700001442
Figure BDA0003083170700001451
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (33mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (18.0mg, 17%).
1H NMR(400MHz，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＝4.0Hz，4H)，3.12(dd，J＝25.2，12.4Hz，2H)，2.39(s，4H)，2.21(s，3H)，2.11-1.51(m，10H).
MS m/z(ESI):497.2[M+H]+.
Example 18
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] nonan-9-yl) -2- (methylamino) -ethan-1-one
Figure BDA0003083170700001452
The first step is as follows: 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] nonan-9-yl) -2-carbonylethyl) carbamate
Figure BDA0003083170700001461
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-carboxylate (200mg, 0.42mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 10mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; 2- (7-Benzobenzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate) (240mg, 0.64mmol) was then added and dissolved in N, N-dimethylformamide (5mL), DIPEA (216mg, 1.68mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice water bath, and stirring was continued for 1 hour after the addition of N- (tert-butoxycarbonyl) -N-methylglycine (87mg, 0.46 mmol). After completion of the reaction, the reaction mixture was extracted with dichloromethane (15mLx3), washed with saturated aqueous sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to give the title compound as a white solid (205mg, 90%).
MS m/z(ESI):541.2[M+H]+.
The second step is that: preparation of 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] nonan-9-yl) -2- (methylamino) -ethan-1-one
Figure BDA0003083170700001462
Tert-butylmethyl (2- ((3-exo) -3- ((4- ((5-methyl-1 h-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-carbonylethyl) carbamate (205mg, 0.38mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 10mL), stirred at room temperature for 30 minutes, then ammonia water (10mL) was added dropwise to the reaction solution in an ice-water bath, and then the reaction solution was concentrated under reduced pressure to give the title compound as a white solid (37.6mg, 22%) by prep-HPLC.
1H NMR(400MHz，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).
MS m/z(ESI):441.2[M+H]+.
Example 19
((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] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone
Figure BDA0003083170700001471
Preparation of ((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] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone reference example 18.
1H NMR(400MHz，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＝6.8Hz，2H)，2.23(s，3H)，2.10-1.43(m，12H).
MS m/z(ESI):453.1[M+H]+.
Example 20
((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] nonan-9-yl) ((S) -pyrrolidin-2-yl) methanone
Figure BDA0003083170700001472
Preparation of ((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] nonan-9-yl) ((S) -pyrrolidin-2-yl) methanone reference example 18.
1H NMR(400MHz，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).
MS m/z(ESI):453.1[M+H]+.
Example 21
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -morpholin-3-yl) methanone
Figure BDA0003083170700001481
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -morpholin-3-yl) methanone reference example 18.
MS m/z(ESI):483.2[M+H]+.
Example 22
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone
Figure BDA0003083170700001482
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) ((R) -pyrrolidin-2-yl) methanone reference example 18.
MS m/z(ESI):467.2[M+H]+.
Example 23
2- ((2-methoxyethyl) amino) -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] nonan-9-yl) ethan-1-one
Figure BDA0003083170700001491
Preparation of 2- ((2-methoxyethyl) amino) -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] nonan-9-yl) ethan-1-one reference example 18.
MS m/z(ESI):485.2[M+H]+.
Example 24
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] nonan-9-yl) -2- ((pyridin-3-ylmethyl) amino) ethan-1-one
Figure BDA0003083170700001492
Preparation of 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] nonan-9-yl) -2- ((pyridin-3-ylmethyl) amino) ethan-1-one reference example 18.
MS m/z(ESI):518.2[M+H]+.
Example 25
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] octan-8-yl) ethan-1-one
Figure BDA0003083170700001493
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] octan-8-yl) ethan-1-one reference example 18.
MS m/z(ESI):533.2[M+H]+.
Example 26
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) ethan-1-one
Figure BDA0003083170700001501
Preparation of 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) ethan-1-one reference example 18.
MS m/z(ESI):441.2[M+H]+.
Example 27
2- (cyclopropylamino) -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) ethan-1-one
Figure BDA0003083170700001502
Preparation of 2- (cyclopropylamino) -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) ethan-1-one reference example 18.
MS m/z(ESI):453.2[M+H]+.
Example 28
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] nonan-9-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Figure BDA0003083170700001511
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then, 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was performed for 10 minutes in an ice-water bath, and 2- (4-methylpiperazin-1-yl) acetic acid (36mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (43.8mg, 40%).
1H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.79(s，1H)，7.68(d，J＝6.0Hz，1H)，7.02(d，J＝6.0Hz，1H)，6.46(s，1H)，5.81(s，1H)，4.71(s，1H)，4.39(s，1H)，3.22(d，J＝12.8Hz，1H)，3.06(d，J＝12.8Hz，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).
MS m/z(ESI):424.2[M+H]+.
Example 29
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] nonan-9-yl) -2- (4-methylpiperazin-1-yl) ethan-1-one
Figure BDA0003083170700001521
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then, 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirring was performed for 10 minutes in an ice-water bath, and 2- (4-methylpiperazin-1-yl) acetic acid (36mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (25.2mg, 24%).
1H NMR(400MHz，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).
MS m/z(ESI):510.2[M+H]+.
Example 30
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] nonan-9-yl) -2- (piperazin-1-yl) ethan-1-one
Figure BDA0003083170700001522
Preparation of 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] nonan-9-yl) -2- (piperazin-1-yl) ethan-1-one reference example 18.
MS m/z(ESI):496.2[M+H]+.
Example 31
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone
Figure BDA0003083170700001531
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, pyridine-2-carboxylic acid (28mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (27.3mg, 21%).
1H NMR(400MHz，DMSO)δ＝12.07(s，1H)，9.86(s，1H)，8.59(d，J＝4.4Hz，1H)，7.94(td，J＝7.7，1.6Hz，1H)，7.73-7.44(m，3H)，7.05-6.50(m，3H)，4.84(d，J＝28.0Hz，2H)，3.94(s，1H)，2.21(s，3H)，2.18-1.59(m，10H).
MS m/z(ESI):475.1[M+H]+.
Example 32
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-3-yl) methanone
Figure BDA0003083170700001541
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, pyridine-3-carboxylic acid (28mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (28.6mg, 22%).
1H NMR(400MHz，DMSO-d6)δ＝12.07(s，1H)，9.87(s，1H)，8.71-8.58(m，2H)，7.84(d，J＝7.6Hz，1H)，7.69(d，J＝6.0Hz，1H)，7.51(dd，J＝7.6，4.8Hz，1H)，6.96(d，J＝5.2Hz，1H)，6.68-6.50(m，2H)，4.83(d，J＝39.2Hz，2H)，3.78(s，1H)，2.21(s，3H)，2.13-1.61(m，10H).
MS m/z(ESI):475.1[M+H]+.
Example 33
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-4-yl) methanone
Figure BDA0003083170700001551
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, pyridine-4-carboxylic acid (28mg, 0.23mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (34.5mg, 27%).
1H 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＝5.6Hz，1H)，7.39(d，J＝5.6Hz，2H)，6.97(d，J＝6.0Hz，1H)，6.57(d，J＝7.6Hz，2H)，4.82(d，J＝41.6 Hz，2H)，3.68(s，1H)，2.21(s，3H)，2.14-1.59(m，10H).
MS m/z(ESI):475.1[M+H]+.
Example 34
(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] nonan-9-yl) methanone
Figure BDA0003083170700001561
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, and 1-methyl-1 h-imidazole-2-carboxylic acid (29mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (15.0mg, 12%).
1H NMR(400MHz，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).
MS m/z(ESI):478.2[M+H]+.
Example 35
(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] nonan-9-yl) methanone
Figure BDA0003083170700001571
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] nonan-9-yl) methanone reference example 21
1H NMR(400MHz，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＝65.2Hz，3H)，3.68(s，3H)，2.22(s，3H)，2.13-1.58(s，10H).
MS m/z(ESI):478.1[M+H]+.
Example 36
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8 (pyridin-3 ylsulfonyl) -8-azabicyclo [ 3.2.1)]Octane-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0003083170700001572
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-carboxylate (40mg, 0.09mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 2mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; n, N-dimethylformamide (5mL) was then added to dissolve it, DIPEA (46mg, 0.36mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after addition of pyridine-3-sulfonyl chloride (18mg, 0.1 mmol). The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (5.6mg, 13%).
1H NMR(400MHz，DMSO)δ＝12.01(s，1H)，9.86(s，1H)，9.05(s，1H)，8.87(d，J＝4.4Hz，1H)，8.31(d，J＝8.0Hz，1H)，7.65(dd，J＝7.8Hz，5.0，2H)，6.97(s，1H)，6.78(s，1H)，6.54(s，1H)，4.33(s，2H)，3.17(d，J＝5.2Hz，1H)，2.14(s，3H)，1.99(s，2H)，1.76-1.56(m，4H)，1.35-1.26(m，2H).
MS m/z(ESI):497.1[M+H]+.
Example 37
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-2-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0003083170700001581
Preparation of N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-2-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 23.
1H NMR(400MHz,CD3OD:CDCl3,v/v＝1:2)δ8.70(d,J＝4.6Hz,1H),8.00(dt,J＝8.0,4.6Hz,2H),7.60(ddd,J＝6.8,4.8,1.8Hz,1H),7.35(d,J＝6.0Hz,1H),6.92(d,J＝6.0Hz,1H),6.19(s,1H),4.43(s,2H),4.40-4.32(m,1H),2.27(s,3H),2.15(ddd,J＝12.7,5.3,2.6Hz,2H),1.88-1.81(m,2H),1.80-1.70(m,2H),1.62(dd,J＝8.6,4.7Hz,2H).
MS m/z(ESI):497.1[M+H]+.
Example 38
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-2-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0003083170700001591
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-carboxylate (100mg, 0.213mmol) was dispersed in 4M HCl 1, 4-epoxyhexacyclic (15mL), the reaction was stirred at room temperature for 60 minutes, the solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 deg.C, DIPEA (1.05mL, 6.39mmol) and pyridine-2-sulfonyl chloride (40mg, 0.224mmol) were added in that order, and the reaction mixture was stirred at 0 deg.C for 2.5 hours. The solvent was removed by concentration under reduced pressure and the residue was isolated by prep-HPLC to give the title compound as a white solid (12.4mg, 25%).
1H NMR(400MHz,DMSO-d6)δ12.07(s,1H),9.85(s,1H),8.78(d,J＝4.0Hz,1H),8.08(td,J＝7.7,1.4Hz,1H),7.96(d,J＝7.8Hz,1H),7.67(dd,J＝6.7,4.7Hz,2H),6.95(s,1H),6.59(d,J＝30.3Hz,2H),4.85-4.71(m,1H),4.18(s,2H),2.17(s,3H),2.05(dd,J＝12.8,4.9Hz,3H),1.68(d,J＝2.6Hz,7H).
MS m/z(ESI):511.1[M+H]+.
Example 39
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-3-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0003083170700001592
Preparation of N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-3-ylsulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 38.
1H NMR(400MHz,CD3OD:CDCl3,v/v＝1:1)δ9.11(s,1H),8.84(d,J＝3.9Hz,1H),8.29(d,J＝8.2Hz,1H),7.70-7.62(m,1H),7.39(d,J＝5.9Hz,1H),6.96(d,J＝5.8Hz,1H),6.62(s,1H),5.05-4.90(m,1H),4.34(d,J＝2.8Hz,2H),2.55-2.19(m,5H),2.19-1.61(m,8H).
MS m/z(ESI):511.1[M+H]+.
Example 40
N2- ((3-exo) -9- ((1-methyl-1H-imidazol-2-yl) sulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine
Figure BDA0003083170700001601
Preparation of N2- ((3-exo) -9- ((1-methyl-1H-imidazol-2-yl) sulfonyl) -9-azabicyclo [3.3.1] nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidine-2, 4-diamine reference example 38.
1H NMR(400MHz，DMSO-d6)δ12.05(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＝4.9Hz，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＝5.5，5.1，1.0Hz，3H)，1.91-1.58(m，7H).
MS m/z(ESI):514.1[M+H]+.
EXAMPLE 41
N, N-dimethyl-2- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) acetamide
Figure BDA0003083170700001602
Figure BDA0003083170700001611
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then N, N-dimethylformamide (5mL) was added to dissolve it, DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after the addition of 2-bromo-N, N-dimethylacetamide (38mg, 0.23 mmol). The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (16.6mg, 17%).
1H NMR(400MHz，DMSO)δ＝12.00(s，1H)，9.80(s，1H)，7.63(s，1H)，6.74(d，J＝128.0Hz，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).
MS m/z(ESI):455.2[M+H]+.
Example 42
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -9- (pyridin-2-ylmethyl) -9-azabicyclo [3.3.1]Nonan-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0003083170700001612
Figure BDA0003083170700001621
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then, this was dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, and the mixture was stirred for 10 minutes in an ice-water bath, and after adding 2- (chloromethyl) pyridine hydrochloride (38mg, 0.23mmol), the mixture was heated to 70 ℃ and stirred overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (20.8mg, 22%).
1H NMR(400MHz，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＝13.6Hz，3H)，2.08-1.50(m，10H).
MS m/z(ESI):461.1[M+H]+.
Example 43
N2- ((3-exo) -9- ((1-methyl-1-hydro-imidazol-2-yl) methyl) -9-azabicyclo [3.3.1]Nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d]Pyrimidine-2, 4-diamines
Figure BDA0003083170700001622
N2- ((3-exo) -9- ((1-methyl-1-hydro-imidazol-2-yl) methyl) -9-azabicyclo [3.3.1]Nonan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d]Preparation of pyrimidine-2, 4-diamine reference example 42.
1H NMR(400MHz，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).
MS m/z(ESI):464.2[M+H]+.
Example 44
3- ((3-exo)) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001631
The first step is as follows: preparation of (3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0003083170700001632
2, 4-dichlorothieno [2,3-d ] pyrimidine (100mg, 0.49mmol), (3-amino-1H-pyrazol-5-yl) methanol (55mg, 0.49mmol), DIPEA (190mg, 1.47mmol) and the reaction mixture were added to N' N-dimethylformamide (2mL), and the reaction mixture was stirred at 70 ℃ overnight. Concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash silica gel column chromatography to give the title compound as a yellow solid (100mg, 73%).
MS m/z(ESI):282.0[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700001633
(3- ((2-chlorothieno [2,3-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg, 0.36mmol), N-Boc-exo-3-aminotropane acetate (113mg, 0.40mmol) and DIPEA (140mg, 1.08mmol) were added to N-butanol (2.5mL), the reaction mixture was uniformly mixed, and then reacted under microwave heating at 150 ℃ for 10 hours, cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was isolated and purified by flash chromatography to give the title compound as a pale yellow solid (60mg, 35%).
MS m/z(ESI):472.0[M+H]+.
The third step: preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001641
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-carboxylate (60mg, 0.13mmol) was dissolved in methanol (10mL), followed by slowly adding dioxane hydrochloride (4N, 2.5mL) to the reaction mixture, reacting at room temperature for 2 hours, concentrating under reduced pressure, adding a mixture of methanol (15mL), DIPEA (0.5mL) and acrylonitrile (1mL) to the resulting crude product, reacting at room temperature for 2 hours, concentrating under reduced pressure, and isolating and purifying by prep-HPLC to give the title compound as a white solid (11.6mg, 21%).
1H NMR(400MHz，CD3OD)δ7.39(dd，J＝6.0Hz，1H)，6.99(dd，J＝5.6Hz，1H),6.02-6.04(m,1H)，4.60(s,2H)，4.21-4.24(m，1H),3.45-3.42(m,2H)，2.83(s，2H)，2.69-2.65(m，2H),2.08-1.91(m，6H)，1.69(t，J＝12.4Hz，2H).
MS m/z(ESI):425.1[M+H]+.
Example 45
3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700001642
Preparation of 3- ((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference is made to example 44.
MS m/z(ESI):439.2[M+H]+.
Example 46
3- ((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] nonan-9-yl) propionitrile
Figure BDA0003083170700001651
Preparation of 3- ((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] nonan-9-yl) propionitrile reference example 44.
MS m/z(ESI):453.2[M+H]+.
Example 47
1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001652
Preparation of 1- (((3-exo) -3- ((4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile reference example 44.
MS m/z(ESI):530.2[M+H]+.
Example 48
3- ((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001661
The first step is as follows: 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-carboxylate
Figure BDA0003083170700001662
To a solution of 2-chloro-6-methyl-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (200mg, 0.72mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (194mg, 0.86mmol), DIPEA (186mg, 1.44mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 98:2) to give the title compound as a pale yellow solid (124mg, 37%).
MS m/z(ESI):470.2[M+H]+.
The second step is that: preparation of 3- ((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] octan-8-yl) propionitrile
Figure BDA0003083170700001663
Dissolving 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-carboxylate (124mg, 0.26mmol) in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirring at room temperature for 30 minutes, and concentrating the reaction solution; methanol (10mL) was then added to dissolve it, DIPEA (137mg, 1.06mmol) was added slowly dropwise, stirring at room temperature for 10 minutes, acrylonitrile (21mg, 0.39mmol) was added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (12.7mg, 12%).
1H NMR(400MHz,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).
MS m/z(ESI):423.2[M+H]+.
Example 49
3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700001671
The first step is as follows: preparation of 5-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine
Figure BDA0003083170700001672
To a solution of 5, 7-dichlorothiazolo [5,4-d ] pyrimidine (206mg, 1mmol) in dimethylsulfoxide (10mL) was added 3-amino-5-methylpyrazole (116mg, 1.2mmol), DIPEA (258mg, 2mmol) in this order, followed by stirring at 70 ℃ for one hour. After completion of the reaction, water (50mL) was added to the reaction mixture to precipitate a solid, which was filtered and slurried with ethyl acetate to give the title compound as a yellow solid (200mg, 75%).
MS m/z(ESI):267.0[M+H]+.
The second step is that: preparation of tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate
Figure BDA0003083170700001681
To a solution of 5-chloro-N- (5-methyl-1 h-pyrazol-3-yl) thiazolo [5,4-d ] pyrimidin-7-amine (200mg, 0.75mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (216mg, 0.9mmol), DIPEA (193mg, 1.5mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to give the title compound as a pale yellow solid (232mg, 66%).
MS m/z(ESI):471.2[M+H]+.
The third step: preparation of 3- ((3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700001682
Tert-butyl- (3-exo) -3- ((7- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thiazolo [5,4-d ] pyrimidin-5-yl) amino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (232mg, 0.49mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; methanol (10mL) was then added to dissolve it, DIPEA (127mg, 0.98mmol) was added slowly dropwise, stirring at room temperature for 10 minutes, acrylonitrile (39mg, 0.74mmol) was added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a pale yellow solid (63mg, 30%).
1H NMR(400MHz，DMSO)δ＝12.06(s，1H)，9.29(s，1H)，8.76(d，J＝18.8Hz，1H)，6.92(d，J＝7.2Hz，1H)，6.57(s，1H)，4.67(s，1H)，3.31(s，2H)，2.58(t，J＝6.2Hz，4H)，2.19(s，3H)，2.00-1.65(m，10H).
MS m/z(ESI):424.2[M+H]+.
Example 50
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001691
The first step is as follows: 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-carboxylate
Figure BDA0003083170700001692
NaH (120mg, 3.01mmol, 60%) was added portionwise to a solution of tert-butyl (3-exo) -3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (427mg, 1.88mmol) in N, N-dimethylformamide (2mL) at room temperature, stirred for 5 minutes at room temperature, then a solution of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376mmol) in N, N-dimethylformamide (1mL) was added dropwise, and the mixture was heated to 120 ℃ under nitrogen and stirred for 2 hours. The reaction solution was cooled to room temperature, and then poured into ice water (10mL) and stirred for 10 minutes, followed by filtration, the filtrate was extracted with ethyl acetate, the organic phases were combined, washed with a saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the organic solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound as a yellow oil (149mg, 87%).
The second step is that: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) oxo) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001693
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-carboxylate (77mg, 0.169mmol) was dissolved in methanol (2mL), 4M HCl 1, 4-dioxane (2mL) was added thereto with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1mL), DIPEA (109mg, 0.844mmol) and acrylonitrile (45mg, 0.844mmol) were successively added thereto, and the resulting reaction mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was preliminarily isolated and purified by silica gel chromatography and further isolated and purified by preparative TLC to give the title compound as a gray solid (7mg, 10%).
1H NMR(400MHz，CD3OD)δ7.50(d，J＝6.1Hz，1H)，7.22(d，J＝5.9Hz，1H)，6.51(s，1H)，5.43-5.26(m，1H)，3.44-3.37(m，2H)，2.78(t，J＝6.9Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.33(s，3H)，2.12-2.00(m，4H)，1.86-1.74(m，4H).
MS m/z(ESI):410.1[M+H]+.
Example 51
3- ((3-exo) -3- ((6- (methoxymethyl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001701
Preparation of 3- ((3-exo) -3- ((6- (methoxymethyl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 48.
MS m/z(ESI):453.2[M+H]+.
Example 52
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] octan-8-yl) propionitrile
Figure BDA0003083170700001711
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] octan-8-yl) propionitrile reference is made to example 48.
MS m/z(ESI):494.2[M+H]+.
Example 53
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (morpholinomethyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001712
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (morpholinomethyl) thieno [2,3-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 48.
MS m/z(ESI):508.3[M+H]+.
Example 54
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] nonan-9-yl) propionitrile
Figure BDA0003083170700001721
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] nonan-9-yl) propionitrile reference example 48.
MS m/z(ESI):535.3[M+H]+.
Example 55
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (pyridin-3-ylthio) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700001722
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (pyridin-3-ylthio) thieno [2,3-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 48.
MS m/z(ESI):532.2[M+H]+.
Example 56
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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001731
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-carboxylate (100mg, 0.22mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, and after addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring at room temperature was continued overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (23.2mg, 21%).
1H NMR(400MHz，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＝8.4Hz，2H)，3.98-3.89(m，2H)，3.80(dd，J＝15.2，6.0Hz，1H)，2.23(s，3H)，1.99(s，4H)，1.84(d，J＝7.2Hz，2H)，1.63(s，2H).
MS m/z(ESI):500.1[M+H]+.
Example 57
1- (((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001741
Preparation of 1- (((3-exo) -3- ((6-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 38.
1H NMR(400MHz，DMSO-d6)δ12.02(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).
MS m/z(ESI):513.1[M+H]+.
Example 58
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0003083170700001742
Preparation of 2- (dimethylamino) -1- ((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] octan-8-yl) ethan-1-one reference example 56.
1H NMR(400MHz，DMSO-d6)δ＝12.06(s，1H)，9.72(s，1H)，7.89(s，1H)，6.99(s，1H)，6.49(d，J＝58.8Hz，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).
MS m/z(ESI):441.1[M+H]+.
Example 59
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2-morpholinoethane-1-one
Figure BDA0003083170700001751
The first step is as follows: 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-carboxylate
Figure BDA0003083170700001752
To a solution of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (250mg, 0.94mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (271mg, 1.13mmol), DIPEA (242mg, 1.88mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 98:2) to give the title compound as a pale white solid (150mg, 34%).
MS m/z(ESI):470.1[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700001753
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then 2- (7-benzotriazol oxide) -N, N' -tetramethyluronium hexafluorophosphate (120mg, 0.31mmol) was added and dissolved in N, N-dimethylformamide (5mL), DIPEA (108mg, 0.84mmol) was slowly added dropwise, stirred for 10 minutes in an ice-water bath, and 2-morpholinoacetic acid (33mg, 0.23mmol) was added followed by stirring for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (17.8mg, 17%).
1H NMR(400MHz，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＝4.0Hz，4H)，3.10-3.01(m，2H)，2.32(s，3H)，2.14(s，2H)，2.09-1.39(m，10H).
MS m/z(ESI):497.1[M+H]+.
Example 60
1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) ethan-1-one
Figure BDA0003083170700001761
Preparation of 1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) -2- (methylamino) ethan-1-one reference example 18.
MS m/z(ESI):441.2[M+H]+.
Example 61
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone
Figure BDA0003083170700001762
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) (pyridin-2-yl) methanone reference example 59.
MS m/z(ESI):475.2[M+H]+.
Example 62
(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] nonan-9-yl) methanone
Figure BDA0003083170700001771
Preparation of (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] nonan-9-yl) methanone reference example 59.
MS m/z(ESI):478.2[M+H]+.
Example 63
2- (dimethylamino) -1- ((1R,3R,5S) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0003083170700001772
Preparation of 2- (dimethylamino) -1- ((1R,3R,5S) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one reference example 13.
MS m/z(ESI):441.2[M+H]+.
Example 64
N, N-dimethyl-2- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) acetamide
Figure BDA0003083170700001773
Figure BDA0003083170700001781
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then N, N-dimethylformamide (5mL) was added to dissolve it, DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirring was carried out for 10 minutes in an ice-water bath, and stirring was continued for 1 hour after the addition of 2-bromo-N, N-dimethylacetamide (38mg, 0.23 mmol). The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (16.4mg, 17%).
1H NMR(400MHz，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).
MS m/z(ESI):441.1[M+H]+.
Example 65
3- ((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] nonan-9-yl) propionitrile
Figure BDA0003083170700001782
The first step is as follows: preparation of (3- ((2-chloro-6-methylthiophen [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0003083170700001791
2, 4-dichloro-6-methylthioeno [3,2-d ] pyrimidine (200mg, 0.91mmol), (3-amino-1H-pyrazol-5-yl) methanol (120mg, 1.09mmol), and DIPEA (350mg, 2.73mmol) were dissolved in N, N-dimethylformamide (10mL), mixed uniformly, and reacted at 70 ℃ overnight. After cooling to room temperature, the reaction mixture was extracted with water (30mL) and ethyl acetate (20 mL. times.3), the organic phases were combined and concentrated under reduced pressure, and the crude product was isolated and purified by flash column chromatography on silica gel to give the title compound as a white solid (200mg, 75%).
MS m/z(ESI):296.0[M+H]+.
The second step is that: preparation 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-carboxylate
Figure BDA0003083170700001792
Adding (3- ((2-chloro-6-methylthieno [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (150mg, 0.51mmol), tert-butyl (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate oxalate (200mg, 0.61mmol) and DIPEA (200mg, 1.53mmol) into n-butanol (3mL), uniformly mixing, reacting for 8 hours under the condition of microwave heating at 165 ℃, cooling to room temperature, concentrating the reaction solution under reduced pressure, and using the obtained crude product (200mg) as an impure product for the next reaction.
MS m/z(ESI):500.1[M+H]+.
The third step: preparation of (3- ((2- (((3-exo) -9-azabicyclo [3.3.1] nonan-3-yl) amino) -6-methylthio [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0003083170700001801
To a 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-carboxylate (200mg, 0.40mmol) in methanol (10mL) was slowly added dropwise dioxane hydrochloride (4N, 5mL), the reaction solution was allowed to react at room temperature for 3 hours, concentrated under reduced pressure, and the resulting crude product was isolated and purified by prep-HPLC to give the title compound as a yellow solid (100mg, 63%).
MS m/z(ESI):400.1[M+H]+.
The fourth step: preparation of 3- ((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] nonan-9-yl) propionitrile
Figure BDA0003083170700001802
(3- ((2- (((3-exo) -9-azabicyclo [3.3.1] nonan-3-yl) amino) -6-methylthiophene [3,2-d ] pyrimidin-4-yl) amino) -1H-pyrazol-5-yl) methanol (100mg, 0.25mmol), acrylonitrile (0.2mL), and DIPEA (0.1mL) were added to methanol (10mL), and after uniform mixing, the mixture was reacted at room temperature for 1 hour, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by prep-HPLC to give the title compound as a white solid (11.7mg, 10%).
1H NMR(400MHz，DMSO-d6)δ12.28(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).
MS m/z(ESI):453.2[M+H]+.
Example 66
3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0003083170700001811
The first step is as follows: preparation of tert-butyl cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate
Figure BDA0003083170700001812
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376mmol), tert-butyl cis-5-aminohexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (102mg, 0.452mmol) and DIPEA (146mg, 1.13mmol) were added to NMP (1mL), and the mixture was heated to 160 ℃ with a microwave under nitrogen protection for 8 hours. The reaction was cooled to room temperature and then poured into ice water (10mL) and stirred for 10 min, filtered, the filter cake was washed with water (15mL) and dried in vacuo to give the title compound as a yellow solid (171mg, crude).
The second step is that: preparation of 3- (cis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1H) -yl) propionitrile
Figure BDA0003083170700001813
Tert-butylcis-5- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate (86mg, 0.188mmol) was dissolved in methanol (2mL), 4M HCl 1, 4-dioxane (2mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2mL), DIPEA (121mg, 0.938mmol) and acrylonitrile (15mg, 0.282mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for further 16 hours. The reaction was diluted with DCM (20mL), washed with water (5mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was isolated and purified by silica gel chromatography to give the title compound as a white solid (17mg, 22%).
1H NMR(400MHz，CD3OD)δ7.36(d，J＝6.0Hz，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).
MS m/z(ESI):409.1[M+H]+.
Example 67
3- (cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1 hydro) -yl) propionitrile
Figure BDA0003083170700001821
The first step is as follows: preparation of tert-butyl-cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1 hydro) -carboxylate
Figure BDA0003083170700001822
To a solution of 2-chloro-N- (5-methyl-1-hydro-pyrazol-3-yl) thieno [3,2-d ] pyrimidin-4-amine (100mg, 0.38mmol) in N-butanol (5mL) were added tert-butyl-cis-5-aminohexahydrocyclopenta [ c ] pyrrole-2 (1-hydro) -carboxylate (102mg, 0.45mmol), DIPEA (98mg, 0.76mmol) in this order, followed by stirring at 160 ℃ for 15 hours under microwave conditions. After the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to give the title compound as a pale yellow solid (80mg, 46%).
MS m/z(ESI):456.2[M+H]+.
The second step is that: preparation of 3- (cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrol-2 (1 hydro) -yl) propionitrile
Figure BDA0003083170700001831
Dissolving tert-butyl-cis-5- ((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) hexahydrocyclopenta [ c ] pyrrole-2 (1 hydro) -carboxylate (80mg, 0.18mmol) in 1, 4-epoxy hexacyclic solution (4.0N, 2mL), stirring at room temperature for 30 minutes, and concentrating the reaction solution; methanol (5mL) was then added to dissolve it, DIPEA (93mg, 0.72mmol) was added slowly dropwise, stirring at room temperature for 10 minutes, acrylonitrile (14mg, 0.27mmol) was added and stirring continued for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (26.3mg, 37%).
1H NMR(400MHz，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＝13.6，7.2Hz，6H)，2.22(s，8H)，1.31(s，3H).
MS m/z(ESI):409.1[M+H]+.
Example 68
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0003083170700001832
The first step is as follows: preparation of tert-butyl 4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidine-1-carboxylate
Figure BDA0003083170700001841
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2,3-d ] pyrimidin-4-amine (100mg, 0.376mmol), 1-BOC-4-aminopiperidine (108mg, 0.539mmol) and DIPEA (146mg, 1.13mmol) were added to NMP (1mL), and the mixture was heated to 130 ℃ by microwave heating under nitrogen protection for 16 hours. The reaction was cooled to room temperature and then poured into ice water (10mL) and stirred for 10 min, filtered, the filter cake was washed with water (5mL) and dried in vacuo to give the title compound as a yellow solid (100mg, crude).
The second step is that: preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0003083170700001842
Tert-butyl 4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidine-1-carboxylate (100mg, 0.233mmol) was dissolved in methanol (2mL), ethyl acetate (2mL) in 4MHCl was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2mL), DIPEA (150mg, 1.17mmol) and acrylonitrile (62mg, 1.17mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 1 hour. The reaction was diluted with DCM (20mL), washed with water (5mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the residue was isolated and purified by silica gel chromatography to give the title compound as a white solid (18mg, 20%).
1H NMR(400MHz，CD3OD)δ7.37(d，J＝6.0Hz，1H)，6.97(d，J＝6.1Hz，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).
MS m/z(ESI):383.1[M+H]+.
Example 69
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001851
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 8.
1H NMR(400MHz，CD3OD)δ7.38(d，J＝6.0Hz，1H)，6.99(d，J＝6.0Hz，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).
MS m/z(ESI):474.0[M+H]+.
Example 70
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2- (methylamino) ethan-1-one
Figure BDA0003083170700001852
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2- (methylamino) ethan-1-one reference example 18.
MS m/z(ESI):401.2[M+H]+.
Example 71
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one
Figure BDA0003083170700001861
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one reference example 17.
MS m/z(ESI):457.2[M+H]+.
Example 72
(4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone
Figure BDA0003083170700001862
Preparation of (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone reference example 31.
MS m/z(ESI):435.2[M+H]+.
Example 73
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0003083170700001863
Preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) propionitrile reference example 1.
MS m/z(ESI):383.2[M+H]+.
Example 74
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700001871
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 1.
MS m/z(ESI):474.1[M+H]+.
Example 75
1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one
Figure BDA0003083170700001872
Preparation of 1- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) -2-morpholinoethan-1-one reference example 17.
MS m/z(ESI):457.2[M+H]+.
Example 76
(4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone
Figure BDA0003083170700001881
Preparation of (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) piperidin-1-yl) (pyridin-2-yl) methanone reference example 31.
MS m/z(ESI):435.2[M+H]+.
Example 77
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0003083170700001882
Preparation of 3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 3.
MS m/z(ESI):381.2[M+H]+.
Example 78
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3,2-d ] pyrimidin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0003083170700001883
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] hex-3-yl) propionitrile reference example 1.
MS m/z(ESI):381.2[M+H]+.
Example 79
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001891
The first step is as follows: preparation of 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0003083170700001892
2, 4-dichloroquinazoline (199mg,1.0mmol), 5-methyl-1H-pyrazol-3-amine (99mg,1.02mmol) and triethylamine (213mg,2.1mmol) were added to anhydrous ethanol (5mL), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the obtained solid was suspended in water-ethanol (v \ v ═ 9:1,20mL), filtered, and the obtained solid was washed with petroleum ether and dried to obtain the title compound (240mg, 92%).
MS m/z(ESI):260.1,262.1[M+H]+.
The second step is that: tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0003083170700001893
2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (40mg,0.154mmol) and tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate (70mg,0.308mmol) were added to N-butanol (3mL), and after stirring well at room temperature, the reaction was carried out at 150 ℃ for 4 hours with a microwave. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give the crude title compound (120mg) which was used directly in the next reaction.
MS m/z(ESI):450.2[M+H]+.
The third step: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001901
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-carboxylate (120mg,0.154mmol) was dissolved in methanol (3mL), 4M HCl in 1, 4-dioxane (10mL) was added with stirring at room temperature, the resulting 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 (10mL), diisopropylethylamine (0.51mL,3.08mmol) and acrylonitrile (10mg,0.154mmol) were added sequentially with stirring at room temperature, the resulting reaction mixture was further stirred at room temperature for 2.5 hours, the solvent was removed by concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography and reverse phase HPLC sequentially to give the title compound (6.0mg, 10%).
1H NMR(400MHz,CD3OD)δ8.04(d,J＝8.1Hz,1H),7.58(t,J＝7.5Hz,1H),7.39(s,1H),7.16(t,J＝7.5Hz,1H),6.62(s,1H),4.35(s,1H),3.37(s,2H),2.76(t,J＝6.9Hz,2H),2.62(t,J＝6.9Hz,2H),2.31(s,3H),2.16-1.74(m,6H),1.67(t,J＝11.7Hz,2H).
MS m/z(ESI):403.2[M+H]+.
Example 80
3- ((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001902
The first step is as follows: preparation of 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0003083170700001911
2, 4-dichloro-7-methoxyquinazoline (500mg, 2.18mmol), 5-methyl-1H-pyrazol-3-amine (223mg, 2.29mmol) and DIPEA (592mg, 4.58mmol) were added to absolute ethanol (10mL), and the mixture was stirred at room temperature for 3 days. The reaction was filtered, and the filter cake was washed with acetonitrile (5mL) and dried in vacuo to give the title compound as a white solid (355mg, 56%).
MS m/z(ESI):290.1[M+H]+.
The second step is that: preparation of 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-carboxylate
Figure BDA0003083170700001912
The compounds 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (355mg, 1.23mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (421mg, 1.47mmol) and DIPEA (475mg, 3.68mmol) were mixed in N-butanol (7mL), and the mixture was heated to 150 ℃ with a microwave and stirred for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a white solid (259mg, 44%).
MS m/z(ESI):480.2[M+H]+.
The third step: 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] octan-8-yl) propionitrile
Figure BDA0003083170700001921
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-carboxylate (259mg, 0.540mmol) was dissolved in methanol (3mL), 4M HCl 1, 4-dioxane (4mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (3mL), DIPEA (349mg, 2.70mmol) and acrylonitrile (43mg, 0.810mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 0.5 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography to give the title compound as a white solid (76.8mg, 33%).
1H NMR(400MHz，Methanol-d4)δ8.12(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).
MS m/z(ESI):433.2[M+H]+.
Example 81
3- ((3-exo) -3- ((7-bromo-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001922
The first step is as follows: preparation of 7-bromo-2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0003083170700001931
7-bromo-2, 4-dichloroquinazoline (3.36g, 12.1mmol), 5-methyl-1H-pyrazol-3-amine (1.29g, 13.3mmol) and TEA (2.57g, 25.4mmol) were each added to anhydrous ethanol (67mL), and the mixture was stirred at room temperature for 16 hours. The reaction was filtered, and the filter cake was washed with absolute ethanol (20mL) and dried in vacuo to give the title compound as a white solid (4.17g, 100%).
The second step is that: 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-carboxylate
Figure BDA0003083170700001932
The compounds 7-bromo-2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (500mg, 1.48mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (465mg, 1.62mmol) and DIPEA (591mg, 4.58mmol) were mixed in NMP (5mL), and the mixture was heated by microwave to 130 ℃ and stirred for reaction for 4 hours. The reaction mixture was cooled to room temperature, poured into 25mL of ice water, and stirred for 30 minutes. The mixture was filtered and the filter cake was washed with acetonitrile (2mL) and dried under reduced pressure to give the title compound as a grey solid (877mg, 100%).
The third step: 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] octan-8-yl) propionitrile
Figure BDA0003083170700001933
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-carboxylate (220mg, 0.416mmol) was dissolved in methanol (2mL), 4M HCl 1, 4-dioxane (2mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2mL), DIPEA (269mg, 2.08mmol) and acrylonitrile (66mg, 1.25mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography to give the title compound as a white solid (17.4mg, 9%).
1H NMR(400MHz，CD3OD)δ7.94(d，J＝8.8Hz，1H)，7.74-7.37(m，1H)，7.24(dd，J＝8.9，2.0Hz，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＝6.9Hz，2H)，2.62(t，J＝6.9Hz，2H)，2.31(s，3H)，2.09-1.61(m，8H).
MS m/z(ESI):481.1[M+H]+.
Example 82
3- ((3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001941
The first step is as follows: preparation of 2, 7-dichloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0003083170700001942
2,4, 7-trichloroquinazoline (2.0g, 8.58mmol), 5-methyl-1H-pyrazol-3-amine (915mg, 9.42mmol) and TEA (1.82g, 18.0mmol) were added to anhydrous ethanol (40mL), and the mixture was stirred at room temperature for 16 hours. The reaction was filtered, and the filter cake was washed with anhydrous ethanol (5mL) and dried in vacuo to give the title compound as a white solid (2.5g, 99%).
MS m/z(ESI):294.0[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700001951
The compounds 2, 7-dichloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (500mg, 1.70mmol), tert-butyl (3-exo) -3-amino-8-azabicyclo [3.2.1] octane-8-carboxylate acetate (535mg, 1.87mmol) and DIPEA (681mg, 5.27mmol) were mixed in NMP (7mL), and the mixture was heated to 180 ℃ with a microwave and stirred for reaction for 2 hours. After the reaction solution was cooled to room temperature, it was added to ice water and stirred, and the precipitated solid was filtered. The filter cake was washed with water, dried in vacuo and then isolated and purified by silica gel column chromatography to give the title compound as a white solid (405mg, 49%).
MS m/z(ESI):484.2[M+H]+.
The third step: 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] octan-8-yl) propionitrile
Figure BDA0003083170700001952
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-carboxylate (405mg, 0.837mmol) was dissolved in methanol (4mL), 4M HCl 1, 4-dioxane (2.5mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (4mL), DIPEA (486mg, 3.77mmol) and acrylonitrile (53mg, 1.00mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preliminary separation and purification by silica gel column chromatography and then separation and purification by prep-HPLC to give the title compound as a white solid (40mg, 11%).
1H NMR(400MHz，Methanol-d4)δ8.02(d，J＝8.8Hz，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＝7.0Hz，2H)，2.62(t，J＝6.9Hz，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).
MS m/z(ESI):437.2[M+H]+.
Example 83
3- ((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001961
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] octan-8-yl) propionitrile reference example 82.
MS m/z(ESI):421.2[M+H]+.
Example 84
3- ((3-exo) -3- ((5-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001962
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] octan-8-yl) propionitrile reference example 80.
1H NMR(400MHz，DMSO-d6)δ12.24(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).
MS m/z(ESI):437.2[M+H]+.
Example 85
3- ((3-exo) -3- ((8-methyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001971
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] octan-8-yl) propionitrile reference example 80.
1H NMR(400MHz，Methanol-d4)δ7.86(d，1H)，7.44(d，J＝7.1Hz，1H)，7.03(t，J＝7.7Hz，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＝6.9Hz，2H)，2.62(t，J＝6.9Hz，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＝12.0Hz，2H).
MS m/z(ESI):417.2[M+H]+.
Example 86
3- ((3-exo) -3- ((8-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001972
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] octan-8-yl) propionitrile reference example 80.
1H NMR(400MHz，Methanol-d4)δ8.01(s，1H)，7.69(d，J＝7.6Hz，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).
MS m/z(ESI):437.2[M+H]+.
Example 87
3- ((3-exo) -3- ((6-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700001981
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] octan-8-yl) propionitrile reference example 80.
1H NMR(400MHz，Methanol-d4)δ8.15(d，J＝2.3Hz，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＝7.0Hz，2H)，2.62(t，J＝7.0Hz，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).
MS m/z(ESI):437.2[M+H]+.
Example 88
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] octan-8-yl) propionitrile
Figure BDA0003083170700001991
The first step is as follows: 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-carboxylate
Figure BDA0003083170700001992
Reacting 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-carboxylate (400mg, 0.758mmol), 3-pyridineboronic acid (187mg, 1.52mmol), Pd (dppf) Cl2(110mg, 0.152mmol) and cesium carbonate (740g, 2.27mmol) were added to a mixed solvent of dioxane (8mL) and water (0.8mL), respectively, and the mixture was heated to 100 ℃ under nitrogen and stirred for 1 hour. After the reaction solution was concentrated, the residue was separated and purified by silica gel column chromatography to give the title compound ofPale yellow colloid (160mg, 40%).
The second step is that: 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] octan-8-yl) propionitrile
Figure BDA0003083170700001993
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-carboxylate (160mg, 0.302mmol) was dissolved in methanol (4mL), 4M HCl 1, 4-dioxane (4mL) was added with stirring at room temperature, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (2mL), DIPEA (195mg, 1.51mmol) and acrylonitrile (48mg, 0.906mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for 2 hours. After the reaction, concentration under reduced pressure, preliminary separation and purification of the residue by silica gel column chromatography gave a gray solid, which was slurried with N, N-dimethylformamide/acetonitrile (2mL/4mL), the filtered solid was then slurried with N, N-dimethylformamide/acetonitrile (1.1mL/2.2mL), the solid was filtered off and dried under vacuum to give the title compound as a white solid (49mg, 34%).
1H NMR(400MHz，CD3OD)δ8.90(d，J＝2.3Hz，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＝6.9Hz，2H)，2.63(t，J＝6.9Hz，2H)，2.34(s，3H)，2.13-1.63(m，8H).
MS m/z(ESI):480.2[M+H]+.
Example 89
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] octan-8-yl) propionitrile
Figure BDA0003083170700002001
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] octan-8-yl) propionitrile reference example 88.
1H NMR(400MHz，CD3OD)δ8.73-8.58(m，2H)，8.21(d，J＝8.5Hz，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＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.33(s，3H)，2.16-1.58(m，8H).
MS m/z(ESI):480.2[M+H]+.
Example 90
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] octan-8-yl) propionitrile
Figure BDA0003083170700002011
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] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):480.3[M+H]+.
Example 91
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] octan-8-yl) propionitrile
Figure BDA0003083170700002012
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] octan-8-yl) propionitrile reference example 88.
1H NMR(400MHz，CD3OD)δ8.54-8.41(m，1H)，8.27(d，J＝2.7Hz，1H)，8.17(d，J＝8.5Hz，1H)，7.88-7.56(m，2H)，7.47(dd，J＝8.5，1.8Hz，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＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.32(s，3H)，2.10-1.64(m，8H).
MS m/z(ESI):510.2[M+H]+.
Example 92
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] octan-8-yl) propionitrile
Figure BDA0003083170700002021
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] octan-8-yl) propionitrile reference example 88.
MS m/z(ESI):510.3[M+H]+.
Example 93
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-phenylquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002022
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-phenylquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 88.
1H NMR(400MHz，DMSO-d6Small amount of CD3OD)δ8.47-8.23(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).
MS m/z(ESI):479.3[M+H]+.
Example 94
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] octan-8-yl) propionitrile
Figure BDA0003083170700002031
The first step is as follows: 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-carboxylate
Figure BDA0003083170700002032
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-carboxylate (100mg, 0.189mmol), (1-cyclopropyl-1H-pyrazol-4-yl) boronic acid (35mg, 0.227mmol), cesium carbonate (185mg, 0.567mmol), chlorine (2-dicyclohexylphosphino-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl) ] palladium (II) (X-Phos Pd G2) (15mg, 0.0189mmol) were added to a mixed solvent of dioxane (2mL) and water (0.4mL), respectively, after three times of nitrogen replacement, the reaction mixture was heated to 100 ℃ and stirred for 2 hours. The reaction solution was cooled and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a brown oil (60mg, 57%).
The second step is that: 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] octan-8-yl) propionitrile
Figure BDA0003083170700002041
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-carboxylate (60mg, 0.108mmol) was dissolved in methanol (2mL), 4M HCl 1, 4-dioxane (2mL) was added with stirring at room temperature, and the reaction was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1mL), DIPEA (70mg, 0.542mmol) and acrylonitrile (17mg, 0.324mmol) were sequentially added, and the resulting reaction mixture was further stirred at room temperature for reaction for 16 hours. The reaction was diluted with DCM (30mL), washed with water (10mL), concentrated under reduced pressure and the residue was initially isolated and purified by silica gel chromatography to give the title compound as a grey solid (20mg, 36%).
1H NMR(400MHz，CD3OD)δ8.20(s，1H)，8.06(d，J＝8.3Hz，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＝6.8Hz，2H)，2.63(t，J＝6.8Hz，2H)，2.32(s，3H)，2.09-1.64(m，8H)，1.24-1.00(m，4H).
MS m/z(ESI):509.2[M+H]+.
Example 95
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] octan-8-yl) propionitrile
Figure BDA0003083170700002051
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] octan-8-yl) propionitrile reference example 94.
1H NMR(400MHz，CD3OD)δ8.09(s，1H)，8.03(d，J＝8.5Hz，1H)，7.93(s，1H)，7.64-7.43(m，1H)，7.38(dd，J＝8.6，1.7Hz，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＝7.0Hz，2H)，2.63(t，J＝7.0Hz，2H)，2.32(s，3H)，2.08-2.01(m，2H)，2.00-1.80(m，4H)，1.77-1.62(m，2H).
MS m/z(ESI):483.2[M+H]+.
Example 96
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] octan-8-yl) propionitrile
Figure BDA0003083170700002052
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] octan-8-yl) propionitrile reference example 94.
MS m/z(ESI):515.3[M+H]+.
Example 97
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (thiazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002061
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (thiazol-4-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 94.
MS m/z(ESI):486.2[M+H]+.
Example 98
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] nonan-9-yl) propionitrile
Figure BDA0003083170700002062
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] nonan-9-yl) propionitrile reference example 88.
MS m/z(ESI):494.3[M+H]+.
Example 99
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] nonan-9-yl) propionitrile
Figure BDA0003083170700002071
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] nonan-9-yl) propionitrile reference example 88.
MS m/z(ESI):497.3[M+H]+.
Example 100
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002072
The first step is as follows: preparation of tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate
Figure BDA0003083170700002073
Reacting 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-carboxylate (300mg, 0.568mmol), morpholine (494mg, 5.68mmol), Pd2(dba)3(104mg, 0.114mmol), DavePhos (90mg, 0.227mmol), t-BuONa (109mg, 1.14mmol) were added to dioxane (6mL) respectively and stirred at 100 ℃ under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20mL), washed with water (20mL) and saturated aqueous sodium chloride (10mL), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil (6) 6mg，22％)。
The second step is that: preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002081
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (66mg, 0.123mmol) was dissolved in methanol (2mL), 4M HCl 1, 4-dioxane (2mL) was added with stirring at room temperature, the reaction was stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (1mL), DIPEA (80mg, 0.617mmol) and acrylonitrile (20mg, 0.369mmol) were sequentially added, and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was preliminarily isolated and purified by silica gel chromatography and further isolated and purified by preparative TLC to give the title compound as a gray solid (12mg, 20%).
1H NMR(400MHz，CD3OD)δ8.06(d，J＝9.3Hz，1H)，7.08(d，J＝9.4Hz，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＝6.7Hz，2H)，2.62(t，J＝6.7Hz，2H)，2.34(s，3H)，2.11-1.61(m，8H).
MS m/z(ESI):488.2[M+H]+.
Example 101
3- ((3-exo) -3- ((7- (3-methoxyazetidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002091
Preparation of 3- ((3-exo) -3- ((7- (3-methoxyazetidin-1-yl) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):488.3[M+H]+.
Example 102
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] octan-8-yl) propionitrile
Figure BDA0003083170700002092
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] octan-8-yl) propionitrile reference is made to example 100.
MS m/z(ESI):516.3[M+H]+.
Example 103
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] octan-8-yl) propionitrile
Figure BDA0003083170700002101
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] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):529.3[M+H]+.
Example 104
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyrrolidin-1-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002102
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (pyrrolidin-1-yl) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):472.3[M+H]+.
Example 105
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (methylamino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002111
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] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):432.3[M+H]+.
Example 106
3- ((3-exo) -3- ((7- (methyl (oxetan-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002112
Preparation of 3- ((3-exo) -3- ((7- (methyl (oxetan-3-ylmethyl) amino) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):502.3[M+H]+.
Example 107
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylazetidin-3-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002121
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (((1-methylazetidin-3-yl) methyl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):501.3[M+H]+.
Example 108
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] octan-8-yl) propionitrile
Figure BDA0003083170700002122
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] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):516.3[M+H]+.
Example 109
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] octan-8-yl) propionitrile
Figure BDA0003083170700002131
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] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):529.3[M+H]+.
Example 110
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] octan-8-yl) propionitrile
Figure BDA0003083170700002132
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] octan-8-yl) propionitrile reference example 100.
MS m/z(ESI):523.3[M+H]+.
Example 111
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002141
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7-morpholinoquinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 100.
MS m/z(ESI):502.3[M+H]+.
Example 112
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] octan-8-yl) propionitrile
Figure BDA0003083170700002142
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] octan-8-yl) propionitrile reference is made to example 100.
1H NMR(400MHz，CD3OD)δ8.29(s，1H)，8.21(d，J＝8.9Hz，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＝6.9Hz，2H)，2.63(t，J＝6.9Hz，2H)，2.33(s，3H)，2.08-2.01(m，2H)，2.00-1.79(m，4H)，1.74-1.63(m，2H).
MS m/z(ESI):469.2[M+H]+.
Example 113
3- ((3-exo) -3- ((7- (2-methoxyethoxy) -4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002151
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] octan-8-yl) propionitrile reference example 80.
MS m/z(ESI):477.3[M+H]+.
Example 114
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-ylmethoxy) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002152
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-ylmethoxy) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 80.
MS m/z(ESI):503.3[M+H]+.
Example 115
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) methoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002153
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) methoxy) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 80.
MS m/z(ESI):502.3[M+H]+.
Example 116
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] octan-8-yl) propionitrile
Figure BDA0003083170700002161
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] octan-8-yl) propionitrile reference is made to example 80.
MS m/z(ESI):510.3[M+H]+.
Example 117
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002162
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- ((1-methylazetidin-3-yl) oxo) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile reference is made to example 80.
MS m/z(ESI):488.3[M+H]+.
Example 118
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] octan-8-yl) propionitrile
Figure BDA0003083170700002171
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] octan-8-yl) propionitrile reference example 80.
MS m/z(ESI):516.3[M+H]+.
Example 119
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (morpholinomethyl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002172
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] nonan-9-yl) propionitrile reference example 80.
MS m/z(ESI):516.3[M+H]+.
Example 120
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methylazetidin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002181
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (1-methylazetidin-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 80.
MS m/z(ESI):486.3[M+H]+.
Example 121
3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002182
Preparation of 3- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -7- (oxetan-3-yl) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile reference example 80.
MS m/z(ESI):473.3[M+H]+.
Example 122
1- (((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002191
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a 4M HCl solution of 1, 4-epoxyhexacyclic ring (10mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 3-cyanoazetidine-1-sulfonyl chloride (44mg, 0.244mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (59.3mg, 54%).
1H NMR(400MHz，CD3OD)δ8.12(s，1H)，7.50(s，1H)，7.29(d，J＝44.1Hz，1H)，7.06(s，1H)，6.58(s，1H)，4.36(s，1H)，4.12(s，2H)，4.03(t，J＝8.4Hz，2H)，3.90(t，J＝7.0Hz，2H)，3.69-3.57(m，1H)，2.20(s，3H)，2.10-1.51(m，8H).
MS m/z(ESI):494.2[M+H]+.
Example 123
1- (((3-exo) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002192
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-carboxylate (174mg, 0.36mmol) was dissolved in a solution of 4M HCl in 1, 4-epoxyhexacyclic ring (20mL), and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (1.19mL, 7.2mmol) and 3-cyanoazetidine-1-sulfonyl chloride (78mg, 0.432mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 16.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (17.7mg, 9%).
1H NMR(400MHz，MeOD-d4)δ8.02(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＝8.5Hz，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＝42.2Hz，2H)，1.76(t，J＝11.9Hz，2H).
MS m/z(ESI):528.2[M+H]+.
Example 124
1- (((3-exo) -3- ((7-fluoro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002201
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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 122.
1H NMR(400MHz，CD3OD)δ8.11(dd，J＝9.1，6.1Hz，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).
MS m/z(ESI):512.1[M+H]+.
Example 125
1- (((3-exo) -3- ((7-cyclopropyl-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002211
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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile reference example 122.
1H NMR(400MHz，CD3OD)δ8.04(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).
MS m/z(ESI):534.1[M+H]+.
Example 126
3- ((3-exo) -3- (((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002212
The first step is as follows: 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-carboxylate
Figure BDA0003083170700002213
To a solution of 2-chloro-N- (5-methyl-1 hydro-pyrazol-3-yl) quinazolin-4-amine (200mg, 0.77mmol) in N-butanol (10mL) were added tert-butyl- (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate (222mg, 0.92mmol), DIPEA (199mg, 1.54mmol) in this order, followed by stirring at 170 ℃ for 4 hours under microwave conditions. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (15mLx3), washed with a saturated aqueous solution of sodium chloride (15mLx3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure, and the obtained product was isolated and purified by silica gel column chromatography (dichloromethane: methanol ═ 95:5) to give the title compound as a white solid (275mg, 77%).
MS m/z(ESI):464.2[M+H]+.
The third step: preparation of 3- ((3-exo) -3- (((4- ((5-methyl-1 hydro-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002221
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-carboxylate (100mg, 0.21mmol) was dissolved in 1, 4-epoxyhexacyclic solution (4.0N, 5mL), stirred at room temperature for 30 minutes and then the reaction solution was concentrated; then it was dissolved in N, N-dimethylformamide (10mL), DIPEA (108mg, 0.84mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, and after addition of 3-nitriloazetidine-1-sulfonyl chloride (45mg, 0.25mmol), stirring at room temperature was continued overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to give the title compound as a white solid (30.5mg, 29%).
1H NMR(400MHz，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).
MS m/z(ESI):508.2[M+H]+.
Example 127
1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002231
The first step of reaction: preparation of 2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine
Figure BDA0003083170700002232
2, 4-dichloro-7-methoxyquinazoline (497mg, 2.17mmol), 5-methyl-1H-pyrazol-3-amine (221mg, 2.28mmol) and DIPEA (0.75mL, 4.56mmol) were added to anhydrous ethanol (10mL), stirred at room temperature for 24 hours, and then heated to 50 ℃ for reaction for 5 hours. The solvent was removed by concentration under reduced pressure, the residue was washed with a mixed solvent of ethanol-water (v/v ═ 1: 9, 20mL), and the residue was dried under reduced pressure to give the title compound (509mg, 81%).
MS m/z(ESI):290.0[M+H]+.
The second step of 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-carboxylate
Figure BDA0003083170700002233
2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (150mg, 0.518mmol), tert-butyl (3-exo) -3- (methylamino) -8-azabicyclo [3.2.1] octane-8-carboxylate (249mg, 1.036mmol), and DIPEA (0.43mL, 2.59mmol) were added to N-butanol (3mL), and heated to 170 ℃ with a microwave synthesizer for 6 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase column chromatography to give the title compound (193mg, 75%).
MS m/z(ESI):494.2[M+H]+.
The third step of 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] octan-8-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002241
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-carboxylate (193mg, 0.39mmol) was dissolved in 4M HCl 1, 4-epoxyhexacyclic compound (20mL), the reaction was stirred at room temperature for 60 minutes, the solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10mL), the reaction mixture was cooled to 0 ℃ and DIPEA (1.93mL, 11.7mmol) and 3-cyanoazetidine-1-sulfonyl chloride (71mg, 0.39mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 4 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (97mg, 46%).
1H NMR(400MHz，DMSO-d6)δ12.11(s，1H)，9.77(s，1H)，8.23(d，J＝8.9Hz，1H)，6.72(s，1H)，6.67(d，J＝8.8Hz，1H)，6.48(s，1H)，5.40-5.25(m，1H)，4.18(s，2H)，4.06(t，J＝8.6Hz，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＝5.8Hz，2H)，1.61(d，J＝11.2Hz，2H).
MS m/z(ESI):538.2[M+H]+.
Example 128
1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002251
The first step of 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-carboxylate
Figure BDA0003083170700002252
2-chloro-7-methoxy-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (50mg, 0.173mmol) and tert-butyl (3-exo) -3-amino-9-azabicyclo [3.3.1] nonane-9-carboxylate oxalate (171mg, 0.518mmol) were added to N-butanol (10mL), heated to 170 ℃ by a microwave synthesizer for 8 hours, concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography to give the title compound (68mg, 80%).
MS m/z(ESI):494.2[M+H]+.
The second step of reaction: 1- (((3-exo) -3- ((7-methoxy-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002253
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-carboxylate (68mg, 0.138mmol) was dissolved in 4M HCl in 1, 4-epoxyhexacyclic ring (15mL) and the reaction was stirred at room temperature for 60 minutes. The solvent was removed by concentration under reduced pressure, the residual solid was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (0.68mL, 4.14mmol) and 3-cyanoazetidine-1-sulfonyl chloride (25mg, 0.138mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 8 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by prep-HPLC to give the title compound (6.9mg, 9%).
1H NMR(400MHz，DMSO-d6)δ12.10(s，1H)，9.83(s，1H)，8.24(d，J＝7.3Hz，1H)，6.65(dd，J＝29.7，20.4Hz，4H)，4.83(s，1H)，4.02(t，J＝8.5Hz，2H)，3.92(dd，J＝14.9，8.4Hz，4H)，3.87-3.73(m，4H)，2.21(s，3H)，2.04(d，J＝4.3Hz，3H)，1.92-1.68(m，7H).
MS m/z(ESI):538.2[M+H]+.
Example 129
1- ((1R, 3S, 5S) -3- ((7-chloro-4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) -2- (dimethylamino) ethan-1-one
Figure BDA0003083170700002261
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-carboxylate was dispersed in dichloromethane (2mL), a 4M HCl solution of 1, 4-epoxyhexacyclic ring (20mL) was added, and the reaction mixture was stirred at room temperature for reaction for 1.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was dried under reduced pressure on an oil pump for 10 minutes. The resulting crude product was dissolved in anhydrous N, N-dimethylformamide (8mL), cooled to 0 ℃ in an ice-water bath, and DIPEA (1.2mL, 7.1mmol), dimethylglycine (0.31mL, 4.72mmol) and HATU (118mg, 0.31mmol) were added sequentially with stirring, and the resulting reaction mixture was stirred at 0 ℃ for 60 minutes. The solvent was removed by concentration under reduced pressure and the crude product was isolated by prep-HPLC to give the title compound as a white solid (20.7mg, 21%).
1H NMR(400MHz，DMSO-d6)δ10.12(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＝3.4Hz，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).
MS m/z(ESI):469.1[M+H]+.
Example 130
2- (dimethylamino) -1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0003083170700002271
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] octan-8-yl) ethan-1-one reference example 129.
1H NMR(400MHz，DMSO-d6)δ12.21(s，1H)，10.13(s，1H)，8.33(s，1H)，7.54(t，J＝7.5Hz，1H)，7.27(d，J＝30.8Hz，1H)，7.08(s，1H)，6.78(s，1H)，6.61(s，1H)，4.56(d，J＝6.1Hz，1H)，4.48(s，1H)，4.32(d，J＝5.3Hz，1H)，3.65(dd，J＝32.9，14.8Hz，2H)，2.53(s，6H)，2.25(s，3H)，1.94(ddd，J＝36.8，20.0，10.6Hz，6H)，1.56(dd，J＝19.2，9.5Hz，2H).
MS m/z(ESI):435.2[M+H]+.
Example 131
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-2-yl) methanone
Figure BDA0003083170700002272
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-2-yl) methanone reference example 129.
1H NMR(400MHz，DMSO-d6)δ12.29(s，1H)，10.80(s，1H)，10.33(s，1H)，8.61(d，J＝4.3Hz，1H)，8.52-8.24(m，1H)，7.96(td，J＝7.8，1.7Hz，1H)，7.73(d，J＝7.8Hz，1H)，7.71-7.57(m，1H)，7.52(ddd，J＝7.5，4.9，1.0Hz，1H)，7.39(d，J＝18.4Hz，1H)，7.21(d，J＝39.2Hz，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).
MS m/z(ESI):455.2[M+H]+.
Example 132
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-3-yl) methanone
Figure BDA0003083170700002281
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-3-yl) methanone reference example 129.
1H NMR(400MHz，DMSO-d6)δ12.25(s，1H)，10.36(s，1H)，10.05(s，1H)，8.78-8.62(m，2H)，8.34(d，J＝29.6Hz，1H)，7.90(d，J＝7.0Hz，1H)，7.62-7.48(m，2H)，7.31(dd，J＝19.3，8.1Hz，1H)，7.12(s，1H)，6.60(s，1H)，4.68(d，J＝4.8Hz，1H)，4.53(d，J＝9.2Hz，1H)，4.02(d，J＝3.1Hz，1H)，2.25(s，3H)，2.16-1.48(m，8H).
MS m/z(ESI):455.2[M+H]+.
Example 133
((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-4-yl) methanone
Figure BDA0003083170700002282
Preparation of ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) (pyridin-4-yl) methanone reference example 129.
1H NMR(400MHz，DMSO-d6)δ12.23(s，1H)，10.21(s，1H)，8.70(d，J＝5.5Hz，2H)，8.32(dd，J＝28.3，8.1Hz，1H)，7.59-7.51(m，1H)，7.45(d，J＝1.8Hz，2H)，7.36-7.22(m，1H)，7.09(t，J＝7.4Hz，1H)，6.86(s，1H)，6.59(s，1H)，4.67(d，J＝4.9Hz，1H)，4.61-4.44(m，1H)，3.94(d，J＝1.9Hz，1H)，2.24(s，3H)，2.09-1.53(m，8H).
MS m/z(ESI):455.2[M+H]+.
Example 134
2, 2-difluoro-1- ((3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octan-8-yl) ethan-1-one
Figure BDA0003083170700002291
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a 4M HCl solution of 1, 4-epoxyhexacyclic ring (10mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃, DIPEA (0.73mL, 4.44mmol) was added, and after mixing well, a mixture of difluoroacetic acid (0.023mL, 0.233mmol) and HATU (169mg, 4.44mmol) (previously dissolved in 1mL of dry N, N-dimethylformamide and reacted for 10 minutes), and the reaction mixture was stirred at 0 ℃ for 1 hour. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (48.9mg, 52%).
1H NMR(400MHz，MeOD-d4)δ7.99(d，J＝7.7Hz，1H)，7.56-7.44(m，1H)，7.40-7.19(m，1H)，7.13-7.03(m，1H)，6.55(d，J＝4.7Hz，1H)，6.33(t，J＝53.6Hz，1H)，4.57(s，2H)，4.46-4.40(m，1H)，2.18(d，J＝33.6Hz，3H)，2.09-1.75(m，6H)，1.56(t，J＝12.1Hz，2H).
MS m/z(ESI):428.1[M+H]+.
Example 135
N4- (5-methyl-1H-pyrazol-3-yl) -N2- ((3-exo) -8- (pyridin-3-ylsulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) quinazoline-2, 4-diamine
Figure BDA0003083170700002301
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a 4M HCl solution of 1, 4-epoxyhexacyclic ring (10mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 3-pyridinesulfonyl chloride hydrochloride (50mg, 0.233mmol) were added in this order, and the reaction mixture was stirred at 0 ℃ for 0.5 hour. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (20.5mg, 19%).
1H NMR(400MHz，DMSO-d6)δ8.98(d，J＝2.0Hz，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＝15.0，9.9，4.2Hz，1H)，7.07(t，J＝7.4Hz，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＝16.7，6.2Hz，2H)，1.64(dd，J＝17.3，6.7Hz，2H)，1.43-1.32(m，2H).
MS m/z(ESI):491.1[M+H]+.
Example 136
N2- ((3-exo) -8- ((2-methoxyethyl) sulfonyl) -8-azabicyclo [3.2.1] octan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) quinazoline-2, 4-diamine
Figure BDA0003083170700002302
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a 4M HCl solution of 1, 4-epoxyhexacyclic ring (10mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (10mL), cooled to 0 ℃ and DIPEA (0.73mL, 4.44mmol) and 2-methoxyethane-1-sulfonyl chloride (37mg, 0.233mmol) were added in that order, and the reaction mixture was stirred at 0 ℃ for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (25.1mg, 43%).
1H NMR(400MHz，DMSO-d6)δ8.31(s，1H)，7.64(s，1H)，7.41(s，1H)，7.24(dd，J＝23.8，8.5Hz，1H)，6.61(s，1H)，4.49-4.43(m，1H)，4.26(s，2H)，3.76(t，J＝6.2Hz，2H)，3.43-3.29(m，5H)，2.32(s，3H)，2.11-1.86(m，6H)，1.74(t，J＝13.5Hz，2H).
MS m/z(ESI):472.2[M+H]+.
Example 137
N2- ((3-exo) -8- (2-fluoroethyl) -8-azabicyclo [3.2.1] octan-3-yl) -N4- (5-methyl-1H-pyrazol-3-yl) quinazoline-2, 4-diamine
Figure BDA0003083170700002311
Tert-butyl (3-exo) -3- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -8-azabicyclo [3.2.1] octane-8-carboxylate (100mg, 0.222mmol) was dissolved in a 4M HCl solution of 1, 4-epoxyhexacyclic ring (10mL) and the reaction was stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N, N-dimethylformamide (5mL), anhydrous potassium carbonate (184mg, 1.33mmol) and 1-bromo-2-fluoroethane (50mg, 0.233mmol) were added in this order, and the reaction mixture was stirred at 40 ℃ for 19 hours. The solvent was removed by concentration under reduced pressure, and the residue was isolated by reverse phase HPLC to give the title compound (27.3mg, 31%).
1H NMR(400MHz，DMSO-d6)δ8.15(d，J＝17.8Hz，1H)，7.56(s，1H)，7.35(d，J＝44.5Hz，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).
MS m/z(ESI):396.2[M+H]+.
Example 138
3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -9-azabicyclo [3.3.1] nonan-9-yl) propionitrile
Figure BDA0003083170700002321
The first step is as follows: preparation of (3- ((2, 7-dichloroquinazolin-4-yl) amino) -1H-pyrazol-5-yl) methanol
Figure BDA0003083170700002322
2,4, 7-trichloroquinazoline (300mg, 1.29mmol), (3-amino-1H-pyrazol-5-yl) methanol (180mg, 1.55mmol), and DIPEA (500mg, 3.87mmol) were added to 1, 4-dioxane (5mL), and the mixture was uniformly mixed and reacted at room temperature overnight. Concentrated under reduced pressure, the crude product was taken up in methanol (5mL), filtered and the solid dried to give the title compound as a white solid (350mg, 87%)
MS m/z(ESI):310.0[M+H]+.
The second step is that: 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-carboxylate
Figure BDA0003083170700002323
Adding (3- ((2, 7-dichloroquinazolin-4-yl) amino) -1H-pyrazol-5-yl) methanol (150mg, 0.49mmol), tert-butyl (3-exo) -3- (methylamino) -9-azabicyclo [3.3.1] nonane-9-carboxylate (150mg, 0.58mmol) and DIPEA (190mg, 1.47mmol) into n-butanol (2mL), uniformly mixing, reacting at microwave 150 ℃ for 10 hours, cooling to room temperature, concentrating the reaction solution under reduced pressure, and separating and purifying the obtained crude product by using flash silica gel column chromatography to obtain a target product which is a white solid (140mg, 55%).
MS m/z(ESI):528.2[M+H]+.
The third step: 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] nonan-9-yl) propionitrile
Figure BDA0003083170700002331
To a 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-carboxylate (140mg, 0.27mmol) in methanol (10mL), dioxane hydrochloride (4N, 2mL) was slowly added dropwise, the reaction was carried out at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, the resulting crude product was dissolved in methanol (15mL), DIPEA (0.5mL), acrylonitrile (25mg, 0.46mmol) and the reaction was carried out at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and isolated and purified by prep-HPLC to give the title compound as a white solid (22mg, 20%).
1H NMR(400MHz，DMSO-d6)δ12.41(s，1H)，10.02(s，1H)，8.35(d，J＝8.4Hz，1H)，7.28(s，1H)，7.06(d，J＝8.4Hz，1H)，6.52-6.54(m，1H)，5.53-5.55(m，1H)，5.25(s，1H)，4.46(t，J＝5.2Hz，2H)，3.31-2.87(m，7H)，2.66-2.59(m，2H)，2.08-1.87(m，5H)，1.60-1.41(m，5H).
MS m/z(ESI):481.2[M+H]+.
Example 139
3- ((3-exo) -3- ((7-chloro-4- ((5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) quinazolin-2-yl) (methyl) amino) -8-azabicyclo [3.2.1] octan-8-yl) propionitrile
Figure BDA0003083170700002341
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] octan-8-yl) propionitrile reference example 138.
H NMR(400MHz，DMSO-d6)δ12.45(s，1H)，10.08(d，J＝8.8Hz，1H)，8.36(d，J＝8.8Hz，1H)，7.29(s，1H)，7.07(d，J＝8.8Hz，1H)，6.62-6.54(m，1H)，5.27-5.11(m，2H)，4.50(d，J＝5.6Hz，2H)，3.31-2.27(m，2H)，2.94(d，J＝16.0Hz，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).
MS m/z(ESI):467.2[M+H]+.
Example 140
3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) propionitrile
Figure BDA0003083170700002342
Preparation of 3- (4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) propionitrile reference example 68.
1H NMR(400MHz，CD3OD:CDCl3，v/v＝1:1)δ8.03(d，J＝8.1Hz，1H)，7.59(d，J＝7.9Hz，1H)，7.44(s，1H)，7.20(t，J＝7.4Hz，1H)，6.63(s，1H)，5.92(s，1H)，4.01-3.87(m，1H)，2.98(d，J＝11.6Hz，2H)，2.77(t，J＝6.9Hz，2H)，2.64(t，J＝6.9Hz，2H)，2.45-2.22(m，5H)，2.19-2.07(m，2H)，1.65(td，J＝14.0，3.4Hz，2H).
MS m/z(ESI):377.1[M+H]+.
Example 141
1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile
Figure BDA0003083170700002351
Preparation of 1- ((4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) piperidin-1-yl) sulfonyl) azetidine-3-carbonitrile reference example 122.
1H NMR(400MHz，CD3OD:CDCl3，v/v＝1:1)δ8.04(d，J＝8.1Hz，1H)，7.65-7.59(m，1H)，7.45(d，J＝8.2Hz，1H)，7.22(t，J＝7.5Hz，1H)，6.31(s，1H)，4.17(t，J＝8.3Hz，2H)，4.12-4.01(m，3H)，3.74(d，J＝12.7Hz，2H)，3.61(ddd，J＝15.1，8.7，6.4Hz，1H)，3.06(t，J＝11.3Hz，2H)，2.32(s，3H)，2.21-2.11(m，2H)，1.64(td，J＝13.6，3.3Hz，2H).
MS m/z(ESI):468.1[M+H]+.
Example 142
3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile
Figure BDA0003083170700002352
Preparation of 3- (endo-6- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) amino) -3-azabicyclo [3.1.0] hex-3-yl) propionitrile reference example 79.
MS m/z(ESI):375.2[M+H]+.
Second, evaluation of biological test
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 measurement of inhibitory Effect of the Compound of the present invention on JAK kinase Activity
Purpose of the experiment: the purpose of this test example was to test the activity of compounds on inhibition of JAK kinase activity.
An experimental instrument: the centrifuge (5702R) is purchased from Eppendorf company, the pipettor is purchased from Eppendorf or Rainin company, and the microplate reader is purchased from BioTek company in the United states and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps: the experiment adopts a fluorescence resonance energy transfer (TR-FRET) method to test the inhibition effect of the compound on the JAK kinase activity, and obtains the half inhibition concentration IC of the compound on the JAK kinase activity50。
The specific experimental operations were as follows:
the kinase reaction was performed in white 384-well plates (PerkinElmer) with 1-5. mu.L of DMSO and ddH per well2O diluted compounds of different concentrations, 1-5. mu.L of the corresponding vehicle was added to the positive control wells, followed by 1-5. mu.L of kinase buffer (HEPES 50-250mM, MgCl) per well25-20mM, etc.), adding 1-5 muL of kinase buffer solution into a negative control hole, adding 1-5 ul of substrate mixed solution containing polypeptide substrate and ATP, incubating at room temperature for 0.5-5 hours, adding 10ul of EDTA and detection solution containing labeled antibody, incubating at room temperature for 1-24 hours, measuring fluorescence signal values of about 620nM and 665nM of each plate hole by using a BioTek Synergy H1 enzyme-labeling instrument, and calculating the inhibition rate according to the fluorescence signal values. Obtaining the IC of the compound by curve fitting according to the inhibition rates of different concentrations50。
The experimental data processing method comprises the following steps:
by applying positive control wells (DMSO control wells) and negative control wells on the plate: (No kinase added) the percent inhibition data {% inhibition 100 {% inhibition for wells treated with compound (test compound value-negative control value) ]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula50The value is obtained.
And (4) experimental conclusion:
the above scheme shows that the compound of the example shown in the invention shows the biological activity in the JAK1/2/3/TYK2 kinase activity test shown in the following table 1.
TABLE 1
Figure BDA0003083170700002361
Figure BDA0003083170700002371
Figure BDA0003083170700002381
Figure BDA0003083170700002391
Figure BDA0003083170700002401
From the above table, it can be seen that: the compounds of the above examples can obviously inhibit the enzymatic activity of JAK1/2/3/TYK2 kinase, and some compounds show strong inhibition effect on JAK1/2/3/TYK2 kinase (NA indicates no detection).
Test example 2 measurement of inhibitory Effect of the Compound of the present invention on the JAK-STAT Signal pathway of cells
Purpose of the experiment:
the purpose of this test example was to test the activity of compounds on inhibition of the JAK-STAT signaling pathway in cells.
An experimental instrument:
microplate shaker (88880024) available from Thermo ScientificTMCompany(s)
Centrifuge (5702R) from Eppendorf
Pipettes were purchased from Eppendorf Inc
The microplate reader is purchased from BioTek company of America, and is a SynergyH1 full-function microplate reader.
The experimental method comprises the following steps:
the experiment adopts a U266 cell line, activates a JAK-STAT signal channel through INF-alpha stimulation, detects the inhibition activity of a compound on the phosphorylation of downstream STAT3 of the compound, and obtains the half inhibition concentration IC of the compound on the activity of the JAK-STAT signal channel 50。
The specific experimental operations were as follows:
3-12 μ L of U266 fine particles are spread in 384-well detection plates, the number of cells in each well is 100-300K, 2 μ L of the compound solution diluted in gradient is added, and the incubation is performed for 2 hours with shaking at 350rpm at room temperature. After 2 hours, 2. mu. LINF-alpha was added to the solution at a final INF-alpha concentration of 1000U/mL and the solution was shaken at room temperature for 15 minutes. 2-5. mu.L (5X) of LANCE Ultra Lysis Buffer 2 solution was added thereto, and the mixture was shaken at room temperature for 2 hours. After 2 hours, 5. mu.L of a final concentration of 0.5nM LANCE Ultra Eu-labeled Anti-STAT3 antibody (PerkinElmer) and a final concentration of 5nM LANCE Ultra high-labeled Anti-STAT3 antibody (PerkinElmer) solution were added and incubated overnight at room temperature. Measuring 665nm fluorescence signal value of each plate hole by a microplate reader, calculating inhibition rate through the fluorescence signal value, and obtaining IC of the compound through curve fitting according to the inhibition rates of different concentrations50。
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition 100- [ (test compound value-negative control value) for wells treated with compound was calculated by counting the percent inhibition data from positive control wells (DMSO control wells) and negative control wells (no cells) on the plate]V (positive control value-negative control value) × 100 }. IC was calculated using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4-parameter nonlinear logistic formula 50The value is obtained.
And (4) experimental conclusion:
the above scheme shows that the compound of the embodiment shown in the invention has the following biological activity on JAK-STAT signal pathway activity of U266 cells in the following table 2.
TABLE 2
Figure BDA0003083170700002411
Figure BDA0003083170700002421
From the above table, it can be seen that: the compound of the above example has obvious inhibition effect on the JAK-STAT signal pathway activity of human myeloma cell U266.
Test 3, Balb/C mouse pharmacokinetic assay
1. The research aims are as follows:
compound example 1, example 8, example 9, example 15, example 17, example 18, example 28, example 31, example 33, example 34, example 38, example 48, example 49, example 59, example 67, example 68, example 80, example 81, example 82, example 88, example 100, example 122, and example 123 were studied using Balb/C mice as test animals, pharmacokinetic behavior in mice (plasma and colon, ileal tissue) after oral administration at a dose of 5mg/kg was analyzed for compounds with superior PK by analyzing drug concentrations in the colon and ileum, and colon/ileum drug concentration, colon/plasma drug concentration ratio for further studies.
2. Test protocol
2.1 test drugs:
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 prepared by oneself.
2.2 test animals:
Balb/C Mouse group was 12 per group, male, Shanghai Jitsie laboratory animals Ltd, animal production license number (SCXK 2013) 0006N 0.311620400001794).
2.3 administration:
Balb/C mice were 12 per group, male; p.o. after fasting overnight, the dose was 5mg/kg and the administration volume was 10 mL/kg.
2.4 sample collection:
mice were dosed with CO before and after dosing at 0, 0.5, 1, 2, 3, 5 and 7 hours2Sacrifice, blood sampling 0.2mL of the heart, placing in EDTA-K2Centrifuging at 4 deg.C and 6000rpm for 6 min in a test tube to separate plasma, and storing at-80 deg.C; the ileum is taken near the cecum and is about 4-5cm long; the colon is also taken near the cecum end, about 2-3cm in length, taken out, weighed, placed in a 2mL centrifuge tube, and stored at-80 ℃.
2.5 sample treatment:
1) plasma samples 40uL added 160uL acetonitrile precipitation, after mixing 3500 x g centrifugal 5 ~ 20 minutes.
2) Plasma and intestinal homogenate samples 30. mu.L were precipitated by adding 90. mu.L acetonitrile containing internal standard (100ng/mL), mixed and centrifuged at 13000rpm for 8 minutes.
3) 70uL of the treated supernatant solution was added to 70uL of water, vortexed and mixed for 10 minutes, and then 20 uL of the supernatant solution was subjected to LC/MS/MS analysis for the concentration of the test compound, and the LC/MS/MS analyzer: ABSciex API 4000 Qtrap.
2.6 liquid phase analysis
Liquid phase conditions: shimadzu LC-20AD pump
Column chromatography: agilent ZORBAX XDB-C18 (50X 2.1mm,3.5 μm) mobile phase:
the solution A is 0.1% formic acid water solution, and the solution B is acetonitrile
Flow rate: 0.4mL/min
Elution time: 0-4.0 min, eluent as follows:
Figure BDA0003083170700002431
Figure BDA0003083170700002441
3. test results and analysis
The main pharmacokinetic parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in table 3:
TABLE 3
Figure BDA0003083170700002442
Figure BDA0003083170700002451
Figure BDA0003083170700002461
NA indicates no detection or no detection (limit of detection of blood concentration is 1ng/ml, C is detected in bloodmaxWhen the NA is NA, the NA in the blood detection index is not detected; when blood is detected CmaxWhen the content is higher than the limit of quantitation by 1ng/ml, the NA in the blood detection index is not detected; NA in tissues (colon and ileum) indicates not detected).
And (4) experimental conclusion:
as can be seen from the results of the mouse Pharmacokinetic (PK) experiments in the table: the compounds of the examples of the invention showed good exposure levels in the colon and ileum, area under the time curve of plasma drug concentration (AUC) and maximum plasma drug concentration (C) max) All reach the screening standard; and the colon/ileum drug concentration and colon/plasma drug concentration ratio of the compound is high, and good selectivity is shown.
Test 4, in vivo efficacy test procedure and results
4.1 purpose of experiment:
the compounds of the examples were evaluated for efficacy in a dss (dextran sulfate sodium) induced colitis model in C57BL/6 mice.
4.2. Experiment main material
4.2.1 instruments
1. Balance Mettler toledo AL104
2. Balance TP-602
4.2.2 reagents
1. Dextran Sodium Sulfate (DSS): MP Biomedicals, LLC, Solon, Ohio, cat No.: 160110
2. Cyclosporine (CsA): norwalk, switzerland, batch number: S0033A
3. Sodium carboxymethylcellulose: chemical reagents of national drug group Co Ltd
4. Tween 80: sigma, cat No.: 8CBM 513V
4.2.3 Experimental animals
Animal species and strains: C57BL/6
sex, age/body weight: female, 6-8 weeks old/18-20 g
The supplier: Shanghai Slac Experimental Animal Co.,Ltd.
4.3. experimental procedure
4.3.1 grouping
Animals were randomized into groups based on animal weight on day-1 using BioBook software to ensure similar weight values for each group of animals to reduce bias, and the grouping and dosing schedule are shown in the table below.
Grouping and dosing regimens
Figure BDA0003083170700002471
a, the solvent is 0.5 percent of CMC-Na +1 percent of Tween 80
b, at intervals of 8 hours
4.3.2 Experimental procedures
1. Reagent preparation
Drinking water containing DSS: an appropriate amount of DSS powder was dissolved in autoclaved drinking water to prepare a 2% DSS solution.
2. Induction of enteritis
On day-1, animals were divided into 12 groups of 10 animals on average. (specific grouping scheme see Table 1)
Starting on day 0, 9:00 to day 6, 9:00, mice in groups 2 to 9 were given 2% DSS-containing aqueous solution for 6 days (from day 0 to day 6), after which the mice were given free water for 3 days (from day 6, 9:00 to day 9 before necropsy). The day of molding was counted as 0 day. The DSS aqueous solution is wrapped by tin foil paper to ensure light resistance. The DSS aqueous solution was replaced every 2 days.
Group 1 mice were free to drink normal water for 9 days (from day 0, 9:00 to day 9 before necropsy).
3. Administration of drugs
The specific dosages, routes of administration and times of administration are referenced in the table above.
4.4 measurement
1) Body weight
The frequency of recording was once a day.
2) Daily disease index (DAI)
The frequency of recording was once a day, rated on 4 scales according to the following criteria:
weight change (0, less than or equal to 1%; 1, 1-5%; 2, 5-10%; 3, 10-15%; 4, > 15%);
bloody stools (0, negative; 4, positive);
stool score (0, Normal; 2, loose stool; 4, diarrhea)
The daily disease index value (DAI) was obtained by dividing the sum of the scores of the above 3 sections by 3. The DAI-time (day) curve was plotted against the daily DAI score and the peak area under the curve (AUC) was calculated. The decreased ratio of DAI AUC is the administration group Calculated by comparing with the Vehicle group, the calculation formula is (DAI AUC)Administration set-DAI AUCVehicle)/DAI AUCVehicle×100％
4.5. The experimental results are as follows:
Figure BDA0003083170700002481
Figure BDA0003083170700002491
4.6. conclusion of the experiment
On a DSS-induced C57BL/6 mouse colitis model, the compounds of the above examples can obviously reduce the daily disease index (DAI) and have obvious drug effects.
Research on compound salt and crystal form thereof
1. Laboratory apparatus
1.1 some parameters of the physicochemical measuring instrument
Figure BDA0003083170700002492
1.2 Instrument and conditions for liquid phase analysis
1.2.1 instruments and devices
Figure BDA0003083170700002493
Figure BDA0003083170700002501
1.2.2 chromatographic conditions
A chromatographic column: ZORBAX (SB-C8, 3.5 μm, 4.6X 75mm)
Flow rate: 1.5mL/min
Column temperature: 40 deg.C
Detection wavelength: 242nm
Sample introduction volume: 5.0. mu.L
Operating time: 15min
Diluent agent: ACN-Water (v/v, 1:1)
Mobile phase: a: water (0.05% trifluoroacetic acid); b: acetonitrile (0.05% trifluoroacetic acid)
T(min) A(％) B(％)
0.00 95 5
8.00 60 40
12.00 10 90
12.10 95 5
15.00 95 5
2. Screening for Compound salt form
The preparation method of the compound salt type comprises the following steps:
the method 1 for preparing the acid salt of the compound shown in the general formula (I) specifically comprises the following steps:
1) weighing a proper amount of free alkali, and dissolving the free alkali by using a benign solvent;
2) weighing a proper amount of counter ion acid, and dissolving the counter ion acid by using an organic solvent;
3) mixing the two solutions, stirring to separate out or dripping a poor solvent and stirring to separate out;
4) quickly centrifuging or standing and drying to obtain a target product;
Wherein:
the benign solvent is selected from 2-butanol, methanol, isopropanol, 2-butanone, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide or N-methylpyrrolidone; preferably one or more of 2-butanol, methanol or dimethyl sulfoxide;
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-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably one or more of methanol, ethanol or acetonitrile;
the poor 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;
the counter-ionic 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, fumaric acid, and the like, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic 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, isethionic 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, 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, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; further preferred is phosphoric acid, maleic acid or benzenesulfonic acid.
The method 2 for preparing the acid salt of the compound shown in the general formula (I) specifically comprises the following steps:
1) weighing a proper amount of free alkali, and suspending with an adverse solvent;
2) weighing a proper amount of counter ion acid, and dissolving the counter ion acid by using an organic solvent;
3) adding the solution into the suspension, and stirring;
4) quickly centrifuging or standing and drying to obtain a salt of the compound;
wherein:
the poor solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dichloromethane, 3-pentanone, isopropyl acetate, ethyl formate, 1, 4-dioxane, chlorobenzene, benzene, toluene, isopropanol, N-butanol, isobutanol, N-dimethylformamide, N-dimethylacetamide, N-propanol, tert-butanol or 2-butanone; preferably one or more of dichloromethane, toluene, acetonitrile, acetone, methanol or ethyl acetate;
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-methyl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1, 4-dioxane, tert-butyl alcohol or N, N-dimethylformamide; preferably one or more of methanol, ethanol or acetonitrile;
The counter-ionic 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetoxy hydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, isoascorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, dodecylsulfuric acid, dibenzoyltartaric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid, fumaric acid, and the like, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic 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, isethionic 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, 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, isethionic acid, 1, 5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; further preferred is phosphoric acid, maleic acid or benzenesulfonic acid.
2.1 salt form Screen of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one
2.1.1 Experimental purposes:
different counter-ionic acids were selected and tested for which they could form the compound salt.
2.1.2 Experimental procedures:
1) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
2) Operating procedure
Dissolving out or suspending into salt by taking methanol as a solvent:
weighing 10mg of free alkali, adding 200 mu L of methanol solvent, heating and stirring at 50 ℃, respectively adding different counter-ion acids (the molar reaction ratio of the alkali to the acid is 1: 1.2, wherein the different counter-ion acids are respectively dissolved by the following organic solutions before adding), stirring for reacting, directly and quickly centrifuging or standing and drying by blowing after solid precipitation is finished to obtain compound salt, adding the counter-solvent into the reaction solution, stirring and precipitating, and quickly centrifuging or standing and drying by blowing to obtain the compound salt after the solid precipitation is not finished, wherein the results are as follows:
serial number Acid(s) After addition of acid Results
1 1.0M benzenesulfonic acid (methanol solution) Dissolved and separated out Salt formation
2 1.0M sulfuric acid (ethanol solution) Dissolved and separated out Salt formation
3 0.5M D-tartaric acid (ethanol solution) Dissolved and separated out Salt formation
4 1.0M p-methylbenzenesulfonic acid (ethanol solution) Dissolved and separated out Salt formation
5 0.25M fumaric acid (ethanol solution) Suspension of Salt formation
6 1.0M oxalic acid (ethanol solution) Adding anti-solvent MTBE into the solution to form oil, and gradually suspending Salt formation
7 1.0M hydrobromic acid (ethanol solution) Dissolved and separated out Salt formation
8 1.0M citric acid (ethanol solution) Dissolving, volatilizing or adding isopropyl ether and MTBE to form oil N/A
9 1.0M maleic acid (methanol solution) Dissolved and separated out Salt formation
10 1.0M succinic acid (methanol solution) Adding isopropyl ether to separate out Salt formation
11 1.0M malonic acid (ethanol solution) Suspension of Without forming salts
12 1.0M acetic acid (methanol solution) Suspension of Without forming salts
13 1.0M adipic acid (methanol solution) Suspension of Salt formation
14 1.0M Hydroxyethylsulfonic acid (methanol solution) Dissolved and separated out Salt formation
15 1.0M benzoic acid (methanol solution) Suspension of Salt formation
2.1.3 results of the experiment
Salt form screening experiments show that the salt forms capable of forming salts with the free base of the compound are maleate, benzenesulfonate, sulfate, isethionate, adipate, p-toluenesulfonate, fumarate, oxalate, hydrobromide, 1, 5-naphthalenedisulfonate and tartrate.
2.2 salt form Screen 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] octan-8-yl) propionitrile
2.2.1 Experimental purposes:
different counter-ionic acids were selected and tested for which they could form the compound salt.
2.2.2 Experimental procedures:
1) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
2) Operating procedure
And (2) forming salt by using methanol as a solvent through a natural volatilization method:
weighing appropriate amount of free alkali, adding methanol to obtain solution with concentration of 20mg/mL, and making into stock solution. The reaction was carried out by adding different counter ion acid solutions (molar reaction ratio of base: acid 1: 1.2 or molar reaction ratio of base: acid 1: 2.2) to 0.5ml or 1ml of stock solution, respectively, and then volatilizing the solvent by opening at room temperature, as follows:
Figure BDA0003083170700002541
Figure BDA0003083170700002551
2.2.3 results of the experiment
The salt forms which can be salified with the compound are phosphate, succinate, acetate, hydrochloride, benzene sulfonate, hydrobromide, oxalate, adipate, ethane sulfonate, benzoate, 1, 5-naphthalene disulfonate, pamoate, hippurate, sulfate, malonate, p-toluenesulfonate, maleate, malate, tartrate and fumarate.
3. Compound salt crystal form screening
3.1 salt Crystal form screening of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one
3.1.1 Experimental purposes:
different counter-ionic acids are selected and by suitable crystallization methods, it is possible to detect which counter-ionic acids can form the compound salt.
3.1.2 Experimental procedures:
3) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
4) Operating procedure
I. Salt-forming crystallization by natural volatilization method with methanol as solvent
Weighing 10mg of free alkali, adding 200 mu L of methanol solvent, adding different counter ion acids (the molar reaction ratio of the alkali to the acid is 1: 1.2) respectively for reaction, then volatilizing the solvent at room temperature in an open manner, adding 200 mu L of ethyl acetate respectively for pulping, wherein the amorphous form or the crystal form is poor. The results are as follows:
Figure BDA0003083170700002552
Figure BDA0003083170700002561
II. Dissolving out or suspending into salt crystals by different solvents
Figure BDA0003083170700002562
Figure BDA0003083170700002571
III beating with different solvents
Taking 10mg of crystal form solids of different salt forms obtained by taking methanol as a solvent, respectively adding 200 mu L of organic solvent, and pulping at 50 ℃. The results are as follows:
Figure BDA0003083170700002572
3.1.3 results of the experiment
The salt crystal form screening experiment shows that the obtained salt forms with crystal forms are maleate, benzene sulfonate, sulfate, isethionate, adipate, p-toluenesulfonate, fumarate, oxalate, hydrobromide, 1, 5-naphthalenedisulfonate and tartrate, wherein the crystallinity and the number of the crystal forms of maleic acid, benzene sulfonate, sulfuric acid, isethionic acid and adipic acid are better, and the salt forms have advantages.
3.2 screening of salt forms 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] octan-8-yl) propionitrile
3.2.1 Experimental purposes:
different counter-ionic acids are selected and by suitable crystallization methods, it is possible to detect which counter-ionic acids can form the compound salt.
3.2.2 Experimental procedures:
1) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
2) Operating procedure
I. Dissolving out or suspending into salt crystals by different solvents
10mg or 20mg of free base is weighed, different counter ion acid solutions (molar reaction ratio of base: acid 1: 1.2 or molar reaction ratio of base: acid 1: 2.2) are added into different solvents as reaction solvents respectively, and reaction is carried out, and the results are as follows:
Figure BDA0003083170700002581
Figure BDA0003083170700002591
3.2.3 results of the experiment
The salt crystal form screening experiment shows that the obtained salt forms with crystal forms are phosphate, succinate, acetate, hydrochloride, benzene sulfonate, hydrobromide, oxalate, adipate, ethane sulfonate, benzoate, 1, 5-naphthalene disulfonate, pamoate, hippurate, sulfate, malonate, p-toluenesulfonate, maleate, malate, tartrate and fumarate, wherein the phosphate, succinate and acetate have advantages.
3.3 salt Crystal form screening of 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] nonan-9-yl) -2- (methylamino) -ethan-1-one
3.3.1 Experimental purposes:
and selecting a proper crystallization method according to the salt form screening result, and screening different salt forms.
3.3.2 Experimental procedures:
1) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
2) Operating procedure
I. Preparation of besylate crystal form a
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, separating out a large amount of solid after dissolving, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the benzene sulfonate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 1, DSC pattern as shown in figure 2 and TGA pattern as shown in figure 3.
II. Preparation of besylate crystal form B
Weighing 10mg of free alkali, adding 200 mu L of acetone, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, stirring at a boiling oil chamber temperature, separating out solid, centrifuging to remove supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain the benzene sulfonate crystal form B. Upon detection analysis, it has the following XRPD pattern as shown in fig. 4.
III preparation of besylate Crystal form C
Weighing 10mg of free alkali, adding 200 mu L of dichloromethane, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, insoluble, stirring at room temperature for 2 days, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the benzene sulfonate crystal form C. By detection analysis, it has the following XRPD pattern as shown in figure 5, DSC pattern as shown in figure 6 and TGA pattern as shown in figure 7.
IV, preparation of besylate crystal form D
Weighing 10mg of free alkali, adding 200 mu L of ethanol, heating and stirring at 50 ℃, slowly adding a 28 mu L1.0M benzene sulfonate methanol solution into the system, insoluble, stirring at room temperature for 2 days, centrifuging to remove supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain a benzene sulfonate crystal form D. Upon detection analysis, it has the following XRPD pattern as shown in fig. 8.
Preparation of crystal form E of V and benzene sulfonate
Weighing 10mg of free alkali, adding 200 mu L of acetonitrile, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, stirring at a boiling oil chamber temperature, separating out solid, centrifuging to remove supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain the benzene sulfonate crystal form E. By detection analysis, it has the following XRPD pattern as shown in figure 9, DSC pattern as shown in figure 10 and TGA pattern as shown in figure 11.
VI preparation of besylate crystal form F
Weighing 10mg of free alkali, adding 200 mu L of chlorobenzene, heating and stirring at 50 ℃, slowly adding a methanol solution of 28 mu L1.0M benzene sulfonate into the system, separating out a solid after dissolving, centrifuging to remove a supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain a benzene sulfonate crystal form F. Upon detection analysis, it has the following XRPD pattern as shown in fig. 12.
VII preparation of besylate crystal form G
Weighing 10mg of free alkali, adding 200 mu L of 3-pentanone, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, separating out solid after oil formation, centrifuging to remove supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain the benzene sulfonate crystal form G. Upon detection analysis, it has the following XRPD pattern as shown in fig. 13.
VIII, preparation of besylate Crystal form H
Weighing 10mg of free alkali, adding 200 mu L of 88% acetone, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of benzene sulfonate methanol solution into the system, separating out solid after dissolving, centrifuging to remove supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain the benzene sulfonate crystal form H. Upon detection analysis, it has the following XRPD pattern as shown in fig. 14.
IX, preparation of sulphate Crystal form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding an ethanol solution of 28 mu L1.0M sulfuric acid into the system, separating out a solid after dissolving, centrifuging to remove a supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain a sulfate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 15, DSC pattern as shown in figure 16 and TGA pattern as shown in figure 17.
Preparation of crystal form A of X, isethionate
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M methanol solution of isethionic acid into the system, separating out solid after dissolving, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the crystal form A of isethionate. By detection analysis, it has the following XRPD pattern as shown in figure 18, DSC pattern as shown in figure 19 and TGA pattern as shown in figure 20.
Preparation of crystalline form B of XI isethionate salt
Weighing 10mg of free alkali, adding 200 mu L of ethyl acetate, heating and stirring at 50 ℃, slowly adding a methanol solution of 28 mu L1.0M of isethionic acid into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the isethionate crystal form B. By detection analysis, it has the following XRPD pattern as shown in figure 21, DSC pattern as shown in figure 21 and TGA pattern as shown in figure 23.
Preparation of crystalline form XII, isethionate C
Weighing 10mg of free alkali, adding 200 mu L of tetrahydrofuran, heating and stirring at 50 ℃, slowly adding a methanol solution of 28 mu L1.0M of isethionic acid into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the isethionate crystal form C. It has the following XRPD pattern shown in figure 24 and DSC pattern shown in figure 25 by detection analysis.
Preparation of XIII, adipate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of adipic acid methanol solution into the system, separating out after dissolving, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the adipate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 26, DSC pattern as shown in figure 27 and TGA pattern as shown in figure 28.
Preparation of form B of XIV adipate
Weighing 10mg of free alkali, adding 200 mu L of ethyl acetate, heating and stirring at 50 ℃, slowly adding a 28 mu L1.0M adipic acid methanol solution into the system, carrying out insoluble stirring overnight, centrifuging to remove a supernatant, and drying the residual solid in a 50 ℃ vacuum drying oven to constant weight to obtain the adipate crystal form B. By detection analysis, it has the following XRPD pattern as shown in figure 29, DSC pattern as shown in figure 30 and TGA pattern as shown in figure 31.
Preparation of XV, p-toluenesulfonate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of adipic acid methanol solution into the system, dissolving and precipitating, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the p-toluenesulfonate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 32, DSC pattern as shown in figure 33 and TGA pattern as shown in figure 34.
Preparation of crystal form B of XVI and p-toluenesulfonate
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M of adipic acid methanol solution into the system, separating out after cooling the solution, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the p-toluenesulfonate crystal form B. By detection analysis, it has the following XRPD pattern as shown in figure 35, DSC pattern as shown in figure 36 and TGA pattern as shown in figure 37.
XVII, preparation of fumarate Crystal form A
Weighing 100mg of free alkali, adding 2mL of methanol, heating and stirring at 50 ℃, slowly adding 1120 mu L of 0.25M fumaric acid ethanol solution into the system, insoluble, stirring at room temperature overnight, filtering, and drying the solid in a vacuum drying oven at 50 ℃ to constant weight to obtain the fumarate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 38, DSC pattern as shown in figure 39 and TGA pattern as shown in figure 40.
XVIII, preparation of fumarate Crystal form B
Weighing 10mg of fumarate crystal form A, adding 200 mu L of methanol, pulping at 50 ℃ for 1 day, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain fumarate crystal form B. It has the following XRPD pattern shown in figure 41 and DSC pattern shown in figure 42 after detection and analysis.
Preparation of form C of XIX, fumarate
Weighing 10mg of fumarate crystal form A, adding 200 mu L of acetone, pulping at 50 ℃ for 1 day, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain fumarate crystal form C. Upon detection analysis, it has the following XRPD pattern as shown in fig. 43.
XX, preparation of oxalate form A
Weighing 100mg of free alkali, adding 2mL of methanol, heating and stirring at 50 ℃, slowly adding 280 mu L1.0M of oxalic acid ethanol solution into the system, continuously stirring overnight after insolubilization, filtering, and drying the solid in a vacuum drying oven at 50 ℃ until the weight is constant to obtain oxalate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 44, DSC pattern as shown in figure 45 and TGA pattern as shown in figure 46.
XXI, preparation of hydrobromide form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L1.0M hydrobromic acid ethanol solution into the system, dissolving and precipitating after clearing, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ until the weight is constant to obtain the hydrobromide crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 47, DSC pattern as shown in figure 48 and TGA pattern as shown in figure 49.
Preparation of XXII, 1, 5-naphthalenedisulfonate crystal form B
Weighing 10mg of free alkali, adding 200 mu L of ethanol, heating and stirring at 50 ℃, slowly adding 224 mu L0.125M 1 of ethanol solution of 1, 5-naphthalenedisulfonic acid into the system, continuously stirring for one night after insolubilization, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ until the weight is constant to obtain the 1, 5-naphthalenedisulfonic acid salt crystal form B. Upon detection analysis, it has the following XRPD pattern as shown in fig. 50.
Preparation of XXIII, 1, 5-naphthalenedisulfonate crystal form C
Weighing 10mg of free alkali, adding 200 mu L of isopropanol, heating and stirring at 50 ℃, slowly adding 224 mu L0.125M 1 of ethanol solution of 1, 5-naphthalenedisulfonic acid into the system, continuously stirring overnight after insolubilization, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ until the weight is constant to obtain the 1, 5-naphthalenedisulfonate crystal form C. By detection and analysis, the XRPD pattern shown in figure 51, the DSC pattern shown in figure 52 and the TGA pattern shown in figure 53 are shown below.
Preparation of XXIV, 1, 5-naphthalenedisulfonate crystal form D
Weighing 10mg of 1, 5-naphthalenedisulfonate crystal form A, adding 200 mu L of water, pulping for 1 day at 50 ℃, centrifuging to remove supernatant, and putting the residual solid in a vacuum drying oven at 50 ℃ to dry to constant weight to obtain 1, 5-naphthalenedisulfonate crystal form D. By detection analysis, it has the following XRPD pattern as shown in figure 54, DSC pattern as shown in figure 55 and TGA pattern as shown in figure 56.
XXV, preparation of tartrate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 56 mu L0.5M of tartaric acid ethanol solution into the system, dissolving and separating out after clearing, centrifuging to remove supernatant, and drying the residual solid in a vacuum drying oven at 50 ℃ to constant weight to obtain tartrate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 57, DSC pattern as shown in figure 58 and TGA pattern as shown in figure 59.
XXVI preparation of the formate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L of methanol solution of 1M formic acid into the system, dissolving and drying at room temperature after dissolving, adding 200 mu L of ethyl acetate, pulping at 50 ℃ for 2 days, centrifuging to remove supernatant, and putting the residual solid into a vacuum drying oven at 50 ℃ to dry to constant weight to obtain the formate crystal form A. Upon detection analysis, it has the following XRPD pattern as shown in fig. 60.
XXVII preparation of hippurate crystal form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding an ethanol solution of 140 mu L0.2M hippuric acid into the system, dissolving and volatilizing at room temperature after clearing, adding 200 mu L of ethyl acetate, pulping at 50 ℃ for 2 days, centrifuging to remove supernatant, and putting the residual solid into a vacuum drying oven at 50 ℃ to dry to constant weight to obtain the crystal form A of the hippurate. Upon detection analysis, it has the following XRPD pattern as shown in fig. 61.
XXVIII, preparation of laurate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding 28 mu L of 1M methanol solution of lauric acid into the system, volatilizing the insoluble matter at room temperature, adding 200 mu L of ethyl acetate, pulping at 50 ℃ for 2 days, centrifuging to remove supernatant, and putting the residual solid into a 50 ℃ vacuum drying oven to be dried to constant weight to obtain the laurate crystal form A. By detection analysis, it has the following XRPD pattern as shown in figure 62, DSC pattern as shown in figure 63 and TGA pattern as shown in figure 64.
XXIX, preparation of stearate form A
Weighing 10mg of free alkali, adding 200 mu L of methanol, heating and stirring at 50 ℃, slowly adding an ethanol solution of 187 mu L0.15M stearic acid into the system, drying the mixture at insoluble room temperature, adding 200 mu L of ethyl acetate, pulping the mixture at 50 ℃ for 2 days, centrifuging the mixture to remove supernatant, and putting the residual solid into a vacuum drying oven at 50 ℃ to dry the solid to constant weight to obtain the stearate crystal form A. Upon detection analysis, it has the following XRPD pattern as shown in fig. 65.
Preparation of form A of XXX, free base
Weighing 1000mg of hydrochloride of free alkali of the compound into a 40mL glass bottle, adding 7mL of methanol, heating and stirring at 50 ℃, adding 1M HCl hydrochloric acid solution to dissolve and clear, filtering, adding 1M NaOH solution until precipitation is separated out (about pH 10), stirring at room temperature overnight, filtering, washing with water, and drying the solid in vacuum at 50 ℃ to obtain the free alkali crystal form A. Upon detection analysis, it has the following XRPD pattern as shown in fig. 66.
3.4 salt Crystal form 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] octan-8-yl) propionitrile
3.4.1 Experimental purposes:
and selecting a proper crystallization method according to the salt form screening result, and screening different crystal forms of the maleate. 3.4.2 Experimental procedure:
1) apparatus and device
Name (R) Model number Source
Analytical balance BSA224S-CW Sartorius
Ultrasonic cleaning instrument SK5200LHC Shanghai department leads ultrasonic instrument
Liquid-transfering gun Eppendorf(50mL,1000μL) Eppendorf
2) Operating procedure
I. Preparation of succinate crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 7.96mg of phosphoric acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, volatilizing at room temperature in an open manner, and drying in vacuum to obtain succinate crystal form A. Upon detection analysis, it had the XRPD pattern shown in figure 67.
II. Preparation of succinate crystal form B
Weighing 10mg of free alkali, adding 1mL of acetonitrile, heating and stirring at 40 ℃, slowly adding a methanol solution of 24 mu L1.0M succinic acid into the system, stirring overnight, centrifuging to remove supernatant, and vacuum-drying the residual solid to obtain the succinate crystal form B. By detection analysis, it has an XRPD pattern as shown in figure 68, a DSC pattern as shown in figure 69 and a TGA pattern as shown in figure 70.
III, preparation of acetate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 3.50mg of acetic acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, volatilizing at room temperature in an open manner, and drying in vacuum to obtain acetate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 71.
IV, preparation of acetate crystal form B
And weighing a proper amount of acetate crystal form A solid, standing overnight under a high-humidity condition, and drying to obtain an acetate crystal form B. Upon detection analysis, it had an XRPD pattern as shown in figure 72.
Preparation of V, acetate crystal form C
Weighing 10mg of free alkali, adding 1mL of acetonitrile, heating and stirring at 40 ℃, slowly adding 1.95mg of acetic acid solution into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and carrying out vacuum drying on the residual solid to obtain acetate crystal form C. Upon detection analysis, it had an XRPD pattern as shown in figure 73.
VI, preparation of acetate form D
Weighing 10mg of free alkali, adding 1mL of toluene, heating and stirring at 40 ℃, slowly adding 1.94mg of acetic acid solution into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and carrying out vacuum drying on the residual solid to obtain acetate crystal form D. Upon detection analysis, it had the XRPD pattern shown in figure 74.
VII preparation of acetate crystal form E
Weighing 10mg of free alkali, adding 1mL of dichloromethane, heating and stirring at 40 ℃, slowly adding 1.99mg of acetic acid solution into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and carrying out vacuum drying on the residual solid to obtain acetate crystal form E. Upon detection analysis, it had an XRPD pattern as shown in figure 75.
VIII, preparation of hydrochloride form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 5.1 mu L of hydrochloric acid solution into 1mL of stock solution, volatilizing the mixture at room temperature in an open manner, and drying the mixture in vacuum to obtain the hydrochloride crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 76.
Preparation of form B of IX, hydrochloride
Weighing 20mg of free alkali, adding 1mL of 2-butanone, heating and stirring at 30 ℃, slowly adding 16.5 mu L of hydrochloric acid solution into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and carrying out vacuum drying on the residual solid to obtain the hydrochloride crystal form C. Upon detection analysis, it had the XRPD pattern shown in figure 77.
Preparation of form X, hydrochloride form C
Weighing 20mg of free alkali, adding 1mL of methanol, heating and stirring at 30 ℃, slowly adding 16.5 mu L of hydrochloric acid solution into the system, carrying out insoluble stirring overnight, centrifuging to remove supernatant, and carrying out vacuum drying on the residual solid to obtain the hydrochloride crystal form D. Upon detection analysis, it had an XRPD pattern as shown in figure 78.
Preparation of crystalline form XI of hydrochloride salt
And weighing a proper amount of hydrochloride crystal form D solid, standing overnight under a high-humidity condition, and drying to obtain a hydrochloride crystal form E. Upon detection analysis, it had an XRPD pattern as shown in figure 79.
XII, preparation of besylate crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 0.5mL of stock solution into a methanol solution of 25 mu L1.0M benzenesulfonic acid, volatilizing the mixture at room temperature in an open manner, and drying the mixture in vacuum to obtain the benzenesulfonate salt crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 80.
Preparation of XIII, hydrobromide form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 25 mu L1.0M hydrobromic acid ethanol solution into 0.5mL of stock solution, volatilizing the mixture at room temperature in an open manner, and drying the mixture in vacuum to obtain the hydrobromide crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 81.
Preparation of form A of XIV and oxalate
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 7.09mg of oxalic acid, adding 100 mu L of methanol, adding 0.5mL of stock solution after dissolving, separating out solid, volatilizing at room temperature in an open manner, and drying in vacuum to obtain oxalate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 82.
Preparation of XV, adipate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 0.5mL of stock solution into a methanol solution of 25 mu L1.0M adipic acid, volatilizing the mixture at room temperature in an open manner, and drying the mixture in vacuum to obtain the adipate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 83.
XVI, preparation of ethane sulfonate crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 0.5mL of stock solution into a methanol solution of 25 mu L1.0M ethanesulfonic acid, separating out a solid, then volatilizing the solid at room temperature in an open manner, and drying the solid in vacuum to obtain the ethanesulfonate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 84.
XVII, preparation of benzoate Crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 0.5mL of stock solution into a methanol solution of 25 mu L1.0M benzoic acid, volatilizing the mixture at room temperature in an open manner, and drying the mixture in vacuum to obtain the benzoate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 85.
Preparation of XVIII, 1, 5-naphthalenedisulfonate crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and (3) adding 204 mu L of 0.125M1, 5-naphthalenedisulfonic acid ethanol solution into 0.5mL of stock solution, separating out solids, evaporating to dryness at room temperature in an open manner, and drying in vacuum to obtain the 1, 5-naphthalenedisulfonic acid salt crystal form A. Upon detection analysis, it had the XRPD pattern shown in figure 86.
Preparation of XIX, pamoate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; adding 204 μ L of 0.125M pamoic acid pyridine solution into 0.5mL stock solution, separating out solid, volatilizing at room temperature, and vacuum drying to obtain pamoic acid salt crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 87.
XX, preparation of hippurate crystal form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and adding 127 mu L of 0.2M hippuric acid ethanol solution into 0.5mL of stock solution, separating out solids, evaporating to dryness at room temperature in an open manner, and drying in vacuum to obtain the crystal form A of the hippurate. Upon detection analysis, it had an XRPD pattern as shown in figure 88.
XXI, preparation of sulphate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and adding 51 mu L of sulfuric acid solution into 1mL of stock solution, separating out solids, evaporating to dryness at room temperature in an open manner, and drying in vacuum to obtain the sulfate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 89.
XXII, preparation of sulphate form B
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; and adding 0.5mL of stock solution into 51 mu L of sulfuric acid solution, separating out solids, evaporating to dryness at room temperature, and drying in vacuum to obtain the sulfate crystal form B. Upon detection analysis, it had an XRPD pattern as shown in figure 90.
XXIII, preparation of malonate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 6.54mg of malonic acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, volatilizing at room temperature in an open manner, and drying in vacuum to obtain malonate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 91.
XXIV, preparation of p-toluenesulfonate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 10.09mg of p-toluenesulfonic acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, volatilizing at room temperature in an open manner, and drying in vacuum to obtain the p-toluenesulfonic acid salt crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 92.
XXV, preparation of maleate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 6.09mg of maleic acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, volatilizing at room temperature in an open manner, and drying in vacuum to obtain the maleate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 93.
XXVI preparation of malate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 6.48mg of malic acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, separating out solid, volatilizing at room temperature, and vacuum drying to obtain malate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 94.
XXVII, preparation of tartrate form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 7.70mg of tartaric acid, adding 200 mu L of methanol, adding 1mL of stock solution after dissolving, separating out solid, volatilizing at room temperature, and drying in vacuum to obtain tartrate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 95.
XXVIII, preparation of fumarate salt form A
Weighing a proper amount of free alkali, and adding methanol to prepare a stock solution with the concentration of 20 mg/mL; weighing 6.16mg of fumaric acid, adding 200 mu L of methanol, dissolving, adding 1mL of stock solution, separating out solid, volatilizing at room temperature, and drying in vacuum to obtain fumarate crystal form A. Upon detection analysis, it had an XRPD pattern as shown in figure 96.
Preparation of form A of XIX, free base
Weighing 9.4g 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, dissolving the tert-butyl ester in methanol (47mL), adding 4M HCl 1, 4-dioxane (94mL) at the temperature of 10-20 ℃ under stirring, reacting for 1-2 hours at the temperature of 20-30 ℃, filtering the reaction solution after the reaction is finished, washing a filter cake by using methanol (20mL), directly using the solid for the next reaction, dissolving the solid in methanol (56mL), dropwise adding DIPEA (10g, 0.0784mol) at the temperature of 10-20 ℃, adjusting the temperature of the reaction solution to be 20-30 ℃ after the dropwise adding is finished, and acrylonitrile (3.1g, 0.0588mol) was added dropwise to the reaction solution, and reacted at a temperature of 20 to 30 ℃ for 2 hours. The reaction solution was filtered, and the filter cake was washed with 15mL of methanol and dried to give a white solid of the compound of formula IV (7.6 g). Upon detection analysis, it has the following XRPD pattern as shown in fig. 97.
4. Stability test of Crystal form
4.1 purpose of experiment:
and (3) examining the physical and chemical stability of the candidate salt crystal form of the candidate compound under the conditions of 5000lx illumination, high temperature 60 ℃, high humidity 92.5% RH and high temperature high humidity 50 ℃ 75% RH, and providing a basis for salt form screening and compound salt storage.
4.2 protocol:
taking about 2mg of different salt crystal forms, inspecting for 5 days and 10 days under the conditions of illumination of 5000lx, high temperature of 60 ℃, high humidity of 92.5% RH and high temperature of 50 ℃ of 75% RH, measuring the salt content by using HPLC and an external standard method, and calculating the change of related substances by using a chromatographic peak area normalization method.
4.3 Experimental results:
1) physicochemical stability results for the salt crystal form of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one:
Figure BDA0003083170700002691
the stability results show that the crystal forms of different salts of the compound have different stability, the fumarate crystal form is unstable under the conditions of high temperature, high temperature and high humidity, and the fumarate crystal form needs to be stored in a normal-temperature and dry environment in the later period.
2) Physicochemical stability results of the salt crystal form 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] octan-8-yl) propionitrile:
Figure BDA0003083170700002701
The stability results show that the compounds have different stability of crystal forms after salification, wherein the stability of the succinate crystal form B and the acetate crystal form D is good.
4.4 conclusion of the experiment
The stability of different crystal forms of different salts under different conditions is integrated, wherein the 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 is stable in a crystal form A of isethionate, a crystal form B of isethionate and a crystal form B of adipate under the conditions of illumination, high temperature and high humidity. Succinate crystal form B and acetate crystal form D of 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 are relatively stable under the conditions of illumination, high temperature and high humidity.
5 hygroscopicity test
5.1 purpose of the experiment
And inspecting the hygroscopicity of different salt crystal forms of the compound under different relative humidity conditions, and providing a basis for screening and storing the salt crystal forms of the compound.
5.2 protocol:
and (3) placing the compound salt crystal form in saturated water vapor with different relative humidity to enable the compound and the water vapor to reach dynamic balance, and calculating the percentage of moisture absorption weight gain of the compound after the balance.
5.3 Experimental results:
5.3.1 hygroscopicity of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one in different salt crystal forms
1) The besylate crystal form A has moisture absorption and weight gain of 2.518 percent under the condition of RH80 percent and has moisture absorption. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the benzene sulfonate crystal form A is not changed, namely the crystal form is not transformed.
2) The sulfate crystal form A absorbs moisture and gains weight of 5.040% under the condition of RH 80%, and has hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the sulfate crystal form A is not changed, namely the crystal form is not transformed.
3) The crystal form A of the isethionate salt is subjected to moisture absorption and moisture desorption circulation for 2 times under the condition of 0-95% relative humidity, and an XRPD spectrogram of the crystal form A of the isethionate salt is not changed, namely the crystal form is not transformed.
4) Adipate form a absorbed moisture and gained 0.942% weight under RH 80%, slightly hygroscopic. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the adipate crystal form A is not changed, namely the crystal form is not transformed.
5) Adipate form B absorbs moisture and increases by 1.521% under the condition of RH 80%, and is slightly hygroscopic. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the adipate crystal form B is not changed, namely the crystal form is not transformed.
6) The p-toluenesulfonate crystal form A has moisture absorption and weight increase of 3.228% under the condition of RH 80%, and has hygroscopicity. And after moisture absorption and moisture desorption circulation is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the p-toluenesulfonate crystal form A is not changed, namely the crystal form is not transformed.
7) The oxalate crystal form A absorbs moisture and gains weight 1.488% under the condition of RH 80%, and has slight hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the oxalate crystal form A is not changed, namely the crystal form is not transformed.
8) The hydrobromide crystal form A absorbs moisture and gains weight of 2.421% under the condition of RH 80%, and has hygroscopicity. And after moisture absorption and moisture desorption circulation is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the hydrobromide crystal form A is not changed, namely the crystal form is not transformed.
4.3.2 hygroscopicity of various salts 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] octan-8-yl) propionitrile
1) The succinate crystal form A absorbs moisture and gains weight of 10.770% under the condition of RH 80%, and has hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the succinate crystal form A is not changed, namely the crystal form is not transformed.
2) Succinate crystal form B has moisture absorption and weight gain of 0.829% under the condition of RH 80%, and has slight moisture absorption. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the succinate crystal form B is not changed, namely the crystal form is not transformed.
3) Acetate form a absorbs moisture and gains 1.586% under the condition of RH 80%, and is slightly hygroscopic. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the acetate crystal form A is changed and is converted into the acetate crystal form B.
4) Acetate form D absorbs moisture and gains 1.911% weight at RH 80% with a slight hygroscopic effect. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the acetate crystal form D is not changed, namely the crystal form is not transformed.
5) The besylate crystal form A has moisture absorption and weight gain of 2.450 percent under the condition of RH80 percent and has moisture absorption. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the benzene sulfonate crystal form A is not changed, namely the crystal form is not transformed.
6) The oxalate crystal form A absorbs moisture and gains weight of 3.838% under the condition of RH 80%, and has hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the oxalate crystal form A is not changed, namely the crystal form is not transformed.
7) Pamoate crystal form A absorbs moisture and gains weight of 6.004% under the condition of RH 80%, and has hygroscopicity. And after 2 times of moisture absorption and moisture desorption circulation under the condition of 0-95% relative humidity, the XRPD spectrogram of the pamoate crystal form A is not changed, namely the crystal form is not transformed.
8) The malate crystal form A absorbs moisture and gains weight of 7.465% under the condition of RH 80%, and has hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the malate crystal form A is not changed, namely the crystal form is not transformed.
9) The p-toluenesulfonate crystal form A has moisture absorption and weight increase of 3.549% under the condition of RH 80%, and has hygroscopicity. And after moisture absorption and moisture desorption circulation is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the p-toluenesulfonate crystal form A is not changed, namely the crystal form is not transformed.
10) The hydrochloride crystal form C has the moisture absorption weight gain of 1.620% under the condition of RH 80%, and has slight hygroscopicity. And after the moisture absorption and desorption cycle is carried out for 2 times under the condition of 0-95% relative humidity, the XRPD spectrogram of the hydrochloride crystal form C is not changed, namely the crystal form is not transformed.
5.4 conclusion of the experiment
Adipate crystal form a, adipate crystal form B, oxalate 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] nonan-9-yl) -2- (methylamino) -ethan-1-one are less hygroscopic; succinate crystal form B, acetate crystal form A, acetate crystal form D and hydrochloride crystal form C of 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 are low in hygroscopicity.
6. Solubility experiments in different media
6.1 purpose of the experiment
Comparing the free base crystalline form A of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one, the crystalline form A of the benzenesulfonate of the 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] nonan-9-yl) -2- (methylamino) -ethan-1-one in The solubility of different pH buffer solutions, artificial simulated gastric fluid (FaSSGF), fasting artificial simulated intestinal fluid (FaSSIF), non-fasting artificial simulated intestinal fluid (FeSSIF), fasting artificial simulated colon fluid (FaSSCoF), non-fasting artificial simulated colon fluid (FeSSCoF) and pure water and other media provides a basis for the evaluation of the druggability of the salt. 6.2 protocol:
About 1mg 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] nonan-9-yl) -2- (methylamino) -ethane-1-one free base crystalline form a and benzenesulfonate crystalline form a were suspended in different media for 6 hours, and thermodynamic solubility of compound at 37 ℃ was determined by HPLC, external standard method.
6.3 Experimental results:
solubility data for 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] nonan-9-yl) -2- (methylamino) -ethan-1-one free base crystalline form a and benzenesulfonate crystalline form a are shown below:
Figure BDA0003083170700002731
6.4 conclusion of the experiment
The result shows that the compound 1- ((3-exo) -3- ((4- ((5-methyl-1 hydrogen-pyrazol-3-yl) amino) thieno [2,3-d ] pyrimidine-2-yl) amino) -9-azabicyclo [3.3.1] nonane-9-yl) -2- (methylamino) -ethane-1-ketone free base crystal form A has certain effect of improving the solubility of the compound in water due to the change of the pH value of the environment after the compound is converted into the benzene sulfonate crystal form A.
7. Thermodynamic stability experiment of crystal form
7.1 purpose of the experiment:
and finding out a salt crystal form with relatively stable thermodynamics through polycrystal screening and crystal form competitive tests.
7.2 protocol:
Selecting organic solvent and water with certain solubility, suspending the compound in a solvent system, stirring and pulping at room temperature and 50 ℃ for 1 week respectively, centrifuging, removing supernatant, vacuum drying the solid at 50 ℃ (-0.1Mpa) overnight, measuring XRPD of the solid, and comparing with XRPD of the raw material compound salt.
7.3 Experimental results:
different crystal forms of different salts are obtained by beating, changing crystallization solvents, crystallization modes and the like. According to crystal form competitive tests and DSC results, a benzene sulfonate crystal form A, a isethionate crystal form B, an adipate crystal form B, a hydrobromide crystal form A, a 1, 5-naphthalenedisulfonate crystal form C and a tartrate crystal form A of a 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-ketone can be judged to be thermodynamically stable crystal forms.

Claims (15)

1.通式(I)所示化合物的酸式盐，化合物的结构如下所示：1. The acid salt of the compound represented by the general formula (I), the structure of the compound is as follows:
Figure FDA0003083170690000011
Figure FDA0003083170690000011
 其中：in: L1选自键、-(CH2)r-、-(CH2)rS(O)2-、-S(O)2(CH2)r-、-(CH2)rS(O)2NRa-、-(CH2)rNRa-、-C(O)(CH2)r-、-C(O)(CH2)rNRa-、-C(O)(CH2)rNRa(CH2)s-、-(CH2)rC(O)-或-(CH2)rC(O)NRa-；L 1 is selected from bond, -(CH 2 ) r -, -(CH 2 ) r S(O) 2 -, -S(O) 2 (CH 2 ) r -, -(CH 2 ) r S(O) 2 NR a -, -(CH 2 ) r NR a -, -C(O)(CH 2 ) r -, -C(O)(CH 2 ) r NR a -, -C(O)(CH 2 ) r NR a (CH 2 ) s -, -(CH 2 ) r C(O)- or -(CH 2 ) r C(O)NR a -; Ra选自氢、C1-6烷基、C1-6羟烷基或C1-6烷氧基；R a is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy; R1选自氢、氰基、卤素、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C3-8环烷基、3-12元杂环基、C6-12芳基或5-10元杂芳基，任选地进一步被氰基、卤素、C1-6烷基、C1-6烷氧基或C1-6羟烷基中的一个或多个取代基所取代，优选氢、氰基、卤素、C1-3烷基、C3-6环烷基、3-8元杂环基，苯基或5-6元含氮杂芳基，任选地进一步被氰基、卤素、C1-3烷基、C1-3烷氧基或C1-3羟烷基中的一个或多个取代基所取代；R 1 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 heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, optionally further by one of cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 hydroxyalkyl or more substituents, preferably hydrogen, cyano, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, phenyl or 5-6 membered nitrogen-containing heteroaryl base, optionally further substituted by one or more substituents in cyano, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 hydroxyalkyl; R2选自氢或C1-6烷基；R 2 is selected from hydrogen or C 1-6 alkyl; R3选自氢、羟基、卤素、氨基、C1-6烷基、C1-6羟烷基、C1-6烷氧基、C1-6烷基单取代的氨基、C1-6烷基双取代的氨基、C3-8环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基，任选地进一步被卤素、氨基、氰基、C1-6烷基、C1-6烷氧基、C1-6羟烷基、C1-6烷基单取代的氨基、C1-6烷基双取代的氨基、C3-8环烷基、3-10元杂环基、C6-12芳基或5-10元杂芳基中的一个或多个取代基所取代，优选氢、羟基、卤素、氨基、C1-3烷基、C3-6环烷基、含1-2个选自N、O或S杂原子的4-7元杂环基，苯基或5-6元含氮杂芳基，任选地进一步被卤素、氨基、氰基、C1-3烷基、C1-3烷氧基、C1-3羟烷基、C1-3烷基单取代的氨基、C1-3烷基双取代的氨基、C3-6环烷基、4-7元杂环基，苯基或5-6元含氮杂芳基中的一个或多个取代基所取代；R 3 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 Alkyl disubstituted amino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 membered aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 alkyl mono-substituted amino, C 1-6 alkyl di-substituted amino, C 3-8 ring Substituted by one or more substituents in alkyl, 3-10-membered heterocyclic group, C 6-12 aryl or 5-10-membered heteroaryl, preferably hydrogen, hydroxyl, halogen, amino, C 1-3 alkane base, C 3-6 cycloalkyl, 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O or S, phenyl or 5-6 membered nitrogen-containing heteroaryl, optionally further Amino substituted 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 substituted by one or more substituents in the amino group, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered nitrogen-containing heteroaryl; R4选自氢、C1-6烷基、C1-6羟烷基或C1-6烷氧基；R 4 is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy; 环A选自芳基、五元含硫杂环基，优选苯基、
Figure FDA0003083170690000012
Figure FDA0003083170690000021
Ring A is selected from aryl, five-membered sulfur-containing heterocyclic group, preferably phenyl,
Figure FDA0003083170690000012
Figure FDA0003083170690000021
 环B选自5-10元含氮杂环基，优选
Figure FDA0003083170690000022
Figure FDA0003083170690000023
Ring B is selected from 5-10 membered nitrogen-containing heterocyclic groups, preferably
Figure FDA0003083170690000022
Figure FDA0003083170690000023
 其中酸为无机酸或有机酸，优选地，所述无机酸选自盐酸、硫酸、硝酸、氢溴酸、氢氟酸、氢碘酸或磷酸；有机酸选自2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、帕莫酸、甲酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸或L-苹果酸；更优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、对甲苯磺酸、氢溴酸、草酸、富马酸、甲酸、马尿酸、月桂酸、硬脂酸；进一步优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、富马酸、马尿酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、草酸或氢溴酸；更进一步优选磷酸、马来酸或苯磺酸；Wherein 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-naphthoic acid, acetic acid, dichloroacetic acid, trichloroacetic acid, acetohydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, 4-Aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid , erythorbic acid, lactic acid, malic acid, mandelic acid, pyroglutamic acid, tartaric acid, lauryl sulfuric acid, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, rich Maleic acid, galactonic acid, gentisic acid, glutaric acid, 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid , salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid or L-malic 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, isethionic 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, 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 acid, hippuric acid, isethionic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; more preferably phosphoric acid, maleic acid or benzenesulfonic acid; m为1、2或3；m is 1, 2 or 3; r为0、1、2或3；r is 0, 1, 2 or 3; s为1、2或3。s is 1, 2 or 3. 2.根据权利要求1所述的酸式盐，其特征在于，所述通式(I)进一步如通式(II)所示：2. acid salt according to claim 1, is characterized in that, described general formula (I) is further shown as general formula (II):
Figure FDA0003083170690000031
Figure FDA0003083170690000031
 其中，n为1或2。where n is 1 or 2. 3.根据权利要求1或2所述的酸式盐，其特征在于，所述R1选自氢、氰基、卤素、C1-3烷基、苯基、
Figure FDA0003083170690000032
Figure FDA0003083170690000033
任选地进一步被氰基、卤素、C1-3烷基、C1-3烷氧基中的一个或多个取代基所取代。3. The acid salt according to claim 1 or 2, wherein the R 1 is selected from hydrogen, cyano, halogen, C 1-3 alkyl, phenyl,
Figure FDA0003083170690000032
Figure FDA0003083170690000033
Optionally further substituted with one or more substituents of cyano, halogen, C 1-3 alkyl, C 1-3 alkoxy. 4.根据权利要求1所述的酸式盐，其特征在于，所述R3选自氢、羟基、氟、氯、溴、氨基、甲氨基、乙基氨基、二甲基氨基、甲基、乙基、羟甲基、甲氧基、乙氧基、苯基、
Figure FDA0003083170690000034
Figure FDA0003083170690000035
任选地进一步被卤素、氨基、C1-3烷基单取代的氨基、C1-3烷基双取代的氨基、C1-3烷基、C1-3羟烷基、C1-3烷氧基、苯基、
Figure FDA0003083170690000036
Figure FDA0003083170690000041
Figure FDA0003083170690000042
中的一个或多个取代基所取代。4. The acid salt according to claim 1, wherein the R is selected from hydrogen, hydroxyl, fluorine, chlorine, bromine, amino, methylamino, ethylamino, dimethylamino, methyl, Ethyl, hydroxymethyl, methoxy, ethoxy, phenyl,
Figure FDA0003083170690000034
Figure FDA0003083170690000035
optionally further halogen, amino, C 1-3 alkyl mono-substituted amino, C 1-3 alkyl disubstituted amino, C 1-3 alkyl, C 1-3 hydroxyalkyl , C 1-3 alkoxy, phenyl,
Figure FDA0003083170690000036
Figure FDA0003083170690000041
Figure FDA0003083170690000042
substituted by one or more of the substituents. 5.根据权利要求1所述的酸式盐，其特征在于，所述通式(I)选自以下化合物：5. acid salt according to claim 1, is characterized in that, described general formula (I) is selected from following compound:
Figure FDA0003083170690000043
Figure FDA0003083170690000043
Figure FDA0003083170690000051
Figure FDA0003083170690000051
Figure FDA0003083170690000061
Figure FDA0003083170690000061
Figure FDA0003083170690000071
Figure FDA0003083170690000071
Figure FDA0003083170690000081
Figure FDA0003083170690000081
Figure FDA0003083170690000091
Figure FDA0003083170690000091
Figure FDA0003083170690000101
Figure FDA0003083170690000101
Figure FDA0003083170690000111
Figure FDA0003083170690000111
Figure FDA0003083170690000121
Figure FDA0003083170690000121
 优选以下化合物：The following compounds are preferred:
Figure FDA0003083170690000122
Figure FDA0003083170690000122
Figure FDA0003083170690000131
Figure FDA0003083170690000131
Figure FDA0003083170690000141
Figure FDA0003083170690000141
 其中酸选自磷酸、丁二酸、盐酸、马来酸、苯磺酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、对甲苯磺酸、醋酸、丙二酸、帕莫酸、乙烷磺酸、苯甲酸、苹果酸、氢溴酸、草酸、富马酸、甲酸、马尿酸、月桂酸或硬脂酸，优选磷酸、丁二酸、马来酸、羟乙基磺酸、1，5-萘二磺酸、对甲苯磺酸、氢溴酸、草酸或富马酸。Wherein the acid is selected from phosphoric acid, succinic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, p-toluenesulfonic acid, acetic acid, Malonic acid, pamoic acid, ethanesulfonic acid, benzoic acid, malic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid or stearic acid, preferably phosphoric acid, succinic acid, maleic acid acid, isethionic acid, 1,5-naphthalenedisulfonic acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid or fumaric acid. 6.根据权利要求5所述的酸式盐，其中化合物选自1-((3-exo)-3-((4-((5-甲基-1氢-吡唑-3-基)氨基)噻吩并[2,3-d]嘧啶-2-基)氨基)-9-氮杂双环[3.3.1]壬烷-9-基)-2-(甲基氨基)-乙烷-1-酮、1-((3-exo)-3-((4-((5-甲基-1氢-吡唑-3-基)氨基)噻吩并[2,3-d]嘧啶-2-基)氨基)-8-氮杂双环[3.2.1]辛烷-8-基)-2-吗啉代乙烷-1-酮或2-(乙胺基)-1-((3-exo)-3-((4-((5-甲基-1H-吡唑-3-基)氨基)噻吩并[2,3-d]嘧啶-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)乙烷-1-酮，并且酸选自盐酸、马来酸、苯磺酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、对甲苯磺酸、氢溴酸、草酸、富马酸、甲酸、马尿酸、月桂酸或硬脂酸；6. The acid salt of claim 5, wherein the compound is selected from 1-((3-exo)-3-((4-((5-methyl-1 hydrogen-pyrazol-3-yl)amino )thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)-2-(methylamino)-ethane-1- Ketone, 1-((3-exo)-3-((4-((5-methyl-1hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl )amino)-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinoethan-1-one or 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)ethan-1-one, and the acid is selected from the group consisting of hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic acid, 1,5-naphthalenedisulfonic acid, tartaric acid, hexane Diacid, sulfuric acid, p-toluenesulfonic acid, hydrobromic acid, oxalic acid, fumaric acid, formic acid, hippuric acid, lauric acid or stearic acid; 或者，化合物为3-((3-exo)-3-((7-甲氧基-4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈，并且酸选自磷酸、丁二酸、醋酸、盐酸、苯磺酸、氢溴酸、草酸、己二酸、乙烷磺酸、苯甲酸、1，5-萘二磺酸、帕莫酸、马尿酸、硫酸、丙二酸、对甲苯磺酸、马来酸、苹果酸、酒石酸或富马酸。Alternatively, the compound is 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl ) amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile, and the acid is selected from phosphoric acid, succinic acid, acetic acid, hydrochloric acid, benzenesulfonic acid, hydrobromic acid, oxalic acid, hexane Diacid, ethanesulfonic acid, benzoic acid, 1,5-naphthalenedisulfonic acid, pamoic acid, hippuric acid, sulfuric acid, malonic acid, p-toluenesulfonic acid, maleic acid, malic acid, tartaric acid or fumaric acid . 7.根据权利要求1-6任意一项所述的酸式盐，其特征在于，酸的个数为0.2-3，优选0.2、0.5、1、1.5、2、2.5或3，更优选0.5、1、2或3。7. The acid salt according to any one of claims 1-6, wherein 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. 8.根据权利要求1-6任意一项所述的酸式盐，其特征在于，所述的酸式盐为水合物或无水物，并且当酸式盐为水合物时，水的个数为0.2-3，优选0.2、0.5、1、1.5、2、2.5或3，更优选0.5、1、2或3。8. The acid salt according to any one of claims 1-6, wherein the acid salt is a hydrate or an anhydrous, and when the acid salt is a hydrate, the number of water 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. 9.根据权利要求6所述的酸式盐，其中1-((3-exo)-3-((4-((5-甲基-1氢-吡唑-3-基)氨基)噻吩并[2,3-d]嘧啶-2-基)氨基)-9-氮杂双环[3.3.1]壬烷-9-基)-2-(甲基氨基)-乙烷-1-酮或3-((3-exo)-3-((7-甲氧基-4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的酸式盐为晶型。9. The acid salt of claim 6, wherein 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]nonan-9-yl)-2-(methylamino)-ethan-1-one or 3 -((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8 - The acid salt of azabicyclo[3.2.1]octan-8-yl)propionitrile is a crystalline form. 10.根据权利要求9所述的酸式盐，其中1-((3-exo)-3-((4-((5-甲基-1氢-吡唑-3-基)氨基)噻吩并[2,3-d]嘧啶-2-基)氨基)-9-氮杂双环[3.3.1]壬烷-9-基)-2-(甲基氨基)-乙烷-1-酮的酸式盐晶型选自苯磺酸盐晶型A～H，硫酸盐晶型A，羟乙基磺酸盐晶型A～C，己二酸盐晶型A～B，对甲苯磺酸盐晶型A～B，富马酸盐晶型A～C，草酸盐晶型A，氢溴酸盐晶型A，1，5-萘二磺酸盐晶型B～D，酒石酸盐晶型A，甲酸盐晶型A，马尿酸盐晶型A，月桂酸盐晶型A，或硬脂酸盐晶型A，其中：10. The acid salt of claim 9, wherein 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]nonan-9-yl)-2-(methylamino)-ethane-1-one acid The salt crystal form of the formula is selected from benzenesulfonate crystal form A～H, sulfate crystal form A, isethionate crystal form A～C, adipate crystal form A～B, p-toluenesulfonate crystal form Form A～B, fumarate crystal form A～C, oxalate crystal form A, hydrobromide salt form A, 1,5-naphthalene disulfonate crystal form B～D, tartrate crystal form A , formate form A, hippurate form A, laurate form A, or stearate form A, wherein: 苯磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为9.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为13.4±0.2°和22.7±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为11.0±0.2°、14.9±0.2°、18.2±0.2°和22.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为17.4±0.2°、17.8±0.2°、18.4±0.2°、19.1±0.2°、19.7±0.2°、20.2±0.2°、21.1±0.2°和25.7±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为24.1±0.2°、24.7±0.2°、25.9±0.2°、27.7±0.2°和29.1±0.2°处具有衍射峰；更更进一步优选地，还包含在2θ(±0.2°)为16.9±0.2°、23.1±0.2°、24.3±0.2°、26.5±0.2°、28.3±0.2°和29.7±0.2°处具有衍射峰；Benzenesulfonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 9.5±0.2°; preferably, it also includes 2θ (±0.2°) at 13.4±0.2° and It has diffraction peaks at 22.7±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 11.0±0.2°, 14.9±0.2°, 18.2±0.2° and 22.2±0.2°; further preferably , also included at 2θ (±0.2°) as 17.4±0.2°, 17.8±0.2°, 18.4±0.2°, 19.1±0.2°, 19.7±0.2°, 20.2±0.2°, 21.1±0.2° and 25.7±0.2° It has diffraction peaks at 2θ (±0.2°), and has diffraction peaks at 24.1±0.2°, 24.7±0.2°, 25.9±0.2°, 27.7±0.2° and 29.1±0.2°; more Still further preferably, it also includes diffraction peaks at 2θ (±0.2°) at 16.9±0.2°, 23.1±0.2°, 24.3±0.2°, 26.5±0.2°, 28.3±0.2° and 29.7±0.2°; 最优选地，其X-射线粉末衍射图谱基本如图1所示，其DSC图谱基本如图2所示，其TGA图谱基本如图3所示；Most preferably, its X-ray powder diffraction pattern is basically shown in Figure 1, its DSC pattern is basically shown in Figure 2, and its TGA pattern is basically shown in Figure 3; 苯磺酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为13.6±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为21.4±0.2°和23.7±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.7±0.2°、9.2±0.2°、18.4±0.2°和23.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.9±0.2°、13.0±0.2°、14.3±0.2°、14.8±0.2°、15.8±0.2°、18.0±0.2°、19.2±0.2°和19.5±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为21.7±0.2°、22.3±0.2°和24.4±0.2°处具有衍射峰；Besylate crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 13.6±0.2°; preferably, it also includes 21.4±0.2° at 2θ (±0.2°) and It has diffraction peaks at 23.7±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.7±0.2°, 9.2±0.2°, 18.4±0.2° and 23.4±0.2°; further preferably , also included in 2θ (±0.2°) as 10.9±0.2°, 13.0±0.2°, 14.3±0.2°, 14.8±0.2°, 15.8±0.2°, 18.0±0.2°, 19.2±0.2° and 19.5±0.2° have diffraction peaks at; more preferably, also include diffraction peaks at 2θ (±0.2°) at 21.7±0.2°, 22.3±0.2° and 24.4±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图4所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 4; 苯磺酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为14.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为21.5±0.2°和22.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.1±0.2°、13.6±0.2°、18.3±0.2°和18.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为22.5±0.2°、23.4±0.2°、23.7±0.2°和24.5±0.2°处具有衍射峰；Besylate crystal form C, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 14.1±0.2°; preferably, it also includes 21.5±0.2° at 2θ (±0.2°) and It has diffraction peaks at 22.1±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.1±0.2°, 13.6±0.2°, 18.3±0.2° and 18.8±0.2°; further preferably , also includes diffraction peaks at 22.5±0.2°, 23.4±0.2°, 23.7±0.2° and 24.5±0.2° at 2θ (±0.2°); 更进一步优选地，其X-射线粉末衍射图谱基本如图5所示，其DSC图谱基本如图6所示，其TGA图谱基本如图7所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 5, its DSC pattern is basically shown in Figure 6, and its TGA pattern is basically shown in Figure 7; 苯磺酸盐晶型D，其X-射线粉末衍射图谱在2θ(±0.2°)为18.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为11.0±0.2°和22.2±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.6±0.2°、21.2±0.2°、21.5±0.2°和25.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.7±0.2°、13.5±0.2°、14.9±0.2°、15.3±0.2°、17.4±0.2°、18.6±0.2°、19.1±0.2°和19.8±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为22.7±0.2°、24.7±0.2°、25.8±0.2°和27.6±0.2°处具有衍射峰；更更进一步优选地，还包含在2θ(±0.2°)为16.9±0.2°、19.4±0.2°、20.4±0.2°、23.1±0.2°、26.3±0.2°、28.2±0.2°和29.1±0.2°处具有衍射峰；Besylate crystal form D, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 18.2±0.2°; preferably, it also includes 11.0±0.2° at 2θ (±0.2°) and It has diffraction peaks at 22.2±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.6±0.2°, 21.2±0.2°, 21.5±0.2° and 25.6±0.2°; further preferably , also included at 2θ (±0.2°) as 8.7±0.2°, 13.5±0.2°, 14.9±0.2°, 15.3±0.2°, 17.4±0.2°, 18.6±0.2°, 19.1±0.2° and 19.8±0.2° It has diffraction peaks at 2θ (±0.2°), and has diffraction peaks at 22.7±0.2°, 24.7±0.2°, 25.8±0.2° and 27.6±0.2°; even more preferably, Also includes diffraction peaks at 2θ (±0.2°) at 16.9±0.2°, 19.4±0.2°, 20.4±0.2°, 23.1±0.2°, 26.3±0.2°, 28.2±0.2° and 29.1±0.2°; 最优选地，其X-射线粉末衍射图谱基本如图8所示；Most preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 8; 苯磺酸盐晶型E，其X-射线粉末衍射图谱在2θ(±0.2°)为21.4±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为11.9±0.2°和21.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.8±0.2°、8.7±0.2°、14.3±0.2°和25.0±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.6±0.2°、12.1±0.2°、15.7±0.2°、16.1±0.2°、16.8±0.2°、22.5±0.2°、26.4±0.2°和27.2±0.2°处具有衍射峰；Besylate crystal form E, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 21.4±0.2°; preferably, it also includes 11.9±0.2° at 2θ(±0.2°) and It has diffraction peaks at 21.1±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.8±0.2°, 8.7±0.2°, 14.3±0.2° and 25.0±0.2°; further preferably , also included at 2θ (±0.2°) as 10.6±0.2°, 12.1±0.2°, 15.7±0.2°, 16.1±0.2°, 16.8±0.2°, 22.5±0.2°, 26.4±0.2° and 27.2±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图9所示，其DSC图谱基本如图10所示，其TGA图谱基本如图11所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 9, its DSC pattern is basically shown in Figure 10, and its TGA pattern is basically shown in Figure 11; 苯磺酸盐晶型F，其X-射线粉末衍射图谱在2θ(±0.2°)为18.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为13.4±0.2°和24.6±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为15.2±0.2°、16.8±0.2°、20.9±0.2°和25.0±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.8±0.2°、9.4±0.2°、18.2±0.2°、19.5±0.2°、21.6±0.2°、22.8±0.2°、23.11±0.2°、24.6±0.2°和29.7±0.2°处具有衍射峰；Besylate crystal form F, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 18.2±0.2°; preferably, it also includes 2θ (±0.2°) at 13.4±0.2° and It has diffraction peaks at 24.6±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 15.2±0.2°, 16.8±0.2°, 20.9±0.2° and 25.0±0.2°; further preferably , also included in 2θ(±0.2°) as 6.8±0.2°, 9.4±0.2°, 18.2±0.2°, 19.5±0.2°, 21.6±0.2°, 22.8±0.2°, 23.11±0.2°, 24.6±0.2° and diffraction peaks at 29.7±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图12所示；Further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 12; 苯磺酸盐晶型G，其X-射线粉末衍射图谱在2θ(±0.2°)为20.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为17.8±0.2°和21.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为15.9±0.2°、17.1±0.2°、20.8±0.2°和22.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为12.4±0.2°、13.1±0.2°、18.7±0.2°、19.7±0.2°和25.7±0.2°处具有衍射峰；Besylate crystal form G, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 20.1±0.2°; preferably, it also includes 17.8±0.2° at 2θ (±0.2°) and It has diffraction peaks at 21.3±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 15.9±0.2°, 17.1±0.2°, 20.8±0.2° and 22.1±0.2°; further preferably , also contains diffraction peaks at 2θ (±0.2°) at 12.4±0.2°, 13.1±0.2°, 18.7±0.2°, 19.7±0.2° and 25.7±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图13所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 13; 苯磺酸盐晶型H，其X-射线粉末衍射图谱在2θ(±0.2°)为21.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为11.9±0.2°和20.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.9±0.2°、14.2±0.2°、17.5±0.2°和26.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.7±0.2°、10.5±0.2°、16.0±0.2°、17.8±0.2°、22.0±0.2°、22.4±0.2°、25.0±0.2°和25.3±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为17.3±0.2°、18.4±0.2°和28.0±0.2°处具有衍射峰；Besylate crystal form H, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 21.3±0.2°; preferably, it also includes 11.9±0.2° at 2θ(±0.2°) and It has diffraction peaks at 20.0±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.9±0.2°, 14.2±0.2°, 17.5±0.2° and 26.4±0.2°; further preferably , also included at 2θ (±0.2°) as 8.7±0.2°, 10.5±0.2°, 16.0±0.2°, 17.8±0.2°, 22.0±0.2°, 22.4±0.2°, 25.0±0.2° and 25.3±0.2° It has diffraction peaks at; further preferably, it also includes diffraction peaks at 2θ (±0.2°) at 17.3±0.2°, 18.4±0.2° and 28.0±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图14所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 14; 硫酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为14.0±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为16.0±0.2°和22.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为13.3±0.2°、19.3±0.2°、21.8±0.2°和22.7±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为7.4±0.2°、11.0±0.2°、11.5±0.2°、12.8±0.2°、15.0±0.2°、17.4±0.2°、21.5±0.2°和27.4±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为8.8±0.2°、10.0±0.2°、15.4±0.2°、16.9±0.2°、19.7±0.2°、20.8±0.2°、22.5±0.2°、23.1±0.2°、23.9±0.2°、24.2±0.2°、27.0±0.2°、28.0±0.2°和28.2±0.2°处具有衍射峰；Sulfate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 14.0±0.2°; preferably, it also includes 2θ(±0.2°) at 16.0±0.2° and 22.0±0.2° It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 13.3±0.2°, 19.3±0.2°, 21.8±0.2° and 22.7±0.2°; further preferably, also Contains at 2θ (±0.2°) at 7.4±0.2°, 11.0±0.2°, 11.5±0.2°, 12.8±0.2°, 15.0±0.2°, 17.4±0.2°, 21.5±0.2° and 27.4±0.2° with Diffraction peaks; more preferably, also included in 2θ(±0.2°) at 8.8±0.2°, 10.0±0.2°, 15.4±0.2°, 16.9±0.2°, 19.7±0.2°, 20.8±0.2°, 22.5± Diffraction peaks at 0.2°, 23.1±0.2°, 23.9±0.2°, 24.2±0.2°, 27.0±0.2°, 28.0±0.2° and 28.2±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图15所示，其DSC图谱基本如图16所示，其TGA图谱基本如图17所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 15, its DSC pattern is basically shown in Figure 16, and its TGA pattern is basically shown in Figure 17; 羟乙基磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为10.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为17.0±0.2°和22.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为7.0±0.2°、19.1±0.2°、20.1±0.2°和20.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为14.2±0.2°、14.7±0.2°、16.3±0.2°、21.4±0.2°、21.8±0.2°、22.2±0.2°、24.6±0.2°和26.0±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为9.3±0.2°、18.8±0.2°、23.8±0.2°和25.4±0.2°处具有衍射峰；Isethionate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 10.7±0.2°; preferably, it also includes 17.0±0.2 at 2θ (±0.2°) ° and 22.9±0.2° have diffraction peaks; more preferably, it also includes diffraction peaks at 2θ (±0.2°) at 7.0±0.2°, 19.1±0.2°, 20.1±0.2° and 20.4±0.2°; further Preferably, it also includes 14.2±0.2°, 14.7±0.2°, 16.3±0.2°, 21.4±0.2°, 21.8±0.2°, 22.2±0.2°, 24.6±0.2° and 26.0±0.2° in 2θ (±0.2°). It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.3±0.2°, 18.8±0.2°, 23.8±0.2° and 25.4±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图18所示，其DSC图谱基本如图19所示，其TGA图谱基本如图20所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 18, its DSC pattern is basically shown in Figure 19, and its TGA pattern is basically shown in Figure 20; 羟乙基磺酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为11.4±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为18.4±0.2°和20.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.1±0.2°、11.4±0.2°、17.4±0.2°和26.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为15.8±0.2°、17.1±0.2°、21.5±0.2°、22.6±0.2°、23.0±0.2°、23.6±0.2°、24.9±0.2°和25.2±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为9.8±0.2°、13.9±0.2°、14.9±0.2°、22.9±0.2°、26.1±0.2°和28.6±0.2°处具有衍射峰；Isethionate crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 11.4±0.2°; preferably, it also includes 18.4±0.2 at 2θ (±0.2°) It has diffraction peaks at ° and 20.3±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 8.1±0.2°, 11.4±0.2°, 17.4±0.2° and 26.6±0.2°; further Preferably, it also includes 15.8±0.2°, 17.1±0.2°, 21.5±0.2°, 22.6±0.2°, 23.0±0.2°, 23.6±0.2°, 24.9±0.2° and 25.2±0.2° at 2θ (±0.2°). It has a diffraction peak at 0.2°; more preferably, it also includes 9.8±0.2°, 13.9±0.2°, 14.9±0.2°, 22.9±0.2°, 26.1±0.2° and 28.6±0.2° at 2θ (±0.2°). There is a diffraction peak at °; 更更进一步优选地，其X-射线粉末衍射图谱基本如图21所示，其DSC图谱基本如图22所示，其TGA图谱基本如图23所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 21, its DSC pattern is basically shown in Figure 22, and its TGA pattern is basically shown in Figure 23; 羟乙基磺酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为20.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为18.5±0.2°和21.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为15.7±0.2°、18.7±0.2°、19.7±0.2°和23.4±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为6.6±0.2°、11.3±0.2°、12.8±0.2°、14.6±0.2°、20.3±0.2°、20.6±0.2°、26.6±0.2°和27.1±0.2°处具有衍射峰；更更进一步优选地，还包含在2θ(±0.2°)为17.7±0.2°、23.0±0.2°、23.8±0.2°、26.2±0.2°、30.2±0.2°和32.1±0.2°处具有衍射峰；最优选地，还包含在2θ(±0.2°)为13.5±0.2°、16.5±0.2°、20.9±0.2°、25.7±0.2°、28.3±0.2°和33.5±0.2°处具有衍射峰；Isethionate crystal form C, its X-ray powder diffraction pattern has diffraction peaks at 20.0±0.2° at 2θ (±0.2°); more preferably, it also includes 18.5±0.2° at 2θ (±0.2°). It has diffraction peaks at 0.2° and 21.4±0.2°; further preferably, it also includes diffraction peaks at 2θ (±0.2°) at 15.7±0.2°, 18.7±0.2°, 19.7±0.2° and 23.4±0.2°; Still more preferably, it also includes 6.6±0.2°, 11.3±0.2°, 12.8±0.2°, 14.6±0.2°, 20.3±0.2°, 20.6±0.2°, 26.6±0.2° and It has a diffraction peak at 27.1±0.2°; more preferably, it also includes 17.7±0.2°, 23.0±0.2°, 23.8±0.2°, 26.2±0.2°, 30.2±0.2° and have diffraction peaks at 32.1±0.2°; most preferably, also include 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° in 2θ (±0.2°) Diffraction peak at 0.2°; 进一步优选地，其X-射线粉末衍射图谱基本如图24所示，其DSC图谱基本如图25所示；Further preferably, its X-ray powder diffraction pattern is basically shown in Figure 24, and its DSC pattern is basically shown in Figure 25; 己二酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为19.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为16.6±0.2°和20.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为18.0±0.2°、18.4±0.2°、18.6±0.2°和22.9±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.1±0.2°、9.8±0.2°、12.6±0.2°、13.0±0.2°、13.3±0.2°、17.8±0.2°、21.1±0.2°和26.4±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为24.2±0.2°和29.5±0.2°处具有衍射峰；Adipate crystalline form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 19.7±0.2°; preferably, it also includes 16.6±0.2° at 2θ (±0.2°) and It has diffraction peaks at 20.0±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 18.0±0.2°, 18.4±0.2°, 18.6±0.2° and 22.9±0.2°; further preferably , also included at 2θ (±0.2°) as 9.1±0.2°, 9.8±0.2°, 12.6±0.2°, 13.0±0.2°, 13.3±0.2°, 17.8±0.2°, 21.1±0.2° and 26.4±0.2° It has diffraction peaks at; further preferably, it also includes diffraction peaks at 24.2±0.2° and 29.5±0.2° in 2θ (±0.2°); 更更进一步优选地，其X-射线粉末衍射图谱基本如图26所示，其DSC图谱基本如图27所示，其TGA图谱基本如图28所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 26, its DSC pattern is basically shown in Figure 27, and its TGA pattern is basically shown in Figure 28; 己二酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为20.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为16.5±0.2°和19.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为13.2±0.2°、17.8±0.2°、21.3±0.2°和27.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.6±0.2°、11.0±0.2°、14.5±0.2°、16.1±0.2°、16.7±0.2°、21.9±0.2°、22.2±0.2°和23.5±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为17.5±0.2°、19.2±0.2°、23.3±0.2°、24.2±0.2°和29.4±0.2°处具有衍射峰；Adipate crystalline form B, its X-ray powder diffraction pattern has diffraction peaks at 20.5±0.2° at 2θ (±0.2°); preferably, it also includes 16.5±0.2° at 2θ (±0.2°) and It has diffraction peaks at 19.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 13.2±0.2°, 17.8±0.2°, 21.3±0.2° and 27.2±0.2°; further preferably , also included at 2θ (±0.2°) as 10.6±0.2°, 11.0±0.2°, 14.5±0.2°, 16.1±0.2°, 16.7±0.2°, 21.9±0.2°, 22.2±0.2° and 23.5±0.2° have diffraction peaks at; more preferably, also include diffraction peaks at 2θ (±0.2°) at 17.5±0.2°, 19.2±0.2°, 23.3±0.2°, 24.2±0.2° and 29.4±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图29所示，其DSC图谱基本如图30所示，其TGA图谱基本如图31所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 29, its DSC pattern is basically shown in Figure 30, and its TGA pattern is basically shown in Figure 31; 对甲苯磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为9.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为14.7±0.2°和17.8±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为10.7±0.2°、13.3±0.2°、21.1±0.2°和25.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.6±0.2°、14.9±0.2°、18.5±0.2°、19.8±0.2°、21.7±0.2°、22.2±0.2°、22.8±0.2°和28.7±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为14.4±0.2°、16.6±0.2°、19.5±0.2°、20.3±0.2°、24.2±0.2°、24.5±0.2°和25.5±0.2°处具有衍射峰；更更进一步优选地，还包含在2θ(±0.2°)为17.3±0.2°、22.4±0.2°、26.1±0.2°、26.7±0.2°、27.5±0.2°、29.7±0.2°和33.2±0.2°处具有衍射峰；P-toluenesulfonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 9.3±0.2°; preferably, it also includes 2θ (±0.2°) at 14.7±0.2° and 17.8±0.2° have diffraction peaks; more preferably, also include diffraction peaks at 2θ (±0.2°) at 10.7±0.2°, 13.3±0.2°, 21.1±0.2° and 25.1±0.2°; further preferably ground, also included at 2θ (±0.2°) as 8.6±0.2°, 14.9±0.2°, 18.5±0.2°, 19.8±0.2°, 21.7±0.2°, 22.2±0.2°, 22.8±0.2° and 28.7±0.2 It has diffraction peaks at °; more preferably, it also includes 14.4±0.2°, 16.6±0.2°, 19.5±0.2°, 20.3±0.2°, 24.2±0.2°, 24.5±0.2° at 2θ (±0.2°) and 25.5±0.2° have diffraction peaks; more preferably, also include 17.3±0.2°, 22.4±0.2°, 26.1±0.2°, 26.7±0.2°, 27.5±0.2° at 2θ (±0.2°) , 29.7±0.2° and 33.2±0.2° have diffraction peaks; 最优选地，其X-射线粉末衍射图谱基本如图32所示，其DSC图谱基本如图33所示，其TGA图谱基本如图34所示；Most preferably, its X-ray powder diffraction pattern is basically shown in Figure 32, its DSC pattern is basically shown in Figure 33, and its TGA pattern is basically shown in Figure 34; 对甲苯磺酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为20.9±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为7.0±0.2°和19.6±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.3±0.2°、10.3±0.2°、11.6±0.2°和25.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为12.4±0.2°、13.2±0.2°、14.6±0.2°、16.3±0.2°、18.2±0.2°、19.0±0.2°、20.3±0.2°、21.6±0.2°和23.0±0.2°处具有衍射峰；The crystal form B of p-toluenesulfonate salt, its X-ray powder diffraction pattern has diffraction peaks at 20.9±0.2° at 2θ (±0.2°); preferably, it also includes 7.0±0.2° at 2θ (±0.2°) and 19.6±0.2° have diffraction peaks; more preferably, also include diffraction peaks at 2θ (±0.2°) at 8.3±0.2°, 10.3±0.2°, 11.6±0.2° and 25.8±0.2°; further preferably ground, also included at 2θ (±0.2°) as 12.4±0.2°, 13.2±0.2°, 14.6±0.2°, 16.3±0.2°, 18.2±0.2°, 19.0±0.2°, 20.3±0.2°, 21.6±0.2 ° and 23.0±0.2° have diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图35所示，其DSC图谱基本如图36所示，其TGA图谱基本如图37所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 35, its DSC pattern is basically shown in Figure 36, and its TGA pattern is basically shown in Figure 37; 富马酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为20.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为12.1±0.2°和17.6±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为15.5±0.2°、17.8±0.2°、21.6±0.2°和25.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.8±0.2°、11.2±0.2°、14.4±0.2°、20.9±0.2°、22.7±0.2°、24.4±0.2°、24.7±0.2°、26.4±0.2°和26.8±0.2°处具有衍射峰；Fumarate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 20.1±0.2° at 2θ (±0.2°); preferably, it also includes 12.1±0.2° at 2θ (±0.2°) and It has diffraction peaks at 17.6±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 15.5±0.2°, 17.8±0.2°, 21.6±0.2° and 25.1±0.2°; further preferably , also included in 2θ(±0.2°) as 8.8±0.2°, 11.2±0.2°, 14.4±0.2°, 20.9±0.2°, 22.7±0.2°, 24.4±0.2°, 24.7±0.2°, 26.4±0.2° and diffraction peaks at 26.8±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图38所示，其DSC图谱基本如图39所示，其TGA图谱基本如图40所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 38, its DSC pattern is basically shown in Figure 39, and its TGA pattern is basically shown in Figure 40; 富马酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为10.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为15.5±0.2°和19.8±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为11.8±0.2°、19.1±0.2°、20.1±0.2°和21.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.6±0.2°、14.1±0.2°、16.5±0.2°、17.2±0.2°、18.0±0.2°、23.9±0.2°、24.5±0.2°和24.8±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为11.3±0.2°、12.2±0.2°、17.6±0.2°和22.0±0.2°处具有衍射峰；Fumarate crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 10.7±0.2°; preferably, it also includes 2θ(±0.2°) at 15.5±0.2° and It has diffraction peaks at 19.8±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 11.8±0.2°, 19.1±0.2°, 20.1±0.2° and 21.3±0.2°; further preferably , also included in 2θ (±0.2°) as 6.6±0.2°, 14.1±0.2°, 16.5±0.2°, 17.2±0.2°, 18.0±0.2°, 23.9±0.2°, 24.5±0.2° and 24.8±0.2° have diffraction peaks at; more preferably, also include diffraction peaks at 2θ (±0.2°) at 11.3±0.2°, 12.2±0.2°, 17.6±0.2° and 22.0±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图41所示，其DSC图谱基本如图42所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 41, and its DSC pattern is basically shown in Figure 42; 富马酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为6.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为15.5±0.2°和19.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为10.8±0.2°、19.9±0.2°、20.4±0.2°和21.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.8±0.2°、12.8±0.2°、8.6±0.2°、13.6±0.2°、16.6±0.2°、17.0±0.2°、18.0±0.2°和23.2±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为24.2±0.2°和24.6±0.2°处具有衍射峰；Fumarate crystal form C, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.1±0.2°; preferably, it also includes 2θ (±0.2°) at 15.5±0.2° and It has a diffraction peak at 19.3±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 10.8±0.2°, 19.9±0.2°, 20.4±0.2° and 21.6±0.2°; further preferably , also included at 2θ (±0.2°) as 6.8±0.2°, 12.8±0.2°, 8.6±0.2°, 13.6±0.2°, 16.6±0.2°, 17.0±0.2°, 18.0±0.2° and 23.2±0.2° has diffraction peaks at; further preferably, it also includes diffraction peaks at 24.2±0.2° and 24.6±0.2° in 2θ (±0.2°); 更更进一步优选地，其X-射线粉末衍射图谱基本如图43所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 43; 草酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为19.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为11.2±0.2°和18.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为和9.0±0.2°、22.4±0.2°、24.6±0.2°和25.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.6±0.2°、14.8±0.2°、17.7±0.2°、18.8±0.2°、20.3±0.2°、20.6±0.2°、23.6±0.2°和24.0±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为7.0±0.2°、13.0±0.2°、14.3±0.2°、15.6±0.2°、16.3±0.2°和20.9±0.2°和处具有衍射峰；Oxalate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 19.3±0.2°; preferably, it also includes 11.2±0.2° and 18.0 at 2θ(±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) and 9.0±0.2°, 22.4±0.2°, 24.6±0.2° and 25.8±0.2°; further preferably , also included at 2θ (±0.2°) as 9.6±0.2°, 14.8±0.2°, 17.7±0.2°, 18.8±0.2°, 20.3±0.2°, 20.6±0.2°, 23.6±0.2° and 24.0±0.2° It has diffraction peaks at; further preferably, it also includes 7.0±0.2°, 13.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.3±0.2° and 20.9±0.2° at 2θ (±0.2°) and has diffraction peaks; 更更进一步优选地，其X-射线粉末衍射图谱基本如图44所示，其DSC图谱基本如图45所示，其TGA图谱基本如图46所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 44, its DSC pattern is basically shown in Figure 45, and its TGA pattern is basically shown in Figure 46; 氢溴酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为11.9±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为22.4±0.2°和27.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为14.9±0.2°、18.6±0.2°、20.5±0.2°和24.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为20.8±0.2°、21.6±0.2°和25.2±0.2°处具有衍射峰；Hydrobromide salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 11.9±0.2°; preferably, it also includes 22.4±0.2° at 2θ (±0.2°) and It has diffraction peaks at 27.1±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 14.9±0.2°, 18.6±0.2°, 20.5±0.2° and 24.4±0.2°; further preferably , also includes diffraction peaks at 20.8±0.2°, 21.6±0.2° and 25.2±0.2° at 2θ (±0.2°); 更进一步优选地，其X-射线粉末衍射图谱基本如图47所示，其DSC图谱基本如图48所示，其TGA图谱基本如图49所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 47, its DSC pattern is basically shown in Figure 48, and its TGA pattern is basically shown in Figure 49; 1，5-萘二磺酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为16.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为10.4±0.2°和18.4±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为20.9±0.2°、21.6±0.2°、23.3±0.2°和26.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为11.5±0.2°、12.4±0.2°、14.5±0.2°、17.5±0.2°、19.0±0.2°、22.0±0.2°、23.8±0.2°和24.3±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为6.7±0.2°、10.1±0.2°、11.7±0.2°、13.0±0.2°、15.5±0.2°和25.1±0.2°处具有衍射峰；1,5-Naphthalene disulfonate crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ (± 0.2°) at 16.5± 0.2°; preferably, it also includes at 2θ (± 0.2°) It has diffraction peaks at 10.4±0.2° and 18.4±0.2°; more preferably, it also has diffraction peaks at 20.9±0.2°, 21.6±0.2°, 23.3±0.2° and 26.3±0.2° at 2θ (±0.2°) Peak; further preferably, it is also included in 2θ(±0.2°) at 11.5±0.2°, 12.4±0.2°, 14.5±0.2°, 17.5±0.2°, 19.0±0.2°, 22.0±0.2°, 23.8±0.2° and 24.3±0.2° have diffraction peaks; more preferably, also include 6.7±0.2°, 10.1±0.2°, 11.7±0.2°, 13.0±0.2°, 15.5±0.2° and There is a diffraction peak at 25.1±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图50所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 50; 1，5-萘二磺酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为8.8±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为15.1±0.2°和24.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为13.4±0.2°、13.9±0.2°、15.5±0.2°和18.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为14.8±0.2°、17.0±0.2°、18.9±0.2°、19.8±0.2°、20.3±0.2°、21.0±0.2°、21.4±0.2°和24.1±0.2°处具有衍射峰；1,5-Naphthalene disulfonate crystal form C, its X-ray powder diffraction pattern has a diffraction peak at 2θ (±0.2°) at 8.8±0.2°; preferably, it also includes a 2θ (±0.2°) as It has diffraction peaks at 15.1±0.2° and 24.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 13.4±0.2°, 13.9±0.2°, 15.5±0.2° and 18.3±0.2° Peak; further preferably, it is also included in 2θ(±0.2°) at 14.8±0.2°, 17.0±0.2°, 18.9±0.2°, 19.8±0.2°, 20.3±0.2°, 21.0±0.2°, 21.4±0.2° and diffraction peaks at 24.1±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图51所示，其DSC图谱基本如图52所示，其TGA图谱基本如图53所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 51, its DSC pattern is basically shown in Figure 52, and its TGA pattern is basically shown in Figure 53; 1，5-萘二磺酸盐晶型D，其X-射线粉末衍射图谱在2θ(±0.2°)为20.4±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为10.4±0.2°和20.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为12.6±0.2°、14.4±0.2°、22.5±0.2°和24.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为7.2±0.2°、10.9±0.2°、15.2±0.2°、16.9±0.2°、18.5±0.2°、24.7±0.2°、25.1±0.2°和26.5±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为9.2±0.2°、14.6±0.2°、16.0±0.2°、19.4±0.2°、21.9±0.2°、27.5±0.2°、28.1±0.2°和33.2±0.2°处具有衍射峰；1,5-Naphthalene disulfonate crystal form D, its X-ray powder diffraction pattern has a diffraction peak at 20.4±0.2° at 2θ (±0.2°); preferably, it also includes a 2θ (±0.2°) as It has diffraction peaks at 10.4±0.2° and 20.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 12.6±0.2°, 14.4±0.2°, 22.5±0.2° and 24.1±0.2° Peak; further preferably, it is also included in 2θ (±0.2°) at 7.2±0.2°, 10.9±0.2°, 15.2±0.2°, 16.9±0.2°, 18.5±0.2°, 24.7±0.2°, 25.1±0.2° and 26.5±0.2° have diffraction peaks; more preferably, also include 9.2±0.2°, 14.6±0.2°, 16.0±0.2°, 19.4±0.2°, 21.9±0.2°, 2θ (±0.2°) at 2θ (±0.2°) There are diffraction peaks at 27.5±0.2°, 28.1±0.2° and 33.2±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图54所示，其DSC图谱基本如图55所示，其TGA图谱基本如图56所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 54, its DSC pattern is basically shown in Figure 55, and its TGA pattern is basically shown in Figure 56; 酒石酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为21.6±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为16.0±0.2°和17.7±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为17.1±0.2°、19.8±0.2°、20.7±0.2°和22.5±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为13.1±0.2°、14.2±0.2°、14.5±0.2°、20.1±0.2°和28.6±0.2°处具有衍射峰；Tartrate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 21.6±0.2° at 2θ (± 0.2°); preferably, it also includes 16.0±0.2° and 17.7± It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 17.1±0.2°, 19.8±0.2°, 20.7±0.2° and 22.5±0.2°; further preferably, also Contains diffraction peaks at 2θ (±0.2°) at 13.1±0.2°, 14.2±0.2°, 14.5±0.2°, 20.1±0.2° and 28.6±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图57所示，其DSC图谱基本如图58所示，其TGA图谱基本如图59所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 57, its DSC pattern is basically shown in Figure 58, and its TGA pattern is basically shown in Figure 59; 甲酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为18.0±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为17.6±0.2°和23.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为12.8±0.2°、14.5±0.2°、21.0±0.2°和24.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.4±0.2°、13.1±0.2°、19.9±0.2°、22.9±0.2°、25.3±0.2°、28.8±0.2°和31.0±0.2°处具有衍射峰；Form A formate salt, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 18.0±0.2°; preferably, it also includes 2θ(±0.2°) at 17.6±0.2° and 23.9 It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 12.8±0.2°, 14.5±0.2°, 21.0±0.2° and 24.8±0.2°; further preferably, Also comprises diffraction peaks at 2θ (±0.2°) at 8.4±0.2°, 13.1±0.2°, 19.9±0.2°, 22.9±0.2°, 25.3±0.2°, 28.8±0.2° and 31.0±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图60所示；More preferably, its X-ray powder diffraction pattern is basically as shown in Figure 60; 马尿酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为19.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为18.0±0.2°和19.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为17.6±0.2°、21.3±0.2°、21.8±0.2°和23.0±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为5.8±0.2°、8.8±0.2°、13.7±0.2°、16.6±0.2°、18.5±0.2°、20.3±0.2°、23.4±0.2°和25.3±0.2°处具有衍射峰；Hippurate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 19.5±0.2°; preferably, it also includes 2θ(±0.2°) at 18.0±0.2° and It has diffraction peaks at 19.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 17.6±0.2°, 21.3±0.2°, 21.8±0.2° and 23.0±0.2°; further preferably , also included at 2θ (±0.2°) as 5.8±0.2°, 8.8±0.2°, 13.7±0.2°, 16.6±0.2°, 18.5±0.2°, 20.3±0.2°, 23.4±0.2° and 25.3±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图61所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 61; 月桂酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)9.6±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)21.3±0.2°和23.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)8.6±0.2°、21.6±0.2°、22.8±0.2°和25.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为12.7±0.2°、15.0±0.2°、16.7±0.2°、17.4±0.2°、17.9±0.2°、20.0±0.2°、22.3±0.2°和24.2±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)14.8±0.2°、18.4±0.2°和26.2±0.2°处具有衍射峰；Laurate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) 9.6±0.2°; preferably, it also includes 21.3±0.2° and 23.0±0.2° at 2θ(±0.2°) It has diffraction peaks at °; more preferably, it also has diffraction peaks at 2θ (±0.2°) 8.6±0.2°, 21.6±0.2°, 22.8±0.2° and 25.4±0.2°; further preferably, it also has diffraction peaks at 2θ(±0.2°) with diffraction peaks at 12.7±0.2°, 15.0±0.2°, 16.7±0.2°, 17.4±0.2°, 17.9±0.2°, 20.0±0.2°, 22.3±0.2° and 24.2±0.2° ; Still further preferably, it also includes diffraction peaks at 2θ(±0.2°) at 14.8±0.2°, 18.4±0.2° and 26.2±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图62所示，其DSC图谱基本如图63所示，其TGA图谱基本如图64所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 62, its DSC pattern is basically shown in Figure 63, and its TGA pattern is basically shown in Figure 64; 硬脂酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为20.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为17.5±0.2°和22.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为16.1±0.2°、20.1±0.2°、21.0±0.2°和23.7±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)5.8±0.2°、7.3±0.2°、18.0±0.2°、19.6±0.2°、22.0±0.2°和23.2±0.2°处具有衍射峰；Stearate crystal form A, its X-ray powder diffraction pattern has a diffraction peak at 20.5±0.2° at 2θ (±0.2°); preferably, it also includes 17.5±0.2° at 2θ (±0.2°) and It has diffraction peaks at 22.3±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 16.1±0.2°, 20.1±0.2°, 21.0±0.2° and 23.7±0.2°; further preferably , also contains diffraction peaks at 2θ(±0.2°) 5.8±0.2°, 7.3±0.2°, 18.0±0.2°, 19.6±0.2°, 22.0±0.2° and 23.2±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图65所示。More preferably, its X-ray powder diffraction pattern is substantially as shown in FIG. 65 . 11.根据权利要求9所述的酸式盐，其中化合物3-((3-exo)-3-((7-甲氧基-4-((5-甲基-1H-吡唑-3-基)氨基)喹唑啉-2-基)氨基)-8-氮杂二环[3.2.1]辛烷-8-基)丙腈的酸式盐晶型，包括丁二酸盐晶型A～B，醋酸盐晶型A～E，盐酸盐晶型A～D，苯磺酸盐晶型A，氢溴酸盐晶型A，草酸盐晶型A，己二酸盐晶型A，乙烷磺酸盐晶型A，苯甲酸盐晶型A，1，5-萘二磺酸盐晶型A，帕莫酸盐晶型A，马尿酸盐晶型A，硫酸盐晶型A～B，丙二酸盐晶型A，对甲苯磺酸盐晶型A，马来酸盐晶型A，苹果酸盐晶型A，酒石酸盐晶型A，或富马酸盐晶型A，其中：11. The acid salt of claim 9, wherein compound 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazole-3- Crystalline acid salts of acid salts, including succinate salts, Form A ~B, acetate crystal form A～E, hydrochloride salt form A～D, benzenesulfonate crystal form A, hydrobromide salt form A, oxalate crystal form A, adipate crystal form A, ethanesulfonate form A, benzoate form A, 1,5-naphthalene disulfonate form A, pamolate form A, hippurate form A, sulfate Forms A～B, malonate form A, p-toluenesulfonate form A, maleate form A, malate form A, tartrate form A, or fumarate form A Type A, where: 丁二酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.8±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为5.8±0.2°和22.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为12.4±0.2°、17.8±0.2°、19.0±0.2°和26.4±0.2°和处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.0±0.2°、11.7±0.2°、13.7±0.2°、14.8±0.2°、18.6±0.2°、20.1±0.2°、20.6±0.2°和23.5±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为16.7±0.2°、25.0±0.2°和27.0±0.2°处具有衍射峰；Succinate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.8±0.2°; preferably, it also includes 5.8±0.2° at 2θ (±0.2°) and It has diffraction peaks at 22.1±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 12.4±0.2°, 17.8±0.2°, 19.0±0.2° and 26.4±0.2°; further preferably ground, also included at 2θ (±0.2°) as 9.0±0.2°, 11.7±0.2°, 13.7±0.2°, 14.8±0.2°, 18.6±0.2°, 20.1±0.2°, 20.6±0.2° and 23.5±0.2° It has diffraction peaks at °; more preferably, it also includes diffraction peaks at 2θ (±0.2°) at 16.7±0.2°, 25.0±0.2° and 27.0±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图67所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 67; 丁二酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为21.6±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.4±0.2°和19.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为10.7±0.2°、16.5±0.2°、18.7±0.2°和19.7±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.9±0.2°、15.5±0.2°、17.0±0.2°、17.3±0.2°、20.3±0.2°、21.1±0.2°、25.7±0.2°和27.1±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为8.1±0.2°、17.9±0.2°和23.1±0.2°处具有衍射峰；Succinate crystal form B, its X-ray powder diffraction pattern has a diffraction peak at 21.6±0.2° at 2θ (±0.2°); preferably, it also includes 8.4±0.2° at 2θ (±0.2°) and It has diffraction peaks at 19.3±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 10.7±0.2°, 16.5±0.2°, 18.7±0.2° and 19.7±0.2°; further preferably , also included at 2θ (±0.2°) as 8.9±0.2°, 15.5±0.2°, 17.0±0.2°, 17.3±0.2°, 20.3±0.2°, 21.1±0.2°, 25.7±0.2° and 27.1±0.2° has diffraction peaks at; further preferably, it also includes diffraction peaks at 2θ (±0.2°) at 8.1±0.2°, 17.9±0.2° and 23.1±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图68所示，其DSC图谱基本如图69所示，其TGA图谱基本如图70所示；More preferably, its X-ray powder diffraction pattern is basically shown in Figure 68, its DSC pattern is basically shown in Figure 69, and its TGA pattern is basically shown in Figure 70; 醋酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为20.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.3±0.2°和20.4±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.8±0.2°、10.2±0.2°、21.6±0.2°和23.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.9±0.2°、16.9±0.2°、19.2±0.2°、26.7±0.2°和27.2±0.2°处具有衍射峰；Acetate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 20.1±0.2° at 2θ (±0.2°); preferably, it also includes 8.3±0.2° and 20.4 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.8±0.2°, 10.2±0.2°, 21.6±0.2° and 23.8±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 8.9±0.2°, 16.9±0.2°, 19.2±0.2°, 26.7±0.2° and 27.2±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图71所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 71; 醋酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为8.1±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为9.6±0.2°和26.5±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为17.0±0.2°、17.2±0.2°、20.2±0.2°和22.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.6±0.2°、10.2±0.2°、14.0±0.2°、15.2±0.2°、16.3±0.2°、16.6±0.2°、19.8±0.2°和26.9±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为21.0±0.2°和23.6±0.2°处具有衍射峰；Acetate crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 8.1±0.2°; preferably, it also includes 9.6±0.2° and 26.5 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 17.0±0.2°, 17.2±0.2°, 20.2±0.2° and 22.6±0.2°; further preferably, Also included at 2θ (±0.2°) at 8.6±0.2°, 10.2±0.2°, 14.0±0.2°, 15.2±0.2°, 16.3±0.2°, 16.6±0.2°, 19.8±0.2° and 26.9±0.2° It has diffraction peaks; more preferably, it also includes diffraction peaks at 21.0±0.2° and 23.6±0.2° in 2θ (±0.2°); 更更进一步优选地，其X-射线粉末衍射图谱基本如图72所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 72; 醋酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为5.4±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为10.3±0.2°和21.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为和15.7±0.2°、19.5±0.2°、22.9±0.2°和25.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.8±0.2°、16.7±0.2°、17.6±0.2°、18.8±0.2°、20.4±0.2°、24.1±0.2°、25.3±0.2°和29.0±0.2°处具有衍射峰；Acetate crystal form C, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.4±0.2°; preferably, it also includes 2θ (±0.2°) at 10.3±0.2° and 21.9 It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) and 15.7±0.2°, 19.5±0.2°, 22.9±0.2° and 25.1±0.2°; further preferably , also included at 2θ (±0.2°) as 10.8±0.2°, 16.7±0.2°, 17.6±0.2°, 18.8±0.2°, 20.4±0.2°, 24.1±0.2°, 25.3±0.2° and 29.0±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图73所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 73; 醋酸盐晶型D，其X-射线粉末衍射图谱在2θ(±0.2°)为4.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.1±0.2°和27.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为10.9±0.2°、13.4±0.2°、17.6±0.2°和18.9±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.3±0.2°、13.9±0.2°、14.4±0.2°、15.2±0.2°、20.3±0.2°、23.2±0.2°、25.8±0.2°和26.7±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为17.2±0.2°、20.7±0.2°、22.0±0.2°和22.6±0.2°处具有衍射峰；Acetate crystal form D, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 4.7±0.2°; preferably, it also includes 8.1±0.2° and 27.1 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 10.9±0.2°, 13.4±0.2°, 17.6±0.2° and 18.9±0.2°; further preferably, Also included at 2θ (±0.2°) at 10.3±0.2°, 13.9±0.2°, 14.4±0.2°, 15.2±0.2°, 20.3±0.2°, 23.2±0.2°, 25.8±0.2°, and 26.7±0.2° have diffraction peaks; more preferably, also include diffraction peaks at 2θ (±0.2°) at 17.2±0.2°, 20.7±0.2°, 22.0±0.2° and 22.6±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图74所示；Still further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 74; 醋酸盐晶型E，其X-射线粉末衍射图谱在2θ(±0.2°)为6.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为19.8±0.2°和20.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.0±0.2°、10.3±0.2°、22.3±0.2°和25.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为15.1±0.2°、26.9±0.2°、28.0±0.2°和29.5±0.2°处具有衍射峰；Acetate crystal form E, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.5±0.2°; preferably, it also includes 2θ (±0.2°) at 19.8±0.2° and 20.1 It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.0±0.2°, 10.3±0.2°, 22.3±0.2° and 25.4±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 15.1±0.2°, 26.9±0.2°, 28.0±0.2° and 29.5±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图75所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 75; 盐酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为9.1±0.2°和20.5±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.3±0.2°、14.2±0.2°、16.2±0.2°和27.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.7±0.2°、10.3±0.2°、19.0±0.2°、25.1±0.2°和26.3±0.2°处具有衍射峰；Hydrochloride salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.5±0.2°; preferably, it also includes 9.1±0.2° and 20.5 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 8.3±0.2°, 14.2±0.2°, 16.2±0.2° and 27.8±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 9.7±0.2°, 10.3±0.2°, 19.0±0.2°, 25.1±0.2° and 26.3±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图76所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 76; 盐酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为10.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.9±0.2°和20.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.5±0.2°、17.9±0.2°、22.2±0.2°和25.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为5.3±0.2°、15.0±0.2°、21.3±0.2°、26.1±0.2°、26.7±0.2°和29.5±0.2°处具有衍射峰；Hydrochloride salt crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 10.2±0.2°; preferably, it also includes 8.9±0.2° and 20.0 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.5±0.2°, 17.9±0.2°, 22.2±0.2° and 25.3±0.2°; further preferably, Also included are diffraction peaks at 2θ (±0.2°) at 5.3±0.2°, 15.0±0.2°, 21.3±0.2°, 26.1±0.2°, 26.7±0.2° and 29.5±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图77所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 77; 盐酸盐晶型C，其X-射线粉末衍射图谱在2θ(±0.2°)为6.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为18.9±0.2°和24.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为13.8±0.2°、18.0±0.2°、21.8±0.2°和27.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.4±0.2°、11.3±0.2°、16.0±0.2°、21.5±0.2°、23.0±0.2°、27.3±0.2°和29.4±0.2°处具有衍射峰；Hydrochloride salt crystal form C, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.3±0.2°; preferably, it also includes 2θ (±0.2°) at 18.9±0.2° and 24.3 It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 13.8±0.2°, 18.0±0.2°, 21.8±0.2° and 27.6±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 9.4±0.2°, 11.3±0.2°, 16.0±0.2°, 21.5±0.2°, 23.0±0.2°, 27.3±0.2° and 29.4±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图78所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 78; 盐酸盐晶型D，其X-射线粉末衍射图谱在2θ(±0.2°)为5.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.8±0.2°和26.3±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.8±0.2°、13.8±0.2°、19.8±0.2°和25.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.3±0.2°、14.2±0.2°、15.8±0.2°、17.3±0.2°、18.5±0.2°和23.3±0.2°处具有衍射峰；Hydrochloride salt crystal form D, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.2±0.2°; preferably, it also includes 8.8±0.2° and 26.3 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.8±0.2°, 13.8±0.2°, 19.8±0.2° and 25.8±0.2°; further preferably, Also included are diffraction peaks at 2θ (±0.2°) at 6.3±0.2°, 14.2±0.2°, 15.8±0.2°, 17.3±0.2°, 18.5±0.2° and 23.3±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图79所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 79; 苯磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为12.1±0.2°和15.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为7.5±0.2°、21.2±0.2°、26.6±0.2°和27.0±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为14.8±0.2°、15.3±0.2°、16.2±0.2°、20.0±0.2°、20.5±0.2°、21.8±0.2°、23.8±0.2°和29.0±0.2°处具有衍射峰；Besylate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 6.7±0.2°; preferably, it also includes 2θ(±0.2°) at 12.1±0.2° and It has diffraction peaks at 15.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 7.5±0.2°, 21.2±0.2°, 26.6±0.2° and 27.0±0.2°; further preferably , also included at 2θ (±0.2°) as 14.8±0.2°, 15.3±0.2°, 16.2±0.2°, 20.0±0.2°, 20.5±0.2°, 21.8±0.2°, 23.8±0.2° and 29.0±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图80所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 80; 氢溴酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.8±0.2°和19.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.8±0.2°、9.6±0.2°、18.5±0.2°和19.7±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.4±0.2°、9.8±0.2°、12.4±0.2°、17.2±0.2°、22.6±0.2°、24.6±0.2°、24.9±0.2°、25.9±0.2°和27.0±0.2°处具有衍射峰；Hydrobromide salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.2±0.2°; preferably, it also includes 8.8±0.2° at 2θ (±0.2°) and It has diffraction peaks at 19.9±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.8±0.2°, 9.6±0.2°, 18.5±0.2° and 19.7±0.2°; further preferably , also included in 2θ(±0.2°) as 9.4±0.2°, 9.8±0.2°, 12.4±0.2°, 17.2±0.2°, 22.6±0.2°, 24.6±0.2°, 24.9±0.2°, 25.9±0.2° and diffraction peaks at 27.0±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图81所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 81; 草酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为8.4±0.2°和24.6±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.6±0.2°、13.1±0.2°、14.7±0.2°和27.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为7.2±0.2°、12.4±0.2°、16.9±0.2°、20.0±0.2°、20.9±0.2°、24.4±0.2°和25.4±0.2°处具有衍射峰；Oxalate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.3±0.2°; preferably, it also includes 8.4±0.2° and 24.6 at 2θ (±0.2°) It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.6±0.2°, 13.1±0.2°, 14.7±0.2° and 27.1±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 7.2±0.2°, 12.4±0.2°, 16.9±0.2°, 20.0±0.2°, 20.9±0.2°, 24.4±0.2° and 25.4±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图82所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 82; 己二酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为7.9±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为21.3±0.2°和23.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为7.7±0.2°、11.1±0.2°、24.7±0.2°和27.4±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为13.1±0.2°、16.5±0.2°、20.1±0.2°、25.1±0.2°和29.7±0.2°处具有衍射峰；Adipate crystalline form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (± 0.2°) at 7.9±0.2°; preferably, it also includes 21.3±0.2° at 2θ (±0.2°) and It has diffraction peaks at 23.1±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 7.7±0.2°, 11.1±0.2°, 24.7±0.2° and 27.4±0.2°; further preferably , also contains diffraction peaks at 2θ (±0.2°) at 13.1±0.2°, 16.5±0.2°, 20.1±0.2°, 25.1±0.2° and 29.7±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图83所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 83; 乙烷磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为5.5±0.2°和13.1±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.5±0.2°、16.4±0.2°、20.0±0.2°和22.0±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为12.9±0.2°和16.0±0.2°处具有衍射峰；Ethanesulfonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.5±0.2°; preferably, it also includes 5.5±0.2° at 2θ (±0.2°) and 13.1±0.2° have diffraction peaks; more preferably, also include diffraction peaks at 2θ (±0.2°) at 9.5±0.2°, 16.4±0.2°, 20.0±0.2° and 22.0±0.2°; further preferably ground, also includes diffraction peaks at 2θ (±0.2°) at 12.9±0.2° and 16.0±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图84所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 84; 苯甲酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为21.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为9.5±0.2°和15.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为5.9±0.2°、14.0±0.2°、15.5±0.2°和25.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.8±0.2°、9.1±0.2°、12.2±0.2°、19.7±0.2°、20.8±0.2°、23.7±0.2°、26.0±0.2°和28.1±0.2°处具有衍射峰；Benzoate crystalline form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 21.5±0.2°; preferably, it also includes 9.5±0.2° at 2θ (±0.2°) and It has diffraction peaks at 15.0±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 5.9±0.2°, 14.0±0.2°, 15.5±0.2° and 25.2±0.2°; further preferably , also included at 2θ (±0.2°) as 6.8±0.2°, 9.1±0.2°, 12.2±0.2°, 19.7±0.2°, 20.8±0.2°, 23.7±0.2°, 26.0±0.2° and 28.1±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图85所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 85; 1，5-萘二磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为9.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为4.7±0.2°和16.5±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为18.4±0.2°、20.6±0.2°、21.9±0.2°和23.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为13.0±0.2°、14.1±0.2°、17.6±0.2°、21.6±0.2°、22.5±0.2°、24.7±0.2°、25.1±0.2°、26.2±0.2°和27.6±0.2°处具有衍射峰；1,5-Naphthalene disulfonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (± 0.2°) at 9.3± 0.2°; preferably, it also includes 2θ (± 0.2°) as It has diffraction peaks at 4.7±0.2° and 16.5±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 18.4±0.2°, 20.6±0.2°, 21.9±0.2° and 23.2±0.2° Peak; further preferably, it is also included in 2θ(±0.2°) at 13.0±0.2°, 14.1±0.2°, 17.6±0.2°, 21.6±0.2°, 22.5±0.2°, 24.7±0.2°, 25.1±0.2° , 26.2±0.2° and 27.6±0.2° have diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图86所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 86; 帕莫酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为21.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为7.9±0.2°和17.8±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为9.9±0.2°、10.7±0.2°、20.8±0.2°和23.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为6.7±0.2°、11.2±0.2°、14.6±0.2°、16.4±0.2°、16.9±0.2°、18.3±0.2°、20.4±0.2°和23.0±0.2°处具有衍射峰；更进一步优选地，还包含在2θ(±0.2°)为12.7±0.2°、19.4±0.2°和22.4±0.2°处具有衍射峰；Palmoate crystal form A, its X-ray powder diffraction pattern has a diffraction peak at 21.5±0.2° at 2θ (±0.2°); preferably, it also includes 7.9±0.2° at 2θ (±0.2°) and It has diffraction peaks at 17.8±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 9.9±0.2°, 10.7±0.2°, 20.8±0.2° and 23.3±0.2°; further preferably , also included at 2θ (±0.2°) as 6.7±0.2°, 11.2±0.2°, 14.6±0.2°, 16.4±0.2°, 16.9±0.2°, 18.3±0.2°, 20.4±0.2° and 23.0±0.2° have diffraction peaks at; more preferably, also include diffraction peaks at 2θ (±0.2°) at 12.7±0.2°, 19.4±0.2° and 22.4±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图87所示；Still more preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 87; 马尿酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为16.1±0.2°和23.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.1±0.2°、11.6±0.2°、21.7±0.2°和25.5±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为11.0±0.2°、16.4±0.2°、17.4±0.2°和24.6±0.2°处具有衍射峰；Hippurate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.7±0.2°; preferably, it also includes 2θ (±0.2°) at 16.1±0.2° and It has diffraction peaks at 23.0±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 8.1±0.2°, 11.6±0.2°, 21.7±0.2° and 25.5±0.2°; further preferably , also contains diffraction peaks at 2θ (±0.2°) at 11.0±0.2°, 16.4±0.2°, 17.4±0.2° and 24.6±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图88所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 88; 硫酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.6±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为26.1±0.2°和29.55±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为12.1±0.2°、16.9±0.2°、17.8±0.2°和26.6±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.3±0.2°、13.8±0.2°、16.6±0.2°、21.9±0.2°、22.9±0.2°、23.9±0.2°、27.2±0.2°和27.7±0.2°处具有衍射峰；更进一步优选地，进一步还包含在2θ(±0.2°)为18.6±0.2°、19.6±0.2°和25.1±0.2°和处具有衍射峰；Sulfate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.6±0.2°; preferably, it also includes 26.1±0.2° and 29.55±0 at 2θ (±0.2°) It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 12.1±0.2°, 16.9±0.2°, 17.8±0.2° and 26.6±0.2°; further preferably, also Contains 2θ (±0.2°) at 8.3±0.2°, 13.8±0.2°, 16.6±0.2°, 21.9±0.2°, 22.9±0.2°, 23.9±0.2°, 27.2±0.2° and 27.7±0.2° with Diffraction peaks; more preferably, further comprising diffraction peaks at 2θ(±0.2°) at 18.6±0.2°, 19.6±0.2° and 25.1±0.2°; 更更进一步优选地，其X-射线粉末衍射图谱基本如图89所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 89; 硫酸盐晶型B，其X-射线粉末衍射图谱在2θ(±0.2°)为5.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为18.9±0.2°和25.5±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.5±0.2°、14.1±0.2°、17.1±0.2°和22.1±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为16.8±0.2°、18.5±0.2°、24.2±0.2°和25.3±0.2°处具有衍射峰；Sulfate salt crystal form B, its X-ray powder diffraction pattern has diffraction peaks at 2θ(±0.2°) at 5.3±0.2°; preferably, it also includes 2θ(±0.2°) at 18.9±0.2° and 25.5±0.2° It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 8.5±0.2°, 14.1±0.2°, 17.1±0.2° and 22.1±0.2°; further preferably, also Contains diffraction peaks at 2θ (±0.2°) at 16.8±0.2°, 18.5±0.2°, 24.2±0.2° and 25.3±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图90所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 90; 丙二酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为10.3±0.2°和10.8±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为4.8±0.2°和16.4±0.2°处具有衍射峰；Malonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.2±0.2°; It has a diffraction peak at 10.8±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 4.8±0.2° and 16.4±0.2°; 进一步优选地，其X-射线粉末衍射图谱基本如图91所示；Further preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 91; 对甲苯磺酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.9±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为7.2±0.2°和25.6±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为14.3±0.2°、15.4±0.2°、19.8±0.2°和27.3±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.8±0.2°、16.4±0.2°和20.3±0.2°处具有衍射峰；p-toluenesulfonate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.9±0.2°; preferably, it also includes 7.2±0.2° at 2θ (±0.2°) and 25.6±0.2° have diffraction peaks; more preferably, also include diffraction peaks at 2θ (±0.2°) at 14.3±0.2°, 15.4±0.2°, 19.8±0.2° and 27.3±0.2°; further preferably ground, also include diffraction peaks at 2θ (±0.2°) at 9.8±0.2°, 16.4±0.2° and 20.3±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图92所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 92; 马来酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为4.3±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为6.8±0.2°和26.2±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为6.1±0.2°、9.7±0.2°、15.5±0.2°和27.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为12.2±0.2°、12.6±0.2°、13.6±0.2°、16.4±0.2°、17.2±0.2°、18.0±0.2°、20.2±0.2°和25.7±0.2°处具有衍射峰；Maleate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 4.3±0.2°; preferably, it also includes 6.8±0.2° at 2θ (±0.2°) and It has diffraction peaks at 26.2±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 6.1±0.2°, 9.7±0.2°, 15.5±0.2° and 27.2±0.2°; further preferably , also included at 2θ (±0.2°) as 12.2±0.2°, 12.6±0.2°, 13.6±0.2°, 16.4±0.2°, 17.2±0.2°, 18.0±0.2°, 20.2±0.2° and 25.7±0.2° has diffraction peaks; 更进一步优选地，其X-射线粉末衍射图谱基本如图93所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 93; 苹果酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为7.7±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为19.6±0.2°和23.9±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为16.2±0.2°、17.3±0.2°、18.5±0.2°和24.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为9.5±0.2°、10.8±0.2°、19.1±0.2°、22.0±0.2°和26.5±0.2°处具有衍射峰；Malate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 7.7±0.2°; preferably, it also includes 2θ (±0.2°) at 19.6±0.2° and 23.9 It has diffraction peaks at ±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 16.2±0.2°, 17.3±0.2°, 18.5±0.2° and 24.2±0.2°; further preferably, Also includes diffraction peaks at 2θ (±0.2°) at 9.5±0.2°, 10.8±0.2°, 19.1±0.2°, 22.0±0.2° and 26.5±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图94所示；More preferably, its X-ray powder diffraction pattern is substantially as shown in Figure 94; 酒石酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为5.5±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为9.5±0.2°和19.0±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为8.2±0.2°、15.0±0.2°、19.9±0.2°和25.8±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为10.9±0.2°、13.9±0.2°、16.4±0.2°、18.6±0.2°和24.6±0.2°处具有衍射峰；Tartrate salt crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 5.5±0.2°; preferably, it also includes 9.5±0.2° and 19.0±0.2° at 2θ (±0.2°) It has a diffraction peak at 0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 8.2±0.2°, 15.0±0.2°, 19.9±0.2° and 25.8±0.2°; further preferably, also Contains diffraction peaks at 2θ (±0.2°) at 10.9±0.2°, 13.9±0.2°, 16.4±0.2°, 18.6±0.2° and 24.6±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图95所示；More preferably, its X-ray powder diffraction pattern is basically as shown in Figure 95; 富马酸盐晶型A，其X-射线粉末衍射图谱在2θ(±0.2°)为6.2±0.2°处具有衍射峰；优选地，还包含在2θ(±0.2°)为6.9±0.2°和25.2±0.2°处具有衍射峰；更优选地，还包含在2θ(±0.2°)为15.8±0.2°、16.6±0.2°、18.7±0.2°和25.2±0.2°处具有衍射峰；进一步优选地，还包含在2θ(±0.2°)为8.7±0.2°、11.1±0.2°、14.3±0.2°、25.9±0.2°和26.7±0.2°处具有衍射峰；Fumarate crystal form A, its X-ray powder diffraction pattern has diffraction peaks at 2θ (±0.2°) at 6.2±0.2°; preferably, it also includes 6.9±0.2° at 2θ (±0.2°) and It has diffraction peaks at 25.2±0.2°; more preferably, it also has diffraction peaks at 2θ (±0.2°) at 15.8±0.2°, 16.6±0.2°, 18.7±0.2° and 25.2±0.2°; further preferably , also contains diffraction peaks at 2θ (±0.2°) at 8.7±0.2°, 11.1±0.2°, 14.3±0.2°, 25.9±0.2° and 26.7±0.2°; 更进一步优选地，其X-射线粉末衍射图谱基本如图96所示。More preferably, its X-ray powder diffraction pattern is substantially as shown in FIG. 96 . 12.一种制备权利要求1-9任意一项所述的酸式盐的方法，具体包括如下步骤：12. a method for preparing the acid salt described in any one of claims 1-9, specifically comprises the steps: 1)称取适量的自由碱，用良性溶剂溶解；1) Weigh an appropriate amount of free base and dissolve it with a benign solvent; 2)称取适量的反离子酸，用有机溶剂溶解；2) Weigh an appropriate amount of counter ionic acid and dissolve it in an organic solvent; 3)把上述两种溶液合并，搅拌析出或滴加不良溶剂后搅拌析出；3) combine above-mentioned two kinds of solutions, stir and separate out or stir and separate out after adding poor solvent; 4)快速离心或静置吹干得目标产物；4) Rapid centrifugation or standing to dry to obtain the target product; 其中：in: 所述的良性溶剂选自2-丁醇、甲醇、异丙醇、2-丁酮、二甲基亚砜、N,N-二甲基甲酰胺、N，N-二甲基乙酰胺或N-甲基吡咯烷酮中的一种或多种；优选2-丁醇、甲醇或二甲基亚砜中的一种或多种；The benign solvent is selected from 2-butanol, methanol, isopropanol, 2-butanone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N - one or more of methylpyrrolidone; preferably one or more of 2-butanol, methanol or dimethyl sulfoxide; 所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-甲基-四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N，N-二甲基甲酰胺中的一种或多种；优选甲醇、乙醇或乙腈中的一种或多种；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-methyl yl-tetrahydrofuran, 2-butanone, 3-pentanone, heptane, methyl tert-butyl ether, isopropyl ether, 1,4-dioxane, tert-butanol or N,N-dimethylformamide one or more of; preferably one or more of methanol, ethanol or acetonitrile; 所述的不良溶剂选自庚烷、水、甲基叔丁基醚、环己烷、甲苯、异丙醚、乙酸乙酯、丙酮或乙腈中的一种或多种；优选水、甲基叔丁基醚或异丙醚中的一种或多种；Described poor solvent is selected from one or more in heptane, water, methyl tertiary butyl ether, cyclohexane, toluene, isopropyl ether, ethyl acetate, acetone or acetonitrile; preferably water, methyl tertiary One or more of butyl ether or isopropyl ether; 所述的反离子酸选自盐酸、硫酸、硝酸、氢溴酸、氢氟酸、氢碘酸、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、帕莫酸、甲酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸或L-苹果酸；优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、对甲苯磺酸、氢溴酸、草酸、富马酸、甲酸、马尿酸、月桂酸、硬脂酸；更优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、富马酸、马尿酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、草酸或氢溴酸；进一步优选磷酸、马来酸或苯磺酸；The counter ionic 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-naphthoic acid, acetic acid, dichloride Acetic acid, trichloroacetic acid, acetylhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyrovalley Amino acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid , 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably phosphoric acid, butyric acid Diacid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic acid, 1,5-naphthalene Disulfonic 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, ethyl acetate Alkanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, isethionic acid, 1,5- Naphthalenedisulfonic acid, tartaric acid, adipic acid, sulfuric acid, oxalic acid or hydrobromic acid; more preferably phosphoric acid, maleic acid or benzenesulfonic acid; 或者，or, 1)称取适量的自由碱，用不良性溶剂混悬；1) Weigh an appropriate amount of free base and suspend it with a poor solvent; 2)称取适量的反离子酸，用有机溶剂溶解；2) Weigh an appropriate amount of counter ionic acid and dissolve it in an organic solvent; 3)将上述溶液加入上述混悬液中，搅拌；3) adding above-mentioned solution to above-mentioned suspension, stirring; 4)快速离心或静置吹干得到化合物的盐；4) Quickly centrifuge or stand to dry to obtain the salt of the compound; 其中：in: 所述的不良性溶剂选自甲醇、丙酮、乙酸乙酯、乙腈、乙醇、88％丙酮、四氢呋喃、2-甲基-四氢呋喃、二氯甲烷、3-戊酮、醋酸异丙酯、甲酸乙酯、1,4-二氧六环、氯苯、苯、甲苯、异丙醇、正丁醇、异丁醇、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、正丙醇、叔丁醇或2-丁酮；优选二氯甲烷、甲苯、乙腈、丙酮、甲醇或乙酸乙酯中的一种或多种；The poor solvent is selected from methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, 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; 所述的有机溶剂选自甲醇、乙醇、乙酸乙酯、二氯甲烷、丙酮、正己烷、石油醚、苯、甲苯、氯仿、乙腈、四氯化碳、二氯乙烷、四氢呋喃、2-甲基-四氢呋喃、2-丁酮、3-戊酮、庚烷、甲基叔丁基醚、异丙醚、1,4-二氧六环、叔丁醇或N，N-二甲基甲酰胺；优选甲醇、乙醇或乙腈中的一种或多种；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-methyl yl-tetrahydrofuran, 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; 所述的反离子酸选自盐酸、硫酸、硝酸、氢溴酸、氢氟酸、氢碘酸、磷酸、2,5-二羟基苯甲酸、1-羟基-2-萘甲酸、醋酸、二氯醋酸、三氯醋酸、乙酰氧肟酸、己二酸、苯磺酸、4-氯苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、4-氨基苯甲酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己烷氨基磺酸、樟脑磺酸、天门冬氨酸、樟脑酸、葡萄糖酸、葡糖醛酸、谷氨酸、异抗坏血酸、乳酸、苹果酸、扁桃酸、焦谷氨酸、酒石酸、十二烷基硫酸、二苯甲酰酒石酸、乙烷-1,2-二磺酸、乙磺酸、蚁酸、富马酸、半乳糖酸、龙胆酸、戊二酸、2-酮戊二酸、乙醇酸、马尿酸、羟乙基磺酸、乳糖酸、抗坏血酸、天冬氨酸、月桂酸、樟脑酸、马来酸、丙二酸、甲磺酸、1,5-萘二磺酸、萘-2-磺酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、硫氰酸、帕莫酸、甲酸、十一碳烯酸、三氟乙酸、苯磺酸、对甲基苯磺酸或L-苹果酸；优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、对甲苯磺酸、氢溴酸、草酸、富马酸、甲酸、马尿酸、月桂酸、硬脂酸；更优选磷酸、丁二酸、醋酸、乙烷磺酸、苯甲酸、帕莫酸、丙二酸、对甲苯磺酸、苹果酸、盐酸、马来酸、苯磺酸、富马酸、马尿酸、羟乙基磺酸、1，5-萘二磺酸、酒石酸、己二酸、硫酸、草酸或氢溴酸；进一步优选磷酸、马来酸或苯磺酸。The counter ionic 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-naphthoic acid, acetic acid, dichloride Acetic acid, trichloroacetic acid, acetylhydroxamic acid, adipic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, benzoic acid, 4-acetylaminobenzoic acid, 4-aminobenzoic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, camphorsulfonic acid, aspartic acid, camphoric acid, gluconic acid, glucuronic acid, glutamic acid, erythorbic acid, lactic acid, malic acid, mandelic acid, pyrovalley Amino acid, tartaric acid, dodecyl sulfate, dibenzoyltartaric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactonic acid, gentisic acid, glutaric acid , 2-ketoglutaric acid, glycolic acid, hippuric acid, isethionic 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, niacin, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid acid, stearic acid, succinic acid, thiocyanic acid, pamoic acid, formic acid, undecylenic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or L-malic acid; preferably phosphoric acid, butyric acid Diacid, acetic acid, ethanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, isethionic acid, 1,5-naphthalene Disulfonic 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, ethyl acetate Alkanesulfonic acid, benzoic acid, pamoic acid, malonic acid, p-toluenesulfonic acid, malic acid, hydrochloric acid, maleic acid, benzenesulfonic acid, fumaric acid, hippuric acid, isethionic 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. 13.一种制备权利要求10或11所述酸式盐的方法，具体包括如下步骤：13. a method for preparing the described acid salt of claim 10 or 11, specifically comprises the steps: 1)称取适量的化合物盐，用不良溶剂混悬；1) Weigh an appropriate amount of compound salt and suspend with poor solvent; 2)振摇以上所得混悬液；2) shaking the above obtained suspension; 3)将以上混悬液快速离心，去除上清液，剩余固体烘干至恒重得到目标产物；3) the above suspension is rapidly centrifuged, the supernatant is removed, and the remaining solid is dried to constant weight to obtain the target product; 其中：in: 所述的不良性溶剂选自甲醇、乙醇、二氯甲烷、1,4-二氧六环、乙腈、氯苯、苯、甲苯、丙酮、乙酸乙酯、水、88％丙酮、醋酸异丙酯、3-戊酮、甲酸乙酯、四氢呋喃、2-甲基-四氢呋喃、异丙醇、正丁醇、异丁醇、正丙醇、叔丁醇或2-丁酮中的一种或多种。The poor solvent is selected from methanol, ethanol, dichloromethane, 1,4-dioxane, acetonitrile, chlorobenzene, benzene, toluene, acetone, ethyl acetate, water, 88% acetone, isopropyl acetate One or more of , 3-pentanone, ethyl formate, tetrahydrofuran, 2-methyl-tetrahydrofuran, isopropanol, n-butanol, isobutanol, n-propanol, tert-butanol or 2-butanone . 14.一种药物组合物，其含有治疗有效量的权利要求1-11中任一项所述化合物的酸式盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。14. A pharmaceutical composition comprising a therapeutically effective amount of an acid salt of a compound of any one of claims 1-11, and one or more pharmaceutically acceptable carriers, diluents or excipients . 15.根据权利要求1-11中任一项所述的酸式盐或权利要求14所述的药物组合物在制备预防和/或治疗与JAK激酶相关疾病药物中的应用，所述的JAK激酶相关疾病优选炎症性疾病和/或肿瘤疾病；15. The application of the acid salt according to any one of claims 1-11 or the pharmaceutical composition according to claim 14 in the preparation of a medicine for preventing and/or treating diseases related to JAK kinase, the JAK kinase Related diseases are preferably inflammatory diseases and/or tumor diseases; 优选地，所述的炎症性疾病选自类风湿性关节炎、皮炎、银屑病、炎症性肠病；其中炎症性肠病优选慢性肠道炎症性疾病，进一步优选溃疡性结肠炎和克罗恩氏病；Preferably, the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease; wherein inflammatory bowel disease is preferably chronic intestinal inflammatory disease, more preferably ulcerative colitis and Crohn's disease En's disease; 所述的肿瘤疾病选自骨髓纤维化、真性红细胞增多症及原发性血小板增多症、骨髓细胞性白血病、急性淋巴细胞性白血病、乳腺导管癌及非小细胞肺癌。The tumor disease is selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myelocytic leukemia, acute lymphoblastic leukemia, breast ductal carcinoma and non-small cell lung cancer.
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