Free base crystalline form of a heteroaromatic derivative and process for its preparation

Abstract

The present application relates to a free base crystal form of a heteroaromatic derivative and a preparation method thereof. Specifically, it relates to a free base crystal form of a compound having a general formula (I), a preparation method and a pharmaceutical composition containing a therapeutically effective amount of the crystal form, and the use thereof as a JAK kinase inhibitor in the treatment of inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease, and tumor diseases such as colon cancer, non-small cell lung cancer.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of drug synthesis, and particularly relates to a crystal form of a heteroaromatic derivative, a preparation method and application thereof. BACKGROUND

[0002] Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase that mediates the signal transduction and activation of various cytokines. The JAK kinase family contains four subfamily members, JAK1, JAK2, JAK3 and TYK2, each of which mediates different types of cytokine signaling pathways. JAK1, JAK2 and TYK2 are expressed in various tissues of the human body, and JAK3 is mainly expressed in hematopoietic tissues. The common feature of cytokine receptors is that the receptors themselves do not have kinase activity, but the intracellular segment of the receptor has a binding site for tyrosine kinase JAK. When the cytokine receptor binds to its ligand, the receptor-coupled JAKs are activated, and then the receptor is phosphorylated. The phosphorylated tyrosine site can bind to STAT protein containing SH2 domain, thereby recruiting STAT to the receptor and phosphorylating it by JAKs. Subsequently, the phosphorylated tyrosine mediates STAT dimerization, and the activated STAT dimer moves to the nucleus and activates the transcription of its target genes, thereby regulating various functions of cells such as growth, activation and differentiation.

[0003] The JAK / STAT signaling pathway mediates the signal transduction of most intracellular cytokines, and plays a key role in biological processes such as immune regulation and immune cell proliferation. The JAK / STAT signaling pathway is widely functional, and is involved in cell proliferation, differentiation, apoptosis, immune regulation and many other important biological processes. It is closely related to various inflammatory diseases such as rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease (ulcerative colitis and Crohn's disease), etc. At the same time, the JAK / STAT signaling pathway is closely related to tumor diseases such as myelofibrosis, polycythemia vera and essential thrombocythemia. Mutations in JAK molecules themselves can also cause acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), breast ductal carcinoma and non-small cell lung cancer (NSCLC) and other tumor diseases.

[0004] Inflammatory bowel disease is a chronic intestinal inflammatory disease, including ulcerative colitis (UC) and Crohn's disease (CD). The current treatment of inflammatory bowel disease drugs mainly include aminosalicylates, glucocorticoids, immunosuppressants, antibiotics, etc. The treatment of UC is mainly based on the principle of regulating immune response and inhibiting inflammation. In clinical practice, sulfasalazine is mainly used to treat mild to moderate UC. However, the commonly used drugs for moderate to severe UC include glucocorticoids, but due to the risk outweighing the benefits, they cannot be used as long-term treatment. Monoclonal antibodies have high costs, drug antibody production affects drug safety and effectiveness, and intravenous administration is not convenient, so there is still a great unmet medical need in this field. Many patients receiving treatment have not been relieved, and up to 80% of Crohn's disease patients and 30% of UC patients eventually need surgical treatment.

[0005] Tofacitinib (Xeljanz) is the first oral JAK inhibitor for the treatment of moderate to severe active UC in adult patients, which has significant inhibitory activity on JAK1, 2, and 3 subtypes, which increases the efficacy of tofacitinib, but also brings more serious side effects. Adverse reactions include infection, tuberculosis, tumor, anemia, liver damage, and increased cholesterol. There are many black box warnings on the package insert of tofacitinib: severe infections (pulmonary tuberculosis, bacteria, fungi, viruses) and malignant tumors (lymphoma, etc.). Due to the wide range of functions mediated by each JAK, these side effects are caused by the simultaneous inhibition of multiple JAKs. Because JAK is widely involved in the regulation of immune cells, JAK inhibitors inevitably cause immune suppression-related side effects, such as severe infections and even tumor occurrence. Even if there are many high-selectivity inhibitors under research, these side effects caused by the inhibition of target points are inevitable.

[0006] In view of the good efficacy of JAK inhibitors and the serious side effects related to multiple targets, it is urgent to develop a JAK inhibitor with higher safety. Since inflammatory bowel disease occurs on the surface of the intestinal cavity of the gastrointestinal tract, the drug does not need to enter the blood system to work, so developing a drug that reduces the systemic exposure of the drug in the blood circulation and increases the local exposure of the drug in the inflammatory site is a good strategy to improve safety. International application WO2016191524A1 reports that Theravance synthesized a series of compounds, which have very low systemic exposure and form enrichment in the inflammatory site of the intestine, which can effectively treat intestinal inflammation without causing serious side effects, indicating that this strategy has great feasibility and may have great clinical application value.

[0007] A series of structures of heteroaromatic derivative inhibitors are disclosed in PCT patent (application number: PCT / CN2019 / 121944), in the subsequent research and development, in order to facilitate the handling, filtration and drying of products, suitable crystals for easy storage, long-term stable products and high bioavailability are sought, the free base crystal form of the above-mentioned compound is comprehensively studied. SUMMARY

[0008] All the contents involved in the patent PCT / CN2019 / 121944 are added to the present application by reference.

[0009] The purpose of the present application is to provide a crystal form of a compound represented by general formula (I), the structure of which is shown as formula (I):

[0010]

[0011] Among them:

[0012] L1 is selected from a bond, -(CH2) r -, -(CH2) r S(O)2-, -S(O)2(CH2) r -, -(CH2) r S(O)2NR a -, -(CH2) r NR a -, -C(O)(CH2) r -, -C(O)(CH2) r NR a -, -C(O)(CH2) r NR a (CH2) s -, -(CH2) r C(O)- or -(CH2) r C(O)NR a -;

[0013] R a is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy;

[0014] R1 is selected from hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, optionally further substituted by cyano, halogen, C 1-6 alkyl, C 1-6alkyl, C 1-6 one or more substituents of the group consisting of hydrogen, cyano, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, phenyl or 5-6 membered nitrogen containing heteroaryl, optionally further substituted by cyano, halogen, C 1-3 alkyl, C 1-3 alkyl, C 1-3 one or more substituents of the group consisting of hydrogen, cyano, halogen, C

[0015] R2is selected from hydrogen or C 1-6 alkyl;

[0016] R3is selected from hydrogen, hydroxy, halogen, amino, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 alkyl monosubstituted amino, C 1-6 alkyl disubstituted amino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 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 monosubstituted amino, C 1-6 alkyl disubstituted amino, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, C 6-12 aryl or 5-10 membered heteroaryl, optionally further substituted by halogen, amino, cyano, C 1-3 alkyl, 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 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 amino, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl or 5-6 membered nitrogen containing heteroaryl, optionally further substituted by halogen, amino, cyano, C

[0017] R4is selected from hydrogen, C 1-6 alkyl, C 1-6 hydroxyalkyl or C 1-6 alkoxy;

[0018] Ring A is selected from aryl, five membered sulfur containing heterocyclyl, preferably phenyl,

[0019]

[0020] Ring B is selected from 5-10 membered nitrogen containing heterocyclyl, preferably

[0021] m is 1, 2 or 3;

[0022] r is 0, 1, 2 or 3;

[0023] s is 1, 2 or 3.

[0024] A preferred embodiment of the present application provides a crystalline form of a compound according to general formula (II)

[0025]

[0026] wherein n is 1 or 2.

[0027] A preferred embodiment of the present application provides that R1is selected from hydrogen, cyano, halogen, C 1-3 alkyl, phenyl,

[0028] optionally further substituted by one or more substituents selected from cyano, halogen, C 1-3 alkyl, C 1-3 alkoxy, phenyl,

[0029] A preferred embodiment of the present application provides that R3is selected from hydrogen, hydroxy, fluoro, chloro, bromo, amino, methylamino, ethylamino, dimethylamino, methyl, ethyl, hydroxymethyl, methoxy, ethoxy, phenyl, optionally further substituted by one or more substituents selected from halogen, amino, C 1-3 alkyl monosubstituted amino, C 1-3 alkyl disubstituted amino, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, phenyl,

[0030] A preferred embodiment of the present application provides that general formula (I) is selected from the following compounds:

[0031]

[0032]

[0033] ​

[0034]

[0035]

[0036]

[0037]

[0038] In a preferred embodiment of the present application, there is provided a crystalline form of l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)-2-(methylamino)-ethan-l-one (Compound III), the structure of which is as follows:

[0039]

[0040] In a further preferred embodiment of the present application, the crystalline Form A of Compound III has an X-ray powder diffraction pattern comprising a peak at 2Θ of 19.7 ± 0.2°; preferably, further comprising peaks at 2Θ of 7.0 ± 0.2° and 16.1 ± 0.2°; more preferably, further comprising peaks at 2Θ of 13.9 ± 0.2°, 16.6 ± 0.2°, 20.9 ± 0.2° and 22.8 ± 0.2°; further preferably, further comprising peaks at 2Θ of 10.5 ± 0.2°, 15.1 ± 0.2°, 19.3 ± 0.2°, 19.7 ± 0.2°, 20.4 ± 0.2°, 24.0 ± 0.2°, 24.5 ± 0.2° and 29.2 ± 0.2°;

[0041] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in terms of 2Θ angle and interplanar spacing d value, are shown in Table 1.

[0042] Table 1

[0043]

[0044]

[0045] The crystalline Form A of Compound III of the present application has an X-ray powder diffraction pattern substantially as shown in Figure 1

[0046] ​In a further preferred embodiment of the present application, the crystal form B of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ and interplanar spacings d values as shown in Table 2.

[0047] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar spacings d values using Cu-Kα radiation are shown in Table 2.

[0048] Table 2

[0049]

[0050]

[0051] The crystal form B of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 2. Figure 2

[0052] In a further preferred embodiment of the present application, the crystal form C of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ and interplanar spacings d values as shown in Table 3.

[0053] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar spacings d values using Cu-Kα radiation are shown in Table 3.

[0054] Table 3

[0055]

[0056]

[0057] ​The crystal form C of the compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 3 ; a DSC pattern substantially as shown in Figure 4 ; and a TGA pattern substantially as shown in Figure 5 .

[0058] In a further preferred embodiment of the present application, the crystal form D of the compound III has an X-ray powder diffraction pattern having a characteristic peak at 2-theta of 23.3 ± 0.2°; preferably, further comprising a characteristic peak at 2-theta of 16.1 ± 0.2° and 17.6 ± 0.2°; more preferably, further comprising a characteristic peak at 2-theta of 7.4 ± 0.2°, 20.4 ± 0.2°, 22.0 ± 0.2° and 22.4 ± 0.2°; further preferably, further comprising a characteristic peak at 2-theta of 11.6 ± 0.2°, 11.8 ± 0.2°, 14.4 ± 0.2°, 16.6 ± 0.2°, 18.8 ± 0.2°, 19.6 ± 0.2°, 23.8 ± 0.2° and 28.9 ± 0.2°; more preferably, further comprising a characteristic peak at 2-theta of 8.7 ± 0.2°, 9.2 ± 0.2°, 10.9 ± 0.2°, 13.6 ± 0.2°, 15.0 ± 0.2°, 15.3 ± 0.2°, 18.0 ± 0.2°, 18.4 ± 0.2°, 20.0 ± 0.2°, 20.8 ± 0.2°, 24.9 ± 0.2°, 27.6 ± 0.2° and 28.1 ± 0.2°.

[0059] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in 2-theta angle and interplanar spacing d value, are shown in Table 4.

[0060] Table 4

[0061]

[0062]

[0063] The crystal form D of the compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 6 ; a DSC pattern substantially as shown in Figure 7 ; and a TGA pattern substantially as shown in Figure 8 .

[0064] In a further preferred embodiment of the present application, the crystalline Form E of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ at 7.3 ± 0.2°; preferably, further comprising characteristic peaks expressed in angles 2Θ at 20.5 ± 0.2° and 21.7 ± 0.2°; more preferably, further comprising characteristic peaks expressed in angles 2Θ at 8.5 ± 0.2°, 17.2 ± 0.2°, 22.1 ± 0.2° and 22.8 ± 0.2°; even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 10.8 ± 0.2°, 11.6 ± 0.2°, 14.4 ± 0.2°, 16.2 ± 0.2°, 16.5 ± 0.2°, 17.7 ± 0.2°, 23.8 ± 0.2° and 28.3 ± 0.2°; even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 27.7 ± 0.2° and 29.4 ± 0.2°.

[0065] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar distances d, using Cu-Kα radiation, are shown in Table 5.

[0066] Table 5

[0067]

[0068]

[0069] The crystalline Form E of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 9 ; a DSC pattern substantially as shown in Figure 10 ; and a TGA pattern substantially as shown in Figure 11 .

[0070] In a further preferred embodiment of the present application, the crystalline Form F of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ at 22.9 ± 0.2°; preferably, further comprising characteristic peaks expressed in angles 2Θ at 12.3 ± 0.2° and 20.2 ± 0.2°; more preferably, further comprising characteristic peaks expressed in angles 2Θ at 12.6 ± 0.2°, 14.6 ± 0.2°, 18.4 ± 0.2° and 24.6 ± 0.2°; even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 8.1 ± 0.2°, 16.1 ± 0.2°, 16.6 ± 0.2°, 17.8 ± 0.2°, 22.0 ± 0.2°, 23.1 ± 0.2°, 29.5 ± 0.2° and 30.2 ± 0.2°;

[0071] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar distances d, using Cu-Kα radiation, are shown in Table 6.

[0072] Table 6

[0073]

[0074]

[0075] The crystal form F of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 12 The DSC pattern of the crystal form F of compound III according to the present application is substantially as shown in Figure 13 The TGA pattern of the crystal form F of compound III according to the present application is substantially as shown in Figure 14

[0076] In a further preferred embodiment of the present application, the crystal form G of compound III has an X-ray powder diffraction pattern having a characteristic peak at 2-theta of 19.6 ± 0.2°; preferably, further comprising characteristic peaks at 2-theta of 15.4 ± 0.2° and 19.0 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta of 6.9 ± 0.2°, 7.7 ± 0.2°, 11.0 ± 0.2° and 22.7 ± 0.2°; further preferably, further comprising characteristic peaks at 2-theta of 13.6 ± 0.2°, 13.8 ± 0.2°, 16.0 ± 0.2°, 17.6 ± 0.2°, 18.1 ± 0.2°, 20.7 ± 0.2°, 21.3 ± 0.2° and 27.3 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta of 8.7 ± 0.2°, 10.4 ± 0.2°, 13.1 ± 0.2°, 14.9 ± 0.2°, 20.3 ± 0.2°, 22.4 ± 0.2°, 23.5 ± 0.2°, 25.5 ± 0.2° and 27.8 ± 0.2°.

[0077] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in 2-theta angle and interplanar spacing d value, are shown in Table 7.

[0078] Table 7

[0079]

[0080]

[0081] The crystal form G of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 15

[0082] ​​In a further preferred embodiment of the present application, the crystalline Form H of compound III has an X-ray powder diffraction pattern comprising a peak at 7.2 ± 0.2° 2Θ; preferably further comprising peaks at 16.0 ± 0.2° and 20.8 ± 0.2° 2Θ; more preferably further comprising peaks at 16.4 ± 0.2°, 17.6 ± 0.2°, 19.7 ± 0.2° and 21.9 ± 0.2° 2Θ; even more preferably further comprising peaks at 8.3 ± 0.2°, 11.7 ± 0.2°, 14.6 ± 0.2°, 15.2 ± 0.2°, 19.1 ± 0.2°, 20.3 ± 0.2°, 23.6 ± 0.2° and 27.3 ± 0.2° 2Θ; even more preferably further comprising peaks at 9.2 ± 0.2°, 13.3 ± 0.2°, 18.4 ± 0.2° and 22.7 ± 0.2° 2Θ.

[0083] The X-ray characteristic diffraction peaks expressed in terms of 2Θ angle and interplanar spacing d value using Cu-Ka radiation are shown in Table 8.

[0084] Table 8

[0085]

[0086]

[0087]

[0088] The crystalline Form H of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 16 ; a DSC pattern substantially as shown in Figure 17 ; and a TGA pattern substantially as shown in Figure 18 .

[0089] In a further preferred embodiment of the present application, the crystalline Form I of compound III has an X-ray powder diffraction pattern comprising a peak at 6.8 ± 0.2° 2Θ; preferably further comprising peaks at 13.7 ± 0.2° and 18.6 ± 0.2° 2Θ; more preferably further comprising peaks at 15.1 ± 0.2°, 15.5 ± 0.2°, 20.5 ± 0.2° and 20.7 ± 0.2° 2Θ; even more preferably further comprising peaks at 8.2 ± 0.2°, 11.8 ± 0.2°, 17.7 ± 0.2°, 20.2 ± 0.2°, 22.4 ± 0.2°, 23.1 ± 0.2°, 23.5 ± 0.2° and 27.0 ± 0.2° 2Θ;

[0090] The X-ray characteristic diffraction peaks expressed in terms of 2Θ angle and interplanar spacing d value using Cu-Ka radiation are shown in Table 9.

[0091] Table 9

[0092]

[0093]

[0094] The crystal form I of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 19 ; a DSC pattern substantially as shown in Figure 20 ; and a TGA pattern substantially as shown in Figure 21 .

[0095] In a further preferred embodiment of the present application, the crystal form J of compound III has an X-ray powder diffraction pattern having a characteristic peak at 2Θ of 20.5±0.2°; preferably, further comprising characteristic peaks at 2Θ of 18.7±0.2° and 20.2±0.2°; more preferably, further comprising characteristic peaks at 2Θ of 6.8±0.2°, 12.2±0.2°, 12.6±0.2° and 22.8±0.2°; further preferably, further comprising characteristic peaks at 2Θ of 14.5±0.2°, 15.5±0.2°, 16.0±0.2°, 16.5±0.2°, 18.4±0.2°, 21.9±0.2°, 23.1±0.2° and 24.6±0.2°; more further preferably, further comprising characteristic peaks at 2Θ of 13.7±0.2°, 15.1±0.2°, 22.5±0.2° and 30.1±0.2°.

[0096] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in 2Θ angle and interplanar spacing d value, are shown in Table 10.

[0097] Table 10

[0098]

[0099]

[0100]

[0101] The crystal form J of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 22 ; a DSC pattern substantially as shown in Figure 23 ; and a TGA pattern substantially as shown in Figure 24 .

[0102] In a further preferred embodiment of the present application, the crystalline Form K of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ at 19.5 ± 0.2°; preferably, further comprising characteristic peaks expressed in angles 2Θ at 6.7 ± 0.2° and 15.9 ± 0.2°; more preferably, further comprising characteristic peaks expressed in angles 2Θ at 10.3 ± 0.2°, 13.7 ± 0.2°, 16.3 ± 0.2° and 22.5 ± 0.2°; even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 10.0 ± 0.2°, 12.2 ± 0.2°, 14.9 ± 0.2°, 19.1 ± 0.2°, 20.2 ± 0.2°, 20.7 ± 0.2°, 23.7 ± 0.2°, 26.2 ± 0.2° and 29.0 ± 0.2°.

[0103] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar distances d using Cu-Kα radiation are shown in Table 11.

[0104] Table 11

[0105]

[0106]

[0107] The crystalline Form K of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 1. Figure 25

[0108] In a further preferred embodiment of the present application, the crystalline Form L of compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2Θ at 7.2 ± 0.2°; preferably, further comprising characteristic peaks expressed in angles 2Θ at 21.3 ± 0.2° and 22.5 ± 0.2°; more preferably, further comprising characteristic peaks expressed in angles 2Θ at 16.0 ± 0.2°, 21.9 ± 0.2°, 22.2 ± 0.2° and 27.3 ± 0.2°; even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 8.4 ± 0.2°, 16.9 ± 0.2°, 17.5 ± 0.2°, 19.5 ± 0.2°, 20.3 ± 0.2°, 23.6 ± 0.2°, 24.1 ± 0.2° and 27.9 ± 0.2°; and even more preferably, further comprising characteristic peaks expressed in angles 2Θ at 11.6 ± 0.2°, 14.5 ± 0.2°, 15.6 ± 0.2°, 16.4 ± 0.2°, 20.1 ± 0.2° and 30.4 ± 0.2°.

[0109] The X-ray characteristic diffraction peaks expressed in angles 2Θ and interplanar distances d using Cu-Kα radiation are shown in Table 12.

[0110] Table 12

[0111] ​

[0112]

[0113] The crystal form L of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 26 ; a DSC pattern substantially as shown in Figure 27 ; and a TGA pattern substantially as shown in Figure 28 .

[0114] In a further preferred embodiment of the present application, the crystal form M of compound III has an X-ray powder diffraction pattern having a characteristic peak at 2-theta 18.6 ± 0.2°; preferably, further comprising characteristic peaks at 2-theta 15.7 ± 0.2° and 25.1 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta 21.7 ± 0.2°, 23.4 ± 0.2°, 24.0 ± 0.2° and 28.1 ± 0.2°; further preferably, further comprising characteristic peaks at 2-theta 10.5 ± 0.2°, 12.9 ± 0.2°, 14.2 ± 0.2°, 16.0 ± 0.2°, 16.8 ± 0.2°, 17.4 ± 0.2°, 19.6 ± 0.2° and 22.3 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta 9.3 ± 0.2°, 21.2 ± 0.2°, 22.8 ± 0.2°, 29.4 ± 0.2° and 32.2 ± 0.2°.

[0115] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in 2-theta angle and interplanar spacing d value, are shown in Table 13.

[0116] Table 13

[0117]

[0118]

[0119]

[0120] The crystal form M of compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 29 ; a DSC pattern substantially as shown in Figure 30 ; and a TGA pattern substantially as shown in Figure 31 .

[0121] In a further preferred embodiment of the present application, the crystalline Form N of the compound III has an X-ray powder diffraction pattern with a characteristic peak at 2-theta = 19.1 ± 0.2°; preferably, further comprising characteristic peaks at 2-theta = 15.4 ± 0.2° and 19.7 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta = 7.6 ± 0.2°, 10.9 ± 0.2°, 21.0 ± 0.2° and 21.3 ± 0.2°; further preferably, further comprising characteristic peaks at 2-theta = 13.5 ± 0.2°, 18.0 ± 0.2°, 18.8 ± 0.2°, 22.6 ± 0.2°, 25.4 ± 0.2°, 26.2 ± 0.2° and 27.3 ± 0.2°;

[0122] The X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d value using Cu-Ka radiation are shown in Table 14.

[0123] Table 14

[0124]

[0125]

[0126] The crystalline Form N of the compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 32

[0127] In a further preferred embodiment of the present application, the crystalline Form O of the compound III has an X-ray powder diffraction pattern with a characteristic peak at 2-theta = 23.8 ± 0.2°; preferably, further comprising characteristic peaks at 2-theta = 12.7 ± 0.2° and 17.9 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta = 14.4 ± 0.2°, 17.6 ± 0.2°, 21.0 ± 0.2° and 24.7 ± 0.2°; further preferably, further comprising characteristic peaks at 2-theta = 8.4 ± 0.2°, 13.0 ± 0.2°, 19.6 ± 0.2°, 20.7 ± 0.2°, 22.7 ± 0.2°, 26.6 ± 0.2°, 28.7 ± 0.2° and 30.9 ± 0.2°; further more preferably, further comprising characteristic peaks at 2-theta = 6.7 ± 0.2°, 12.0 ± 0.2°, 14.8 ± 0.2°, 15.8 ± 0.2°, 16.5 ± 0.2°, 19.0 ± 0.2° and 23.0 ± 0.2°.

[0128] The X-ray characteristic diffraction peaks expressed in terms of 2-theta angle and interplanar spacing d value using Cu-Ka radiation are shown in Table 15.

[0129] Table 15

[0130] ​

[0131]

[0132] The crystal form O of the compound III according to the present application has an X-ray powder diffraction pattern as substantially shown in Figure 33 ; a DSC pattern as substantially shown in Figure 34 ; and a TGA pattern as substantially shown in Figure 35 .

[0133] In a further preferred embodiment of the present application, the crystal form P of the compound III has an X-ray powder diffraction pattern comprising a characteristic peak at 2-theta 23.2 ± 0.2°; preferably, further comprising characteristic peaks at 2-theta 14.9 ± 0.2° and 16.5 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta 8.3 ± 0.2°, 13.4 ± 0.2°, 19.2 ± 0.2° and 20.2 ± 0.2°; further preferably, further comprising characteristic peaks at 2-theta 7.8 ± 0.2°, 9.3 ± 0.2°, 11.6 ± 0.2°, 12.6 ± 0.2°, 16.0 ± 0.2°, 18.5 ± 0.2°, 19.6 ± 0.2° and 27.4 ± 0.2°; more preferably, further comprising characteristic peaks at 2-theta 15.3 ± 0.2° and 22.1 ± 0.2°.

[0134] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in 2-theta angle and interplanar spacing d value, are shown in Table 16.

[0135] Table 16

[0136]

[0137]

[0138]

[0139] The crystal form P of the compound III according to the present application has an X-ray powder diffraction pattern as substantially shown in Figure 36 ; a DSC pattern as substantially shown in Figure 37 ; and a TGA pattern as substantially shown in Figure 38 .

[0140] In a further preferred embodiment of the present application, the crystal form Q of the compound III has an X-ray powder diffraction pattern comprising characteristic peaks expressed in angles 2θ at 16.4 ± 0.2°; preferably, further comprising characteristic peaks at 13.5 ± 0.2° and 20.0 ± 0.2°; more preferably, further comprising characteristic peaks at 9.1 ± 0.2°, 14.7 ± 0.2°, 15.9 ± 0.2° and 27.9 ± 0.2°; further preferably, further comprising characteristic peaks at 7.7 ± 0.2°, 11.7 ± 0.2°, 11.9 ± 0.2°, 18.4 ± 0.2°, 19.5 ± 0.2°, 22.3 ± 0.2°, 26.4 ± 0.2° and 27.3 ± 0.2°.

[0141] The X-ray characteristic diffraction peaks using Cu-Ka radiation, expressed in angles 2θ and interplanar distances d, are shown in Table 17.

[0142] Table 17

[0143]

[0144]

[0145] The crystal form Q of the compound III according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 39 ; a DSC pattern substantially as shown in Figure 40 ; and a TGA pattern substantially as shown in Figure 41 .

[0146] The present application provides a 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)propanenitrile (Compound IV), whose structure is as follows:

[0147]

[0148] its X-ray powder diffraction pattern has a diffraction peak at 8.2 ± 0.2° in terms of 2 theta (± 0.2°); preferably, further comprising diffraction peaks at 9.7 ± 0.2° and 20.4 ± 0.2° in terms of 2 theta (± 0.2°); more preferably, further comprising diffraction peaks at 13.5 ± 0.2°, 17.4 ± 0.2°, 21.1 ± 0.2° and 26.6 ± 0.2° in terms of 2 theta (± 0.2°); further preferably, further comprising diffraction peaks at 16.5 ± 0.2°, 16.8 ± 0.2°, 14.1 ± 0.2°, 19.1 ± 0.2°, 19.4 ± 0.2°, 22.8 ± 0.2°, 27.1 ± 0.2° and 28.5 ± 0.2° in terms of 2 theta (± 0.2°); further more preferably, further comprising diffraction peaks at 9.4 ± 0.2°, 19.8 ± 0.2° and 23.6 ± 0.2° in terms of 2 theta (± 0.2°);

[0149] X-ray characteristic diffraction peaks expressed in terms of 2 theta angle and interplanar spacing d value using Cu-Ka radiation are shown in Table 18.

[0150] Table 18

[0151]

[0152]

[0153] The 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)propanenitrile according to the present application has an X-ray powder diffraction pattern substantially as shown in Figure 42 a DSC pattern substantially as shown in Figure 43 and a TGA pattern substantially as shown in Figure 44.

[0154] In a further preferred embodiment of the present application, the above-mentioned crystal form is a solvated crystal form, wherein the solvent is selected from the group consisting of water, methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, t-butyl alcohol, 2-butanone, 3-pentanone, n-heptane, ethyl formate, isopropyl acetate, cyclohexane, methyl t-butyl ether or isopropyl ether.

[0155] In a further preferred embodiment of the present application, the number of solvents is 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.

[0156] The present application also provides a method for preparing the crystal form of the compound shown in general formula (I), which specifically comprises the following steps:

[0157] 1) an appropriate amount of the compound is weighed and suspended in a poor solvent, and the suspension density is preferably 50-200 mg / mL;

[0158] 2) the obtained suspension is shaken at a certain temperature for a certain time, and the temperature is preferably 0-50°C and the time is preferably 1-10 days;

[0159] 3) the above suspension is quickly centrifuged, the supernatant is removed, and the target product is obtained by drying to constant weight;

[0160] wherein:

[0161] The poor solvent is selected from one or more of acetone, ethyl formate, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, ethyl formate, isopropyl acetate, tert-butyl alcohol, 2-butanone or 3-pentanone; preferably one or more of ethyl acetate, tetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dichloromethane, isopropyl acetate or isopropyl alcohol.

[0162] The present application also provides a method for preparing the crystal form of the compound shown in general formula (I), which specifically comprises the following steps:

[0163] 1) an appropriate amount of the compound is weighed and dissolved in a good solvent;

[0164] 2) an anti-solvent is added to the obtained solution at a certain temperature, and the solution is stirred until the solid precipitates, and the temperature is preferably 0-25°C;

[0165] 3) the above suspension is quickly centrifuged, the supernatant is removed, and the target product is obtained by drying to constant weight;

[0166] wherein:

[0167] The good solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 88% acetone, 2-methyl-tetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropyl alcohol, n-butanol, isobutyl alcohol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, tert-butyl alcohol, 2-butanone or 3-pentanone; preferably one or two of methanol, dimethyl sulfoxide or isobutyl alcohol.

[0168] The poor solvent is selected from one or more of dichloromethane, toluene, ethyl formate, ethyl acetate, 2-methyl-tetrahydrofuran, ethanol, n-heptane, 1,4-dioxane, water, isopropyl acetate, cyclohexane, methyl-tert-butyl ether, toluene, isopropyl ether; preferably one or more of water, n-heptane, cyclohexane and methyl-tert-butyl ether.

[0169] It is another object of the present application to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of the compound described above, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0170] The present application also relates to the use of any of the crystalline forms of the compounds described above or the pharmaceutical composition described above for the preparation of a medicament for the prevention and / or treatment of a disease associated with JAK kinases, preferably an inflammatory disease and / or a tumor disease.

[0171] The present application further relates to the use for the preparation of a medicament for the prevention and / or treatment of a disease associated with JAK kinases, wherein the inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, inflammatory bowel disease; wherein the inflammatory bowel disease is preferably a chronic intestinal inflammatory disease, further preferably ulcerative colitis and Crohn's disease;

[0172] The tumor disease is selected from myelofibrosis, polycythemia vera and essential thrombocythemia, myelocytic leukemia, acute lymphocytic leukemia, breast ductal carcinoma and non-small cell lung cancer. BRIEF DESCRIPTION OF DRAWINGS

[0173] Figure 1 XRPD pattern of Compound III free base Form A is shown.

[0174] Figure 2 XRPD pattern of Compound III free base Form B is shown.

[0175] Figure 3-5 XRPD, DSC, TGA pattern of Compound III free base Form C is shown.

[0176] Figure 6-8 XRPD, DSC, TGA pattern of Compound III free base Form D is shown.

[0177] Figure 9-11 XRPD, DSC, TGA pattern of Compound III free base Form E is shown.

[0178] Figure 12-14 XRPD, DSC, TGA pattern of Compound III free base Form F is shown.

[0179] Figure 15XRPD pattern for Compound III free base Form G.

[0180] Figure 16-18 XRPD, DSC, TGA patterns for Compound III free base Form H.

[0181] Figure 19-21 XRPD, DSC, TGA patterns for Compound III free base Form I.

[0182] Figure 22-24 XRPD, DSC, TGA patterns for Compound III free base Form J.

[0183] Figure 25 XRPD pattern for Compound III free base Form K.

[0184] Figure 26-28 XRPD, DSC, TGA patterns for Compound III free base Form L.

[0185] Figure 29-31 XRPD, DSC, TGA patterns for Compound III free base Form M.

[0186] Figure 32 XRPD pattern for Compound III free base Form N.

[0187] Figure 33-35 XRPD, DSC, TGA patterns for Compound III free base Form O.

[0188] Figure 36-38 XRPD, DSC, TGA patterns for Compound III free base Form P.

[0189] Figure 39-41 XRPD, DSC, TGA patterns for Compound III free base Form Q.

[0190] Figure 42-44 XRPD, DSC, TGA patterns for Compound IV free base Form A. DETAILED DESCRIPTION

[0191] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0192] The term "alkyl" refers to saturated aliphatic hydrocarbon groups which are straight-chain or branched-chain groups containing 1 to 20 carbon atoms, preferably alkyl groups containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment, and are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate, and are preferably methyl, ethyl, i-propyl, t-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, hydroxyl-substituted alkyl, and cyano-substituted alkyl.

[0193] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl. The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. The cycloalkyl group may be optionally substituted or unsubstituted. 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, carboxyl or carboxylate.

[0194] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; and most preferably, it contains 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably oxetanyl, pyrrolidonyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused, and bridged heterocyclic groups; wherein the spirocyclic, fused, and bridged heterocyclic groups are optionally connected to other groups by single bonds, or further connected to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate.

[0195] The term "aryl" means a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring system having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring which is attached to the parent structure is the aryl ring. The aryl group can be substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0196] The term "heteroaryl" means a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furanyl, 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 preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, pyridyl, thiazolyl, and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring which is attached to the parent structure is the heteroaryl ring. The heteroaryl group can be optionally substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0197] The term "alkoxy" means -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Preferably, the alkyl group contains 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 3 carbon atoms. Non-limiting examples of alkyl groups include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy. The alkyl group can be optionally substituted or unsubstituted, and when substituted, the substituent(s) are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0198] "Haloalkyl" means an alkyl group as defined above substituted with one or more halogens.

[0199] "Haloalkoxy" means an alkoxy group, as defined above, substituted with one or more halogens.

[0200] "Haloalkyl" means an alkyl group, as defined above, substituted with one or more halogens.

[0201] "Alkenyl" means an alkenyl group, also called an alkene group, wherein the alkenyl group can be further substituted with other relevant groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate.

[0202] "Hydroxyl" means an -OH group.

[0203] "Halogen" means fluorine, chlorine, bromine, or iodine.

[0204] "Amino" means -NH2.

[0205] "Cyano" means -CN.

[0206] "Nitro" means -NO2.

[0207] "THF" means tetrahydrofuran.

[0208] "EtOAc" means ethyl acetate.

[0209] "DMSO" means dimethyl sulfoxide.

[0210] "LDA" means lithium diisopropylamide.

[0211] "DMAP" means 4-dimethylaminopyridine.

[0212] "EtMgBr" means ethylmagnesium bromide.

[0213] "HOSu" means N-hydroxysuccinimide.

[0214] "EDCl" means l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0215] "IPA" means isopropyl alcohol.

[0216] "MeOH" means methanol.

[0217] "EtOH" means ethanol.

[0218] "DMF" means N,N-dimethylformamide.

[0219] "DIPEA" means N,N-diisopropylethylamine.

[0220] "HEPES" means 4-(2-hydroxyethyl)piperazineethanesulfonic acid.

[0221] The phrases "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 are used interchangeably and have the same meaning, i.e., X can be any one of A, B, or C, or any combination thereof.

[0222] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0223] "Substituted" means that one or more hydrogen atoms, preferably up to five, more preferably one to three, of the group are independently of each other replaced with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0224] "Stereoisomeric" includes geometric isomers (cis-trans isomers), optical isomers, and conformational isomers.

[0225] The hydrogen atoms described in the present application can be replaced by its isotope deuterium, and any hydrogen atom in the compounds of the embodiments described in the present application can be replaced by deuterium.

[0226] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, to facilitate absorption of the active ingredient into the organism, and to facilitate the biological activity of the active ingredient.

[0227] X-ray powder diffraction pattern (XRPD) refers to the experimentally observed diffraction pattern or parameters derived therefrom, which is characterized by peak position (abscissa) and peak intensity (ordinate). Those skilled in the art will appreciate that experimental error is dependent on the conditions of the instrument, the preparation of the sample and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray diffraction patterns will vary with the conditions of the instrument and those skilled in the art will appreciate that suitable error limits for XRPD can be: 2Θ ± 0.5°; 2Θ ± 0.4°; 2Θ ± 0.3°; 2Θ ± 0.2°. It is particularly important to note that the relative intensities of the X-ray diffraction pattern can also vary with experimental conditions and therefore the order of peak intensities cannot be used as a sole or determining factor. In addition, due to experimental factors such as sample height, a general shift in peak angle can occur and some shift is generally allowed. Thus, those skilled in the art will appreciate that any crystalline form having the same or similar characteristic peaks as the patterns of the present application are within the scope of the present application.

[0228] "TGA" refers to a thermal gravimetric analysis (TGA) experiment.

[0229] "DSC" refers to a differential scanning calorimetry (DSC) experiment.

[0230] "HPLC" refers to a high performance liquid chromatography (HPLC) experiment.

[0231] "PK" refers to a pharmacokinetic (PK) experiment.

[0232] The application is further described in connection with the following examples which do not limit the scope of the application.

[0233] I. Preparation of Compounds

[0234] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements are made on a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0235] Liquid chromatography-mass spectrometry (LC-MS) measurements are made on an Agilent 1200 Infinity Series Mass Spectrometer. HPLC measurements are made using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18150 x 4.6 mm column).

[0236] Thin layer chromatography silica gel plates were used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, TLC used specifications are 0.15 mm to 0.20 mm, thin layer chromatography separation and purification of products used specifications are 0.4 mm to 0.5 mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as a carrier.

[0237] The starting materials in the examples of the present application are known and commercially available, or can be synthesized using or according to methods known in the art.

[0238] Unless otherwise specified, all reactions of the present application were carried out under continuous magnetic stirring, under a dry nitrogen or argon atmosphere, with dry solvents, and the reaction temperature unit is Celsius.

[0239] Example 1

[0240] 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)propanenitrile

[0241]

[0242] First step: preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4- amine

[0243]

[0244] To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidine (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol) were added successively, then heated and stirred at 70 °C for 1 hour. After the reaction was completed, water (50 mL) was added to the reaction solution, and the precipitated solid was filtered and treated with ethyl acetate to obtain the title compound as a light yellow solid (135 mg, 51%).

[0245] MS m / z (ESI): 266.0 [M+H] + .

[0246] Second step: preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0247]

[0248] To a solution of 2-chloro-N-(5-methyl-lH-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4- amine (135 mg, 0.51 mmol) in n-butanol (5 mL), was added tert-butyl-(3-exo)-3-amino-8- azabicyclo[3.2.1]octane-8-carboxylate (138 mg, 0.61 mmol), DIPEA (129 mg, 1 mmol) sequentially, then stirred under microwave condition at 160 °C for 15 hours. The reaction was extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride solution (15 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a light yellow solid (146 mg, 63%).

[0249] MS m / z (ESI): 456.2 [M+H] + .

[0250] Third Step: Preparation of 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0251]

[0252] Tert-butyl-(3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (146 mg, 0.32 mmol) was dissolved in 1,4-oxane solution of hydrochloric acid (4.0 N, 5 mL), stirred at room temperature for 30 minutes, then the reaction was concentrated; then methanol (10 mL) was added to dissolve it, DIPEA (166 mg, 1.28 mmol) was added dropwise slowly, stirred at room temperature for 10 minutes, then acrylonitrile (25 mg, 0.48 mmol) was added and stirred for another 2 hours. The reaction was concentrated under reduced pressure, the resulting product was purified by prep-HPLC to give the title compound as a white solid (14.4 mg, 11%).

[0253] 1H NMR (400 MHz, DMSO) δ 12.02 (s, 1H), 9.70 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.44 (d, J = 59.6 Hz, 2H), 4.14 (s, 1H), 3.29 (s, 2H), 2.62 (s, 4H), 2.22 (s, 3H), 1.89 (s, 2H), 1.64 (dd, J = 47.8, 17.6 Hz, 6H).

[0254] MS m / z (ESI): 409.2 [M+H] + .

[0255] Example 2

[0256] 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)propanenitrile

[0257]

[0258] 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)propanenitrile was prepared according to Example 1.

[0259] MS m / z (ESI): 423.2 [M+H] + .

[0260] Example 3

[0261] 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)propanenitrile

[0262]

[0263] First Step: Preparation of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3- d]pyrimidin-4-amine

[0264]

[0265] To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (205 mg, 1 mmol) in N-methylpyrrolidine (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol) were added successively, then heated at 70 °C for 1 h. The reaction was completed by adding water (50 mL) to the reaction mixture, and a solid was precipitated. The solid was filtered and washed with ethyl acetate to give the title compound as a yellow solid (250 mg, 94%).

[0266] MS m / z (ESI): 266.0 [M+H] + .

[0267] Second Step: Preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0268]

[0269] To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (256 mg, 1.13 mmol), DIPEA (242 mg, 1.88 mmol) were added successively, then stirred at 160 °C for 15 h under microwave condition. The reaction was completed by extracting the reaction mixture with ethyl acetate (15 mL x 3), washing with saturated aqueous sodium chloride solution (15 mL x 3), collecting the organic phase, drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure. The resulting product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a yellowish solid (200 mg, 47%).

[0270] MS m / z (ESI): 456.1 [M+H] + .

[0271] Third Step: Preparation of 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)propanenitrile

[0272]

[0273] tert-Butyl-(3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.44 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL), and the reaction was stirred at room temperature for 30 minutes, then concentrated. Then methanol (10 mL) was added to dissolve it, and DIPEA (227 mg, 1.76 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 10 minutes. After the addition of acrylonitrile (35 mg, 0.66 mmol), the reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (31.6 mg, 18%).

[0274] 1 H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 9.93 (s, 1H), 7.73 (s, 1H), 6.88 (d, J = 117.2 Hz, 3H), 4.27 (s, 1H), 3.37 (s, 2H), 2.70 (s, 4H), 2.32 (s, 3H), 1.99 (s, 2H), 1.86 - 1.61 (m, 6H).

[0275] MS m / z (ESI): 409.2 [M+H] + .

[0276] Example 4

[0277] 3-((3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[4,5-d]pyrimidin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0278]

[0279] 3-((3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[4,5-d]pyrimidin-5-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 1.

[0280] MS m / z (ESI): 410.2 [M+H] + .

[0281] Example 5

[0282] 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)propanenitrile

[0283]

[0284] First Step: Preparation of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4- d]pyrimidin-7-amine

[0285]

[0286] To a solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol) were added successively, then heated at 70 °C with stirring for 1 hour. The reaction was completed by adding water (50 mL) to the reaction solution, and a solid was precipitated. The solid was filtered and treated with ethyl acetate to obtain the title compound as a yellow solid (200 mg, 75%).

[0287] MS m / z (ESI): 267.0 [M+H] + .

[0288] Second Step: Preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0289]

[0290] To a solution of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.75 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (204 mg, 0.9 mmol), DIPEA (193 mg, 1.5 mmol) were added successively, then stirred at 160 °C under microwave conditions for 15 hours. The reaction was completed by extracting the reaction solution with ethyl acetate (15 mL x 3), washing with saturated aqueous sodium chloride solution (15 mL x 3), collecting the organic phase, drying with anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure. The resulting product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain the title compound as a light yellow solid (74 mg, 22%).

[0291] MS m / z (ESI): 457.1 [M+H] + .

[0292] Third Step: Preparation of 3-((3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thiazolo[5,4- d]pyrimidin-5-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0293]

[0294] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (74 mg, 0.16 mmol) was dissolved in a solution of hydrochloric acid 1,4-epoxyhexane (4.0 N, 2 mL) and stirred at room temperature for 30 minutes, then concentrated. It was then dissolved in methanol (10 mL) and DIPEA (83 mg, 0.64 mmol) was added slowly dropwise. After stirring at room temperature for 10 minutes, acrylonitrile (9 mg, 0.24 mmol) was added and stirring was 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 (16.3 mg, 25%).

[0295] 1 H NMR (400 MHz, DMSO) δ 12.07 (s, 1H), 9.33 (s, 1H), 8.76 (d, J = 20.4 Hz, 1H), 6.96 (s, 1H), 6.55 (d, J = 12.0 Hz, 1H), 4.14 (s, 1H), 3.31 (s, 2H), 2.61 (s, 4H), 2.21 (s, 3H), 1.91 (s, 2H), 1.78 - 1.54 (m, 6H).

[0296] Example 6

[0297] 1-(((3-exo)-3-((4-((5-(hydroxymethyl)-lH-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

[0298]

[0299] First Step: Preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-lH-pyrazol-5- yl)methanol

[0300]

[0301] To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-lH-pyrazol-5-yl)methanol (55 mg, 0.49 mmol), DIPEA (190 mg, 1.47 mmol) in N,N-dimethylformamide (2 mL) was stirred at 70 °C overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give the title compound as a yellow solid (100 mg, 73%).

[0302] MS m / z (ESI): 282.0 [M+H] + .

[0303] Second Step: Preparation of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0304]

[0305] To a solution of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-lH-pyrazol-5-yl)methanol (100 mg, 0.36 mmol), tert-butyl (3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (135 mg, 0.53 mmol), DIPEA (140 mg, 1.08 mmol) in n-butanol (2.5 mL) was stirred at 150 °C for 10 h in a microwave. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the title compound as a white solid (70 mg, 39%).

[0306] MS m / z (ESI): 500.1 [M+H] + .

[0307] Third Step: Preparation of l-(((3-exo)-3-((4-((5-(hydroxymethyl)-lH-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

[0308]

[0309] To a solution of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (70 mg, 0.14 mmol) in methanol (10 mL) was added hydrochloric acid dioxane (4 N, 2.5 mL) slowly dropwise, and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the crude product was dissolved in DMF (5 mL). DIPEA (0.3 mL) and 3-cyanooxetane-1-sulfonyl chloride (22 mg, 0.12 mmol) were added sequentially at 0 °C. The reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure, and the product was purified by prep-HPLC to give the title compound as a white solid (9.7 mg, 13%).

[0310] 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 7.68 (d, J = 4.4 Hz, 1H), 7.04 (d, J = 6.0 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H), 5.33-5.35 (m, 1H), 4.44 (d, J = 5.2 Hz, 2H), 4.05-4.01 (m, 4H), 3.94-3.90 (m, 2H), 382-3.79 (m, 1H), 2.89 (d, J = 8.4 Hz, 3H), 2.08-1.68 (m, 11H).

[0311] MS m / z (ESI): 544.1 [M+H] + .

[0312] Example 7

[0313] 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonanyl)sulfonyl)azetidine-3-carbonitrile

[0314]

[0315] 1-(((3-exo)-3-((7-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[5,4-d]pyrimidin-5-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonanyl)sulfonyl)azetidine-3-carbonitrile was prepared according to Example 6.

[0316] MS m / z (ESI): 545.2 [M+H] + .

[0317] Example 8

[0318] 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

[0319]

[0320] 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 (200 mg, 0.439 mmol) was dissolved in a 4 M solution of HCl in 1,4-dioxane (20 mL) and the reaction stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (1.45 mL, 8.78 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (95 mg, 0.527 mmol) were added sequentially and the reaction mixture stirred at 0 °C for 16.5 hours. The solvent was removed under reduced pressure and the residue separated by reverse phase HPLC to give the title compound (70 mg, 32%).

[0321] 1 H NMR (400 MHz, MeOD-d4) δ 7.37 (d, J = 6.0 Hz, 1H), 6.94 (d, J = 6.0 Hz, 1H), 6.25 (s, 1H), 4.44 - 4.34 (m, 1H), 4.26 (s, 2H), 4.16 (t, J = 8.5 Hz, 2H), 4.12 - 4.05 (m, 2H), 3.57 (ddd, J = 15.3, 8.7, 6.5 Hz, 1H), 2.31 (s, 3H), 2.23 - 2.10 (m, 4H), 2.01 (d, J = 7.4 Hz, 2H), 1.73 (dd, J = 18.2, 7.1 Hz, 2H).

[0322] MS m / z (ESI): 500.1 [M+H] + .

[0323] Example 9

[0324] 3-((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)sulfonyl)azetidine-3-carbonitrile

[0325]

[0326] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then dissolved in N,N-dimethylformamide (10 mL), DIPEA (108 mg, 0.84 mmol) was added slowly dropwise and stirred at room temperature for 10 min. 3-Cyanooxetan-l-sulfonyl chloride (45 mg, 0.25 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and the resulting product was purified by prep-HPLC to give the title compound as a white solid (14.4 mg, 13%).

[0327] 1 H NMR (400 MHz, DMSO) δ = 12.02 (s, 1H), 9.81 (s, 1H), 7.61 (s, 1H), 6.90 (s, 1H), 6.59 (d, J = 57.6 Hz, 2H), 4.74 (s, 1H), 3.96 (t, J = 8.4 Hz, 2H), 3.85 (dd, J = 16.8 Hz, 6.4, 4H), 3.75 - 3.67 (m, 1H), 2.14 (s, 3H), 2.00 (d, J = 8.4 Hz, 2H), 1.87 - 1.60 (m, 8H).

[0328] MS m / z (ESI): 514.1 [M+H] + .

[0329] Example 10

[0330] 1-(((3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonanyl)sulfonyl)azetidine-3-carbonitrile

[0331]

[0332] First Step: Preparation of tert-Butyl-(3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3- yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0333]

[0334] To a solution of 2-chloro-N-(5-methyl-lH-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4- amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-(methylamino)-9- azabicyclo[3.3.1]nonane-9-carboxylate (287 mg, 1.13 mmol), DIPEA (242 mg, 1.88 mmol) were added successively, then stirred at 160 °C under microwave condition for 15 h. The reaction was extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride solution (15 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a light white solid (228 mg, 50%).

[0335] MS m / z (ESI): 484.2 [M+H] + .

[0336] Second Step: Preparation of l-(((3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile

[0337]

[0338] Tert-butyl-(3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin- 2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane solution of hydrochloric acid (4.0 N, 5 mL), stirred at room temperature for 30 min, then the reaction was concentrated; then it was dissolved in N,N-dimethylformamide (10 mL), DIPEA (108 mg, 0.84 mmol) was added slowly dropwise, stirred at room temperature for 10 min, then 3-nitriloazetidine-1-sulfonyl chloride (45 mg, 0.25 mmol) was added, and the stirring was continued at room temperature overnight. The reaction was concentrated under reduced pressure, and the product was obtained by prep-HPLC to give the title compound as a white solid (46.0 mg, 42%).

[0339] 1H NMR (400 MHz, DMSO) δ = 12.09 (s, 1H), 9.79 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.43 (s, 1H), 5.77 (s, 1H), 3.98 (dt, J = 14.4, 8.4 Hz, 6H), 3.84 - 3.74 (m, 1H), 2.90 (s, 3H), 2.22 (s, 3H), 2.13 - 1.61 (m, 10H).

[0340] MS m / z (ESI): 528.2 [M+H] + .

[0341] Example 11

[0342] 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

[0343]

[0344] First Step 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

[0345]

[0346] 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 (150 mg, 0.536 mmol) and 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4- amine (150 mg, 0.536 mmol) were added to n-butanol (10 mL) and heated to 170 °C for 8 hours in a microwave synthesizer. The solvent was removed by concentration under reduced pressure, the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution successively. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was isolated by column chromatography on silica gel (73 mg, 28%).

[0347] MS m / z (ESI): 484.2 [M+H] + .

[0348] Second Step 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

[0349]

[0350] tert-Butyl (3-exo)-3-(methyl(6-methyl-4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (73 mg, 0.151 mmol) was dissolved in 4M HC1 in 1,4-dioxane (20 mL) and stirred at room temperature for 30 min. The solvent was removed by concentration under reduced pressure and the residue was dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.75 mL, 4.53 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (30 mg, 0.166 mmol) were added sequentially and the reaction mixture was stirred at 0 °C for 4.5 h. The solvent was removed by concentration under reduced pressure and the residue was separated by prep-HPLC to give the title compound (31.5 mg, 40%).

[0351] 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 9.66 (s, 1H), 7.35 (s, 1H), 6.48 (s, 1H), 5.31-5.15 (m, 1H), 4.18 (d, J = 1.0 Hz, 2H), 4.06 (t, J = 8.6 Hz, 2H), 4.00-3.91 (m, 2H), 3.80 (ddd, J = 12.8, 8.9, 6.5 Hz, 1H), 2.90 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H), 2.07-1.99 (m, 2H), 1.95 (dd, J = 18.2, 7.0 Hz, 2H), 1.88-1.79 (m, 2H), 1.62 (dd, J = 11.8, 4.1 Hz, 2H).

[0352] MS m / z (ESI): 528.2 [M+H] + .

[0353] Example 12

[0354] 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

[0355]

[0356] First Step 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

[0357]

[0358] To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4- amine (100 mg, 0.376 mmol) and tert-butyl (3-exo)-3-(methylamino)-8- azabicyclo[3.2.1]octane-8-carboxylate (181 mg, 0.752 mmol) in n-butanol (3 mL) was heated to 170 °C for 18 h in a microwave synthesizer. The solvent was removed by concentration under reduced pressure and the residue was used directly for the next step.

[0359] MS m / z (ESI): 470.2 [M+H] + .

[0360] Second Step 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

[0361]

[0362] To a solution 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 in 4 M HC1 in 1,4- dioxane (20 mL) was stirred at room temperature for 30 min. The solvent was removed by concentration under reduced pressure and the residue was purified by reverse phase column chromatography to give 117 mg of white solid.

[0363] The above white solid was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled to 0 °C, and DIPEA (0.14 mL, 0.632 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (57 mg, 0.316 mmol) were added sequentially. The reaction mixture was stirred at 0 °C for 17 h. The solvent was removed by concentration under reduced pressure, and the residue was separated by prep-HPLC to give the title compound (16.4 mg, 10%).

[0364] 1 H NMR (400 MHz, MeOD-d4) δ 7.37 (d, J = 5.9 Hz, 1H), 6.98 (d, J = 5.7 Hz, 1H), 6.40 (s, 1H), 5.40-5.28 (m, 1H), 4.31-4.24 (m, 2H), 4.17 (t, J = 8.5 Hz, 2H), 4.11-4.04 (m, 2H), 3.57 (ddd, J = 15.4, 8.9, 6.7 Hz, 1H), 3.04 (s, 3H), 2.31 (s, 3H), 2.17 (dd, J = 8.6, 3.3 Hz, 2H), 2.11-2.01 (m, 2H), 2.00-1.92 (m, 2H), 1.75 (ddd, J = 10.8, 4.3, 2.7 Hz, 2H).

[0365] MS m / z (ESI): 514.1 [M+H] + .

[0366] Example 13

[0367] 2-(dimethylamino)-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

[0368]

[0369] Tert-butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then 2-(7-oxobenzo[d]thiazol-3-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) was added and dissolved in N,N-dimethylformamide (5 mL), DIPEA (108 mg, 0.84 mmol) was added dropwise slowly, stirred for 10 minutes in ice water bath, after adding dimethylglycine (24 mg, 0.23 mmol), continue to stir for 1 hour. The reaction was concentrated under reduced pressure, the product was obtained by prep-HPLC to give the title compound as a white solid (17.1 mg, 18%).

[0370] 1 H NMR (400 MHz, DMSO) δ = 12.00 (s, 1H), 9.80 (s, 1H), 7.61 (s, 1H), 6.98-6.45 (m, 3H), 4.76 (s, 1H), 4.59 (s, 1H), 4.27 (s, 1H), 3.30 (s, 6H), 3.05 (s, 2H), 2.16 (s, 3H), 2.14 (s, 2H), 2.07-1.92 (m, 2H), 1.86-1.40 (m, 6H).

[0371] MS m / z (ESI): 455.2 [M+H] + .

[0372] Example 14

[0373] 2-(Dimethylamino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[0374]

[0375] 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 (40 mg, 0.09 mmol) was dissolved in 1,4-epoxyhexanecarboxylic acid hydrochloride solution (4.0 N, 2 mL), and stirred at room temperature for 30 minutes, then concentrated. After 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) was added, it was dissolved in N,N-dimethylformamide (5 mL), and DIPEA (46 mg, 0.36 mmol) was added dropwise slowly. After stirring for 10 minutes in an ice water bath, dimethylglycine (10 mg, 0.1 mmol) 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 obtain the title compound as a white solid (4.4 mg, 11%).

[0376] 1 H NMR (400 MHz, DMSO) δ = 12.08 (s, 1H), 9.88 (s, 1H), 7.65 (s, 1H), 7.11-6.46 (m, 3H), 4.47 (d, J = 30.0 Hz, 3H), 3.06 (s, 2H), 2.21 (s, 9H), 2.04-1.66 (m, 6H), 1.62-1.44 (m, 2H).

[0377] MS m / z (ESI): 441.2 [M+H] + .

[0378] Example 15

[0379] 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

[0380]

[0381] 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 (40 mg, 0.09 mmol) was dissolved in 1,4-epoxyhexanecarboxylic acid hydrochloride solution (4.0 N, 2 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then 2-(7-oxobenzothiazol-2-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (51 mg, 0.13 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (46 mg, 0.36 mmol) was added dropwise slowly and stirred for 10 min in an ice water bath. 2-Morpholinoacetic acid (14.5 mg, 0.1 mmol) was added and stirred for 1 h. The reaction was concentrated under reduced pressure and the product was obtained as a white solid (7.8 mg, 18%) by prep-HPLC.

[0382] 1 H NMR (400 MHz, DMSO) δ = 12.07 (s, 1H), 9.88 (s, 1H), 7.66 (s, 1H), 7.11-6.49 (m, 3H), 4.48 (d, J = 26.4 Hz, 3H), 3.60 (s, 4H), 3.17 (s, 2H), 2.46 (s, 4H), 2.23 (s, 3H), 1.98 (s, 2H), 1.90-1.45 (m, 6H).

[0383] MS m / z (ESI): 483.2 [M+H] + .

[0384] Example 16

[0385] 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)-2-morpholinoethan-1-one

[0386]

[0387] 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)-2-morpholinoethan-1-one was prepared according to Reference Example 244.

[0388] 1H NMR (400 MHz, DMSO-d6) δ = 9.85 (s, 1H), 8.22 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.53 (s, 1H), 5.37 (s, 1H), 4.54 (d, J = 16.4 Hz, 2H), 3.58 (d, J = 4.0 Hz, 4H), 3.04 (d, J = 13.2 Hz, 2H), 2.85 (s, 3H), 2.45 (s, 4H), 2.23 (s, 3H), 2.03 - 1.97 (m, 2H), 1.87 - 1.59 (m, 6H).

[0389] MS m / z (ESI): 497.2 [M+H] + .

[0390] Example 17

[0391] 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-morpholinoethan-1-one

[0392]

[0393] tert-Butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexan-2-ol hydrochloride solution (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then 2-(7-oxobenzo[d]thiazol-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL), DIPEA (108 mg, 0.84 mmol) was added dropwise slowly, stirred for 10 minutes in an ice water bath, 2-morpholinoacetic acid (33 mg, 0.23 mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the product was obtained by prep-HPLC to give the title compound as a white solid (18.0 mg, 17%).

[0394] 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).

[0395] MS m / z(ESI):497.2[M+H] + .

[0396] Example 18

[0397] 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)-ethan-1-one

[0398]

[0399] Step 1: Preparation of tert-butyl methyl (2-((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-carbonylethyl)carbamate

[0400]

[0401] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (200 mg, 0.42 mmol) was dissolved in 1,4-oxane hydrochloride solution (4.0 N, 10 mL), and the reaction was stirred at room temperature for 30 minutes before being concentrated. 2-(7- Oxobenzo[d]thiazol-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (240 mg, 0.64 mmol) was then added and dissolved in N,N-dimethylformamide (5 mL), and DIPEA (216 mg, 1.68 mmol) was added dropwise slowly. The reaction was stirred for 10 minutes in an ice water bath, and N-(tert- butoxycarbonyl)-N-methylglycine (87 mg, 0.46 mmol) was added, and the reaction was stirred for an additional hour. The reaction was extracted with dichloromethane (15 mL x 3), and the organic phase was washed with saturated aqueous sodium chloride (15 mL x 3). The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a white solid (205 mg, 90%).

[0402] MS m / z (ESI): 541.2 [M+H] + .

[0403] Second Step: Preparation of 1-((3-exo)-3-((4-((5-methyl-lH-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

[0404]

[0405] tert-Butyl methyl (2-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)-2-oxoethyl)carbamate (205 mg, 0.38 mmol) was dissolved in 1,4-oxane hydrochloride solution (4.0 N, 10 mL), and the reaction was stirred at room temperature for 30 minutes. Ammonia (10 mL) was added dropwise to the reaction in an ice water bath, and the reaction was concentrated under reduced pressure. The resulting product was purified by prep-HPLC to give the title compound as a white solid (37.6 mg, 22%).

[0406] 1H NMR (400 MHz, DMSO) δ = 12.10 (s, 1H), 9.88 (s, 1H), 7.68 (s, 1H), 6.96 (s, 1H), 6.61 (s, 2H), 4.84 (s, 1H), 4.69 (s, 1H), 4.12 (s, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.15-1.96 (m, 3H), 1.87-1.47 (m, 10H).

[0407] MS m / z (ESI): 441.2 [M+H] + .

[0408] Example 19

[0409] ((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

[0410]

[0411] ((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 was prepared according to Example 18.

[0412] 1 H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 9.89 (s, 1H), 7.66 (s, 1H), 7.06-6.51 (m, 3H), 4.55-4.35 (m, 3H), 3.73 (s, 1H), 3.01 (s, 1H), 2.64 (d, J = 6.8 Hz, 2H), 2.23 (s, 3H), 2.10-1.43 (m, 12H).

[0413] MS m / z (ESI): 453.1 [M+H] + .

[0414] Example 20

[0415] ((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)((S)-pyrrolidin-2-yl)methanone

[0416]

[0417] ((3-exo)-3-((4-((5-methyl-lH-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 was prepared according to Example 18.

[0418] 1 H NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 9.90 (s, 1H), 7.67 (s, 1H), 5.98 - 6.54 (m, 3H), 4.58 - 4.35 (m, 3H), 4.09 - 4.02 (m, 1H), 3.11 (s, 1H), 2.97 - 2.64 (m, 2H), 2.23 (s, 3H), 2.10 - 1.37 (m, 10H).

[0419] MS m / z (ESI): 453.1 [M+H] + .

[0420] Example 21

[0421] ((3-exo)-3-((4-((5-methyl-lH-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

[0422]

[0423] ((3-exo)-3-((4-((5-methyl-lH-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 was prepared according to Example 18.

[0424] MS m / z (ESI): 483.2 [M+H] + .

[0425] Example 22

[0426] ((3-exo)-3-((4-((5-methyl-lH-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

[0427]

[0428] ((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 was prepared according to Example 18.

[0429] MS m / z (ESI): 467.2 [M+H] + .

[0430] Example 23

[0431] 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

[0432]

[0433] 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 was prepared according to Example 18.

[0434] MS m / z (ESI): 485.2 [M+H] + .

[0435] Example 24

[0436] 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

[0437]

[0438] 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 was prepared according to Example 18.

[0439] MS m / z (ESI): 518.2 [M+H] + .

[0440] Example 25

[0441] 2-((4-methoxybenzyl)amino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[0442]

[0443] 2-((4-methoxybenzyl)amino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one was prepared according to Reference Example 18.

[0444] MS m / z (ESI): 533.2 [M+H] + .

[0445] Example 26

[0446] 2-((4-methoxybenzyl)amino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[0447]

[0448] 2-((4-methoxybenzyl)amino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one was prepared according to Reference Example 18.

[0449] MS m / z (ESI): 441.2 [M+H] + .

[0450] Example 27

[0451] 2-((4-methoxybenzyl)amino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[0452]

[0453] 2-(cyclopropylamino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one was prepared according to Example 18.

[0454] MS m / z (ESI): 453.2 [M+H] + .

[0455] Example 28

[0456] 1-((3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)- 9-azabicyclo[3.3.1]nonan-9-yl)-2-(4-methylpiperazin-l-yl)ethan-l-one

[0457]

[0458] tert-Butyl-(3-exo)-3-(methyl(4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane solution of hydrochloric acid (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL), DIPEA (108 mg, 0.84 mmol) was added dropwise slowly, stirred for 10 minutes in an ice water bath, 2-(4-methylpiperazin-l-yl)acetic acid (36 mg, 0.23 mmol) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (43.8 mg, 40%).

[0459] 1H NMR (400 MHz, DMSO) δ = 12.07 (s, 1H), 9.79 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.02 (d, J = 6.0 Hz, 1H), 6.46 (s, 1H), 5.81 (s, 1H), 4.71 (s, 1H), 4.39 (s, 1H), 3.22 (d, J = 12.8 Hz, 1H), 3.06 (d, J = 12.8 Hz, 1H), 2.85 (s, 3H), 2.40 (s, 8H), 2.22 (s, 3H), 2.17 (s, 3H), 2.12-2.02 (m 2H), 1.90-1.61 (m, 8H).

[0460] MS m / z (ESI): 424.2 [M+H] + .

[0461] Example 29

[0462] 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-(4-methylpiperazin-1-yl)ethan-1-one

[0463]

[0464] 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 (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexan-2-ol hydrochloride solution (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then 2-(7-oxobenzo[d]oxazol-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL), DIPEA (108 mg, 0.84 mmol) was added dropwise slowly, stirred for 10 minutes in an ice water bath, 2-(4-methylpiperazin-1-yl)acetic acid (36 mg, 0.23 mmol) 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 obtain the title compound as a white solid (25.2 mg, 24%).

[0465] 1H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.92 (s, 1H), 7.68 (s, 1H), 6.96 - 6.61 (m, 3H), 4.85 (s, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.10 (s, 2H), 2.37 (s, 8H), 2.21 (s, 3H), 2.14 (s, 3H), 2.09 - 1.99 (m, 2H), 1.97 - 1.46 (m, 8H).

[0466] MS m / z (ESI): 510.2 [M+H] + .

[0467] Example 30

[0468] 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

[0469]

[0470] 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 was prepared according to Example 18.

[0471] MS m / z (ESI): 496.2 [M+H] + .

[0472] Example 31

[0473] ((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

[0474]

[0475] Tert-butyl-(3-exo)-3-((7-((5-methyl-1hydro-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in a 1,4-epoxyhexacyclo solution (4.0 N, 5 mL) of hydrochloric acid. The mixture was stirred at room temperature for 30 minutes, and the reaction solution was concentrated. 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was then added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. Pyridine-2-carboxylic acid (28 mg, 0.23 mmol) was added, and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (27.3 mg, 21%).

[0476] 1 H NMR (400MHz, DMSO) δ=12.07 (s, 1H), 9.86 (s, 1H), 8.59 (d, J=4.4 Hz, 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).

[0477] MS m / z(ESI):475.1[M+H] + .

[0478] Example 32

[0479] ((3-exo)-3-((4-((5-methyl-1hydrogen-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)(pyridin-3-yl)methanone

[0480]

[0481] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was added dropwise slowly and stirred for 10 min in an ice water bath. Pyridine-3-carboxylic acid (28 mg, 0.23 mmol) was added and stirred for 1 h. The reaction was concentrated under reduced pressure and the product was obtained as a white solid (28.6 mg, 22%) by prep-HPLC.

[0482] 1 H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.87 (s, 1H), 8.71-8.58 (m, 2H), 7.84 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 6.0 Hz, 1H), 7.51 (dd, J = 7.6, 4.8 Hz, 1H), 6.96 (d, J = 5.2 Hz, 1H), 6.68-6.50 (m, 2H), 4.83 (d, J = 39.2 Hz, 2H), 3.78 (s, 1H), 2.21 (s, 3H), 2.13-1.61 (m, 10H).

[0483] MS m / z (ESI): 475.1 [M+H] + .

[0484] Example 33

[0485] ((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-9- azabicyclo[3.3.1]nonan-9-yl)(pyridin-4-yl)methanone

[0486]

[0487] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was added dropwise slowly and stirred for 10 min in an ice water bath. Pyridine-4-carboxylic acid (28 mg, 0.23 mmol) was added and stirred for 1 h. The reaction was concentrated under reduced pressure and the product was obtained as a white solid (34.5 mg, 27%) by prep-HPLC.

[0488] 1 H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 9.87 (s, 1H), 8.69 (d, J = 6.0 Hz, 2H), 7.69 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 5.6 Hz, 2H), 6.97 (d, J = 6.0 Hz, 1H), 6.57 (d, J = 7.6 Hz, 2H), 4.82 (d, J = 41.6 Hz, 2H), 3.68 (s, 1H), 2.21 (s, 3H), 2.14 - 1.59 (m, 10H).

[0489] MS m / z (ESI): 475.1 [M+H] + .

[0490] Example 34

[0491] (1-Methyl-lH-imidazol-2-yl)((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)methanone

[0492]

[0493] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexanecarboxylic acid hydrochloride solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then 2-(7-oxobenzo[d]thiazol-3-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was added dropwise slowly and stirred for 10 min in an ice water bath. 1-Methyl-lH-imidazole-2-carboxylic acid (29 mg, 0.23 mmol) was added and stirred for 1 h. The reaction was concentrated under reduced pressure and the product was obtained as a white solid (15.0 mg, 12%) by prep-HPLC.

[0494] 1 H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 9.87 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 6.97 (s, 2H), 6.65 (s, 2H), 4.91-4.80 (m, 3H), 3.77 (s, 3H), 2.22 (s, 3H), 2.14-1.60 (m, 10H).

[0495] MS m / z (ESI): 478.2 [M+H] + .

[0496] Example 35

[0497] (1-Methyl-lH-imidazol-4-yl)((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonanyl)methanone

[0498]

[0499] (1-Methyl-lH-imidazol-4-yl)((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno [2,3-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonanyl)methanone was prepared according to Example 21

[0500] 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).

[0501] MS m / z(ESI):478.1[M+H] + .

[0502] Example 36

[0503] N 4 -(5-methyl-1H-pyrazol-3-yl)-N 2 -((3-exo)-8(pyridin-3-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0504]

[0505] 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 (40 mg, 0.09 mmol) was dissolved in a 1,4-epoxyhexacyclo solution (4.0 N, 2 mL) at room temperature and stirred for 30 minutes. The reaction mixture was then concentrated. N,N-dimethylformamide (5 mL) was then added to dissolve the mixture. DIPEA (46 mg, 0.36 mmol) was slowly added dropwise, and the mixture was stirred in an ice-water bath for 10 minutes. Pyridine-3-sulfonyl chloride (18 mg, 0.1 mmol) was added and stirring continued for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to yield the title compound as a white solid (5.6 mg, 13%).

[0506] 1 H 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=5.2 Hz, 1H), 2.14 (s, 3H), 1.99 (s, 2H), 1.76-1.56 (m, 4H), 1.35-1.26 (m, 2H).

[0507] MS m / z (ESI): 497.1 [M+H] + .

[0508] Example 37

[0509] N4-(5-methyl-lH-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8- azabicyclo[3.2.1]nonan-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0510]

[0511] N4-(5-methyl-lH-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8- azabicyclo[3.2.1]nonan-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine was prepared according to Reference Example 23.

[0512] 1 H NMR (400 MHz, CD3OD:CDCl3, v / v = 1:2) δ 8.70 (d, J = 4.6 Hz, 1H), 8.00 (dt, J = 8.0, 4.6 Hz, 2H), 7.60 (ddd, J = 6.8, 4.8, 1.8 Hz, 1H), 7.35 (d, J = 6.0 Hz, 1H), 6.92 (d, J = 6.0 Hz, 1H), 6.19 (s, 1H), 4.43 (s, 2H), 4.40 - 4.32 (m, 1H), 2.27 (s, 3H), 2.15 (ddd, J = 12.7, 5.3, 2.6 Hz, 2H), 1.88 - 1.81 (m, 2H), 1.80 - 1.70 (m, 2H), 1.62 (dd, J = 8.6, 4.7 Hz, 2H).

[0513] MS m / z (ESI): 497.1 [M+H] + .

[0514] Example 38

[0515] N4-(5-methyl-lH-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-2-ylsulfonyl)-8- azabicyclo[3.2.1]nonan-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0516]

[0517] Tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.213 mmol) was dispersed in 4 M HC1 in 1,4-dioxane (15 mL), the reaction was stirred at room temperature for 60 min, the solvent was removed by concentration under reduced pressure, the residue was dissolved in anhydrous N,N-dimethylformamide (10 mL), cooled to 0 °C, DIPEA (1.05 mL, 6.39 mmol) and pyridine-2-sulfonyl chloride (40 mg, 0.224 mmol) were added successively, the reaction mixture was continued to be stirred at 0 °C for 2.5 h. The solvent was removed by concentration under reduced pressure, the residue was separated by prep-HPLC to give the title compound as a white solid (12.4 mg, 25%).

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 9.85 (s, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.08 (td, J = 7.7, 1.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.67 (dd, J = 6.7, 4.7 Hz, 2H), 6.95 (s, 1H), 6.59 (d, J = 30.3 Hz, 2H), 4.85 - 4.71 (m, 1H), 4.18 (s, 2H), 2.17 (s, 3H), 2.05 (dd, J = 12.8, 4.9 Hz, 3H), 1.68 (d, J = 2.6 Hz, 7H).

[0519] MS m / z (ESI): 511.1 [M+H] + .

[0520] Example 39

[0521] N4-(5-methyl-lH-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

[0522]

[0523] N4-(5-methyl-lH-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 was prepared according to Example 38.

[0524] 1H NMR (400 MHz, CD3OD:CDCl3, v / v = 1 : 1) δ 9.11 (s, 1H), 8.84 (d, J = 3.9 Hz, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.70-7.62 (m, 1H), 7.39 (d, J = 5.9 Hz, 1H), 6.96 (d, J = 5.8 Hz, 1H), 6.62 (s, 1H), 5.05-4.90 (m, 1H), 4.34 (d, J = 2.8 Hz, 2H), 2.55-2.19 (m, 5H), 2.19-1.61 (m, 8H).

[0525] MS m / z (ESI): 511.1 [M+H] + .

[0526] Example 40

[0527] 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

[0528]

[0529] 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 was prepared according to Example 38.

[0530] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.86 (s, 1H), 7.67 (d, J = 2.9 Hz, 1H), 7.45 (s, 1H), 7.08 (s, 1H), 6.96 (d, J = 4.9 Hz, 1H), 6.73-6.47 (m, 2H), 4.88-4.74 (m, 1H), 4.12 (s, 2H), 3.87 (s, 3H), 2.19 (s, 3H), 2.09 (ddd, J = 5.5, 5.1, 1.0 Hz, 3H), 1.91-1.58 (m, 7H).

[0531] MS m / z (ESI): 514.1 [M+H] + .

[0532] Example 41

[0533] 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

[0534]

[0535]

[0536] tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin- 2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloride solution (4.0 N, 5 mL), and stirred at room temperature for 30 minutes, then concentrated. It was then dissolved in N,N-dimethylformamide (5 mL), and DIPEA (108 mg, 0.84 mmol) was added dropwise slowly. After stirring for 10 minutes in an ice water bath, 2-bromo-N,N-dimethylacetamide (38 mg, 0.23 mmol) was added, and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure, and the resulting product was purified by prep-HPLC to give the title compound as a white solid (16.6 mg, 17%).

[0537] 1 H NMR (400 MHz, DMSO) δ = 12.00 (s, 1H), 9.80 (s, 1H), 7.63 (s, 1H), 6.74 (d, J = 128.0 Hz, 3H), 4.62 (s, 1H), 3.42 (s, 2H), 3.04 (s, 3H), 2.86 (s, 2H), 2.77 (s, 3H), 2.16 (s, 3H), 1.96-1.47 (m, 10H).

[0538] MS m / z (ESI): 455.2 [M+H] + .

[0539] Example 42

[0540] N 4 -(5-methyl-1H-pyrazol-3-yl)-N 2 -((3-exo)-9-(pyridin-2-ylmethyl)-9-azabicyclo[3.3.1]nonan-3-yl)thieno[2,3-d]pyrimidine- 2,4-diamine

[0541]

[0542]

[0543] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-epoxyhexan solution of hydrochloric acid (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then it was dissolved in N,N-dimethylformamide (5 mL), DIPEA (108 mg, 0.84 mmol) was added slowly dropwise, stirred for 10 minutes in an ice water bath, after adding 2-(chloromethyl)pyridine hydrochloride (38 mg, 0.23 mmol), the temperature was raised to 70 °C and stirred overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (20.8 mg, 22%).

[0544] 1 H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 9.85 (s, 1H), 8.47 (d, J = 4.0 Hz, 1H), 7.81-7.48 (m, 3H), 7.33-6.52 (m, 4H), 4.74 (s, 1H), 3.92 (s, 2H), 2.89 (s, 2H), 2.23 (d, J = 13.6 Hz, 3H), 2.08-1.50 (m, 10H).

[0545] MS m / z (ESI): 461.1 [M+H] + .

[0546] Example 43

[0547] N 2 -((3-exo)-9-((1- methyl- 1H-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]nonan-3-yl)-N 4 -(5-methyl-lH-pyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine

[0548]

[0549] N 2 -((3-exo)-9-((1- methyl- 1H-imidazol-2-yl)methyl)-9-azabicyclo[3.3.1]nonan-3-yl)-N 4 -(5-methyl-lH-pyrazol-3-yl)thieno[2,3-d]pyrimidine-2,4-diamine was prepared according to Example 42.

[0550] 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).

[0551] MS m / z(ESI):464.2[M+H] + .

[0552] Example 44

[0553] 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

[0554]

[0555] Step 1: Preparation of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-1H-pyrazol-5-yl)methanol

[0556]

[0557] 2,4-Dichlorothieno[2,3-d]pyrimidine (100 mg, 0.49 mmol), (3-amino-1H-pyrazol-5-yl)methanol (55 mg, 0.49 mmol), and DIPEA (190 mg, 1.47 mmol) were added to N'N-dimethylformamide (2 mL). The reaction mixture was stirred at 70°C overnight. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by flash silica gel column chromatography to afford the title compound as a yellow solid (100 mg, 73%).

[0558] MS m / z(ESI):282.0[M+H] + .

[0559] Step 2: Preparation of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0560]

[0561] To a solution of (3-((2-chlorothieno[2,3-d]pyrimidin-4-yl)amino)-lH-pyrazol-5- yl)methanol (100 mg, 0.36 mmol), N-Boc-exo-3-aminotropanecarboxylate (113 mg, 0.40 mmol), DIPEA (140 mg, 1.08 mmol) in n-butanol (2.5 mL) was heated at 150 °C for 10 h in a microwave reactor. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography using silica gel to give the title compound as a light yellow solid (60 mg, 35%).

[0562] MS m / z (ESI): 472.0 [M+H] + .

[0563] Step 3: Preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0564]

[0565] To a solution of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.13 mmol) in methanol (10 mL) was added hydrochloric acid in dioxane (4 N, 2.5 mL) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of methanol (15 mL), DIPEA (0.5 mL), and acrylonitrile (1 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound as a white solid (11.6 mg, 21%).

[0566] 1 H NMR (400 MHz, CD3OD) δ 7.39 (dd, J = 6.0 Hz, 1H), 6.99 (dd, J = 5.6 Hz, 1H), 6.02-6.04 (m, 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 = 12.4 Hz, 2H).

[0567] MS m / z (ESI): 425.1 [M+H] + .

[0568] Example 45

[0569] 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)propanenitrile

[0570]

[0571] 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)propanenitrile was prepared according to Example 44.

[0572] MS m / z (ESI): 439.2 [M+H] + .

[0573] Example 46

[0574] 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)propanenitrile

[0575]

[0576] 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)propanenitrile was prepared according to Example 44.

[0577] MS m / z (ESI): 453.2 [M+H] + .

[0578] Example 47

[0579] 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

[0580]

[0581] Refer to Example 44 for the 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.

[0582] MS m / z(ESI):530.2[M+H] + .

[0583] Example 48

[0584] 3-((3-exo)-3-((6-methyl-4-((5-methyl-1-hydrogen-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0585]

[0586] Step 1: Preparation of tert-butyl-(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]octane-8-carboxylate

[0587]

[0588] To a solution of 2-chloro-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (200 mg, 0.72 mmol) in n-butanol (10 mL) were added tert-butyl-(3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (194 mg, 0.86 mmol) and DIPEA (186 mg, 1.44 mmol), followed by stirring at 160°C under microwave conditions for 15 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (15 mL x 3) and washed with saturated sodium chloride (15 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting product was purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to afford the title compound as a pale yellow solid (124 mg, 37%).

[0589] MS m / z(ESI):470.2[M+H] + .

[0590] Step 2: Preparation of 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

[0591]

[0592] tert-Butyl-(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]octane-8-carboxylate (124 mg, 0.26 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL), and the reaction was stirred at room temperature for 30 minutes, then concentrated. The product was dissolved in methanol (10 mL), and DIPEA (137 mg, 1.06 mmol) was added dropwise slowly. The reaction was stirred at room temperature for 10 minutes, and acrylonitrile (21 mg, 0.39 mmol) was added. The reaction was stirred for 2 hours. The reaction was concentrated under reduced pressure, and the product was purified by prep-HPLC to give the title compound as a white solid (12.7 mg, 12%).

[0593] 1 H NMR (400 MHz, DMSO) d = 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).

[0594] MS m / z (ESI): 423.2 [M+H] + .

[0595] Example 49

[0596] 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5-yl)amino)- 9-azabicyclo[3.3.1]nonan-9-yl)propionitrile

[0597]

[0598] Step 1: Preparation of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7- amine

[0599]

[0600] To a solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (206 mg, 1 mmol) in dimethyl sulfoxide (10 mL), 3-amino-5-methylpyrazole (116 mg, 1.2 mmol), DIPEA (258 mg, 2 mmol) were added successively, then heated at 70 °C for one hour. The reaction was completed by adding water (50 mL) to the reaction mixture, and a solid was precipitated. The solid was filtered and washed with ethyl acetate to give the title compound as a yellow solid (200 mg, 75%).

[0601] MS m / z (ESI): 267.0 [M+H] + .

[0602] Step 2: Preparation of tert-butyl-(3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4- d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0603]

[0604] To a solution of 5-chloro-N-(5-methyl-1H-pyrazol-3-yl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.75 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate (216 mg, 0.9 mmol), DIPEA (193 mg, 1.5 mmol) were added successively, then heated at 160 °C for 15 hours under microwave condition. The reaction was completed by extracting the reaction mixture with ethyl acetate (15 mL x 3), washing with saturated aqueous sodium chloride solution (15 mL x 3), collecting the organic phase, drying over anhydrous sodium sulfate, filtering, and concentrating the organic phase under reduced pressure. The resulting product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a yellowish solid (232 mg, 66%).

[0605] MS m / z (ESI): 471.2 [M+H] + .

[0606] Step 3: Preparation of 3-((3-exo)-3-((7-((5-methyl-1H-pyrazol-3-yl)amino)thiazolo[5,4-d]pyrimidin-5- yl)amino)-9-azabicyclo[3.3.1]nonanyl)propanenitrile

[0607]

[0608] tert-Butyl-(3-exo)-3-((7-((5-methyl-lH-pyrazol-3-yl)amino)thiazolo[5,4- d]pyrimidin-5-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (232 mg, 0.49 mmol) was dissolved in 1,4-epoxyhexanecarboxylic acid hydrochloride solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then dissolved in methanol (10 mL), DIPEA (127 mg, 0.98 mmol) was added dropwise slowly, and the reaction was stirred at room temperature for 10 min. Acrylonitrile (39 mg, 0.74 mmol) was added, and the reaction was stirred for 2 h. The reaction was concentrated under reduced pressure, and the product was purified by prep-HPLC to give the title compound as a light yellow solid (63 mg, 30%).

[0609] 1 H NMR (400 MHz, DMSO) δ = 12.06 (s, 1H), 9.29 (s, 1H), 8.76 (d, J = 18.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.57 (s, 1H), 4.67 (s, 1H), 3.31 (s, 2H), 2.58 (t, J = 6.2 Hz, 4H), 2.19 (s, 3H), 2.00 - 1.65 (m, 10H).

[0610] MS m / z (ESI): 424.2 [M+H] + .

[0611] Example 50

[0612] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxy)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0613]

[0614] First Step: Preparation of tert-Butyl-(3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0615]

[0616] NaH (120 mg, 3.01 mmol, 60%) was added portionwise to a solution of tert-butyl (3-exo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (427 mg, 1.88 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 5 minutes before dropwise addition of a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 120 °C under nitrogen for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (10 mL) and stirred for 10 minutes. The mixture was filtered and the filtrate was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution and the organic phase was collected and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound as a yellow oil (149 mg, 87%).

[0617] Second Step: Preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxy)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0618]

[0619] Tert-butyl (3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)oxy)-8- azabicyclo[3.2.1]octane-8-carboxylate (77 mg, 0.169 mmol) was dissolved in methanol (2 mL) and 4M HCI in 1,4-dioxane (2 mL) 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 and the residue was dissolved in anhydrous methanol (1 mL). DIPEA (109 mg, 0.844 mmol) and acrylonitrile (45 mg, 0.844 mmol) were added sequentially and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel and then by preparative TLC to give the title compound as a grey solid (7 mg, 10%).

[0620] 1H NMR (400 MHz, CD3OD) δ 7.50 (d, J = 6.1 Hz, 1H), 7.22 (d, J = 5.9 Hz, 1H), 6.51 (s, 1H), 5.43-5.26 (m, 1H), 3.44-3.37 (m, 2H), 2.78 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.12-2.00 (m, 4H), 1.86-1.74 (m, 4H).

[0621] MS m / z (ESI): 410.1 [M+H] + .

[0622] Example 51

[0623] 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)propanenitrile

[0624]

[0625] 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)propanenitrile was prepared according to Example 48.

[0626] MS m / z (ESI): 453.2 [M+H] + .

[0627] Example 52

[0628] 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)propanenitrile

[0629]

[0630] 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)propanenitrile was prepared according to Example 48.

[0631] MS m / z (ESI): 494.2 [M+H] + .

[0632] Example 53

[0633] 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)propanenitrile

[0634]

[0635] 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)propanenitrile was prepared according to Example 48.

[0636] MS m / z (ESI): 508.3 [M+H] + .

[0637] Example 54

[0638] 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)propanenitrile

[0639]

[0640] 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)propanenitrile was prepared according to Example 48.

[0641] MS m / z (ESI): 535.3 [M+H] + .

[0642] Example 55

[0643] 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)propanenitrile

[0644]

[0645] 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)propanenitrile was prepared according to Reference Example 48.

[0646] MS m / z (ESI): 532.2 [M+H] + .

[0647] Example 56

[0648] 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)propanenitrile was prepared according to Reference Example 48.

[0649]

[0650] tert-Butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.22 mmol) was dissolved in a solution of hydrochloric acid 1,4-epoxyhexane (4.0 N, 5 mL) and stirred at room temperature for 30 minutes, then the reaction was concentrated; it was then dissolved in N,N- dimethylformamide (10 mL), DIPEA (108 mg, 0.84 mmol) was added slowly dropwise, and stirred at room temperature for 10 minutes, then 3-carbamoylazetidine-1-sulfonyl chloride (45 mg, 0.25 mmol) was added and stirring was continued at room temperature overnight. The reaction was concentrated under reduced pressure, and the resulting product was subjected to prep-HPLC to obtain the title compound as a white solid (23.2 mg, 21%).

[0651] 1 H NMR (400 MHz, DMSO-d6) d = 12.07 (s, 1H), 9.74 (s, 1H), 7.90 (s, 1H), 7.00 (s, 1H), 6.54 (s, 2H), 4.27 (s, 1H), 4.13 (s, 2H), 4.04 (t, J = 8.4 Hz, 2H), 3.98 - 3.89 (m, 2H), 3.80 (dd, J = 15.2, 6.0 Hz, 1H), 2.23 (s, 3H), 1.99 (s, 4H), 1.84 (d, J = 7.2 Hz, 2H), 1.63 (s, 2H).

[0652] MS m / z (ESI): 500.1 [M+H] + .

[0653] Example 57

[0654] 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

[0655]

[0656] 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 was prepared according to Example 38.

[0657] 1 H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 9.64 (s, 1H), 6.77-6.45 (m, 3H), 4.25-4.23 (m, 1H), 4.12 (s, 2H), 4.06-4.02 (m, 2H), 3.95-3.88 (m, 2H), 3.83-3.77 (m, 1H), 2.24-2.21 (m, 4H), 1.99-1.98 (m, 5H), 1.84-1.81 (m, 2H), 1.64-1.59 (m, 3H).

[0658] MS m / z (ESI): 513.1 [M+H] + .

[0659] Example 58

[0660] 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

[0661]

[0662] 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 was prepared according to Example 56.

[0663] 1H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 9.72 (s, 1H), 7.89 (s, 1H), 6.99 (s, 1H), 6.49 (d, J = 58.8 Hz, 2H), 4.59-4.28 (m, 3H), 3.04 (s, 2H), 2.15 (s, 9H), 1.98-1.80 (m, 6H), 1.59-1.45 (m, 2H).

[0664] MS m / z (ESI): 441.1 [M+H] + .

[0665] Example 59

[0666] 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-morpholinoethan-1-one

[0667]

[0668] First Step: Preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0669]

[0670] To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (250 mg, 0.94 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate (271 mg, 1.13 mmol), DIPEA (242 mg, 1.88 mmol) were added successively, then stirred under microwave condition at 160 °C for 15 hours. The reaction was extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride solution (15 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the product was isolated and purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to give the title compound as a light white solid (150 mg, 34%).

[0671] MS m / z (ESI): 470.1 [M+H] + .

[0672] Step 2: Preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[0673]

[0674] Tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2- yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL) and stirred at room temperature for 30 min. The reaction was concentrated, then 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.31 mmol) was added and dissolved in N,N-dimethylformamide (5 mL). DIPEA (108 mg, 0.84 mmol) was added dropwise slowly and stirred for 10 min in an ice water bath. 2-Morpholinoacetic acid (33 mg, 0.23 mmol) was added and stirred for 1 h. The reaction was concentrated under reduced pressure and the product was obtained as a white solid (17.8 mg, 17%) by prep-HPLC.

[0675] 1 H NMR (400 MHz, DMSO-d6) d = 11.99 (s, 1H), 9.69 (s, 1H), 7.84 (s, 1H), 7.07-6.23 (m, 3H), 4.77 (s, 1H), 4.58 (s, 1H), 4.30 (s, 1H), 3.52 (d, J = 4.0 Hz, 4H), 3.10-3.01 (m, 2H), 2.32 (s, 3H), 2.14 (s, 2H), 2.09-1.39 (m, 10H).

[0676] MS m / z (ESI): 497.1 [M+H] + .

[0677] Example 60

[0678] 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

[0679]

[0680] Refer to Example 18 for the 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.

[0681] MS m / z(ESI):441.2[M+H] + .

[0682] Example 61

[0683] ((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

[0684]

[0685] Refer to Example 59 for the 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.

[0686] MS m / z(ESI):475.2[M+H] + .

[0687] Example 62

[0688] (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

[0689]

[0690] Refer to Example 59 for the 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.

[0691] MS m / z(ESI):478.2[M+H] + .

[0692] Example 63

[0693] 2-(dimethylamino)-l-((lR,3r,5S)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[0694]

[0695] 2-(dimethylamino)-l-((lR,3r,5S)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one was prepared according to Reference Example 13.

[0696] MS m / z (ESI): 441.2 [M+H] + .

[0697] Example 64

[0698] N,N-dimethyl-2-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)acetamide

[0699]

[0700] tert-Butyl-(3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)- 8-azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane solution of hydrochloric acid (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction solution was concentrated; then N,N-dimethylformamide (5 mL) was added to dissolve it, DIPEA (108 mg, 0.84 mmol) was slowly added dropwise, stirred for 10 minutes under ice water bath, after adding 2-bromo-N,N-dimethylacetamide (38 mg, 0.23 mmol), continue to stir for 1 hour. The reaction solution was concentrated under reduced pressure, the product was obtained by prep-HPLC to give the title compound as a white solid (16.4 mg, 17%).

[0701] 1H NMR (400 MHz, DMSO-d6) d = 12.05 (s, 1H), 9.74 (s, 1H), 7.90 (d, J = 4.0 Hz, 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).

[0702] MS m / z (ESI): 441.1 [M+H] + .

[0703] Example 65

[0704] 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)propanenitrile

[0705]

[0706] First Step: Preparation of (3-((2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)- 1H-pyrazol-5-yl)methanol

[0707]

[0708] 2,4-dichloro-6-methylthieno[3,2-d]pyrimidine (200 mg, 0.91 mmol), (3-amino-1H- pyrazol-5-yl)methanol (120 mg, 1.09 mmol), DIPEA (350 mg, 2.73 mmol) were dissolved in N,N-dimethylformamide (10 mL), mixed well and reacted overnight at the condition 70 °C. Cooled to room temperature, added water (30 mL) to the reaction solution respectively, extracted with ethyl acetate (20 mL*3), combined the organic phase, concentrated under reduced pressure, the obtained crude product was separated and purified by flash silica gel column to obtain the title compound as a white solid (200 mg, 75%).

[0709] MS m / z (ESI): 296.0 [M+H] + .

[0710] Second Step: 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

[0711]

[0712] To a solution of (3-((2-chloro-6-methylthieno[3,2-d]pyrimidin-4-yl)amino)-lH- pyrazol-5-yl)methanol (150 mg, 0.51 mmol), tert-butyl (3-exo)-3-amino-9- azabicyclo[3.3.1]nonane-9-carboxylate oxalate (200 mg, 0.61 mmol), DIPEA (200 mg, 1.53 mmol) in n-butanol (3 mL), after homogenization, the reaction was heated at 165 °C in microwave for 8 h, cooled to room temperature, the reaction was concentrated under reduced pressure, the obtained crude (200 mg) was used in the next step without purification.

[0713] MS m / z (ESI): 500.1 [M+H] + .

[0714] Third step: Preparation of (3-((2-(((3-exo)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6- methylthieno[3,2-d]pyrimidin-4-yl)amino)-lH-pyrazol-5-yl)methanol

[0715]

[0716] To a solution of tert-butyl (3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)-6- methylthieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (200 mg, 0.40 mmol) in methanol (10 mL), hydrochloric acid dioxane (4 N, 5 mL) was added slowly drop wise, the reaction was stirred at room temperature for 3 h, concentrated under reduced pressure, the obtained crude was separated and purified by prep-HPLC to give the title compound as a yellow solid (100 mg, 63%).

[0717] MS m / z (ESI): 400.1 [M+H] + .

[0718] Fourth step: Preparation of 3-((3-exo)-3-((4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)-6- methylthieno[3,2-d]pyrimidin-2-yl)amino)-9-azabicyclo[3.3.1]nonanyl)propanenitrile

[0719]

[0720] (3-((2-(((3-exo)-9-azabicyclo[3.3.1]nonan-3-yl)amino)-6-methylthieno[3,2- d]pyrimidin-4-yl)amino)-lH-pyrazol-5-yl)methanol (100 mg, 0.25 mmol), acrylonitrile (0.2 mL), DIPEA (0.1 mL) were taken in methanol (10 mL), mixed homogenously and allowed to react at room temperature for 1 h, concentrated under reduced pressure, the crude obtained was purified by prep-HPLC to get the title compound as white solid (11.7 mg, 10%).

[0721] 1 H NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.12 (s, 1H), 7.09 - 6.64 (m, 2H), 6.29 - 6.23 (s, 1H), 5.22 - 4.94 (m, 1H), 4.67 - 4.37 (m, 3H), 2.95 (s, 2H), 2.85 - 2.81 (m, 2H), 2.70 - 2.57 (m, 5H), 1.95 - 1.49 (m, 10H).

[0722] MS m / z (ESI): 453.2 [M+H] + .

[0723] Example 66

[0724] 3-(cis-5-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino) hexahydrocyclopenta[c]pyrrol-2(lH)-yl)propanenitrile

[0725]

[0726] First Step: Preparation of tert-butyl cis-5-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3- d]pyrimidin-2-yl)amino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

[0727]

[0728] 2-Chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4-amine (100 mg, 0.376 mmol), tert-butyl cis-5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (102 mg, 0.452 mmol), and DIPEA (146 mg, 1.13 mmol) were added to NMP (1 mL) and heated in a microwave oven at 160°C under nitrogen for 8 hours. The reaction mixture was cooled to room temperature, poured into ice water (10 mL), stirred for 10 minutes, filtered, and the filter cake was washed with water (15 mL) and dried in vacuo to afford the title compound as a yellow solid (171 mg, crude product).

[0729] Step 2: 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

[0730]

[0731] 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 (86 mg, 0.188 mmol) was dissolved in methanol (2 mL). 4 M HCl in 1,4-dioxane (2 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (2 mL). DIPEA (121 mg, 0.938 mmol) and acrylonitrile (15 mg, 0.282 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with DCM (20 mL) and washed with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a white solid (17 mg, 22%).

[0732] 1 H 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).

[0733] MS m / z(ESI):409.1[M+H] + .

[0734] Example 67

[0735] 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2- yl)amino)hexahydropyrrolo[c]pyrrol-2(1H)-yl)propanenitrile

[0736]

[0737] First Step: Preparation of tert-butyl-cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)hexahydropyrrolo[c]pyrrole-2(1H)-carboxylate

[0738]

[0739] To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)thieno[3,2-d]pyrimidin-4-amine (100 mg, 0.38 mmol) in n-butanol (5 mL), tert-butyl-cis-5-amino hexahydropyrrolo[c]pyrrole- 2(1H)-carboxylate (102 mg, 0.45 mmol), DIPEA (98 mg, 0.76 mmol) were added successively, then stirred at 160 °C under microwave condition for 15 hours. The reaction was extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride solution (15 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the resulting product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a light yellow solid (80 mg, 46%).

[0740] MS m / z (ESI): 456.2 [M+H] + .

[0741] Second Step: Preparation of 3-(cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2- d]pyrimidin-2-yl)amino)hexahydropyrrolo[c]pyrrol-2(1H)-yl)propanenitrile

[0742]

[0743] Tert-butyl-cis-5-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (80 mg, 0.18 mmol) was dissolved in a 4.0 N solution of 1,4-epoxyhexacyclohexane (2 mL). The mixture was stirred at room temperature for 30 minutes, and the reaction solution was concentrated. Methanol (5 mL) was then added to dissolve the mixture, and DIPEA (93 mg, 0.72 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, followed by the addition of acrylonitrile (14 mg, 0.27 mmol) and continued stirring for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting product was analyzed by prep-HPLC to yield the title compound as a white solid (26.3 mg, 37%).

[0744] 1 H 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).

[0745] MS m / z(ESI):409.1[M+H] + .

[0746] Example 68

[0747] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)propionitrile

[0748]

[0749] Step 1: Preparation of tert-butyl 4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate

[0750]

[0751] To a solution of 2-chloro-N-(5-methyl-lH-pyrazol-3-yl)thieno[2,3-d]pyrimidin-4- amine (100 mg, 0.376 mmol), l-BOC-4-aminopiperidine (108 mg, 0.539 mmol), DIPEA (146 mg, 1.13 mmol) in NMP (1 mL) was heated to 130 °C for 16 h under microwave. The reaction was cooled to room temperature and poured into ice water (10 mL) and stirred for 10 min. The mixture was filtered, the filter cake was washed with water (5 mL) and dried under vacuum to give the title compound as a yellow solid (100 mg, crude).

[0752] Step 2: Preparation of 3-(4-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)piperidin-l-yl)propanenitrile

[0753]

[0754] To a solution of tert-butyl 4-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2- yl)amino)piperidine-l-carboxylate (100 mg, 0.233 mmol) in methanol (2 mL) was added 4M HC1 in ethyl acetate (2 mL) at room temperature. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure and the residue was re-dissolved in anhydrous methanol (2 mL). DIPEA (150 mg, 1.17 mmol) and acrylonitrile (62 mg, 1.17 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with DCM (20 mL) and washed with water (5 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a white solid (18 mg, 20%).

[0755] 1 H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 6.0 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.55 (s, 0.5H), 5.81 (s, 0.5H), 3.92 - 3.74 (m, 1H), 3.04 - 2.88 (m, 2H), 2.81 - 2.57 (m, 4H), 2.44 - 2.15 (m, 5H), 2.14 - 1.97 (m, 2H), 1.73 - 1.52 (m, 2H).

[0756] MS m / z (ESI): 383.1 [M+H] + .

[0757] Example 69

[0758] 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

[0759]

[0760] 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 was prepared according to Reference Example 8.

[0761] 1 H NMR (400 MHz, CD3OD) δ 7.38 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 6.0 Hz, 1H), 6.49 (s, 0.5H), 5.83 (s, 0.5H), 4.20-4.10 (m, 2H), 4.07-3.99 (m, 2H), 3.99-3.89 (m, 1H), 3.77-3.61 (m, 3H), 3.09-2.99 (m, 2H), 2.28 (s, 3H), 2.17-2.06 (m, 2H), 1.67-1.51 (m, 2H).

[0762] MS m / z (ESI): 474.0 [M+H] + .

[0763] Example 70

[0764] 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

[0765]

[0766] 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 was prepared according to Reference Example 18.

[0767] MS m / z (ESI): 401.2 [M+H] + .

[0768] Example 71

[0769] 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

[0770]

[0771] 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 was prepared according to Reference Example 17.

[0772] MS m / z (ESI): 457.2 [M+H] + .

[0773] Example 72

[0774] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)(pyridin-2-yl)methanone

[0775]

[0776] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)piperidin-1- yl)(pyridin-2-yl)methanone was prepared according to Reference Example 31.

[0777] MS m / z (ESI): 435.2 [M+H] + .

[0778] Example 73

[0779] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)propanenitrile

[0780]

[0781] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)propanenitrile was prepared according to Reference Example 1.

[0782] MS m / z (ESI): 383.2 [M+H] + .

[0783] Example 74

[0784] 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)azetidin-3-carbonitrile

[0785]

[0786] 1-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)sulfonyl)azetidin-3-carbonitrile was prepared according to Reference Example 1.

[0787] MS m / z (ESI): 474.1 [M+H] + .

[0788] Example 75

[0789] 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

[0790]

[0791] 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 was prepared according to Reference Example 17.

[0792] MS m / z (ESI): 457.2 [M+H] + .

[0793] Example 76

[0794] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)(pyridin-2-yl)methanone

[0795]

[0796] (4-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[3,2-d]pyrimidin-2-yl)amino)piperidin-1- yl)(pyridin-2-yl)methanone was prepared according to Reference Example 31.

[0797] MS m / z (ESI): 435.2 [M+H] + .

[0798] Example 77

[0799] 3-(endo-6-((4-((5-methyl-1H-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile

[0800]

[0801] 3-(endo-6-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile was prepared according to Example 3.

[0802] MS m / z (ESI): 381.2 [M+H] + .

[0803] Example 78

[0804] 3-(endo-6-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile

[0805]

[0806] 3-(endo-6-((4-((5-methyl-lH-pyrazol-3-yl)amino)thieno[2,3-d]pyrimidin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile was prepared according to Example 1.

[0807] MS m / z (ESI): 381.2 [M+H] + .

[0808] Example 79

[0809] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0810]

[0811] First Step: Preparation of 2-chloro-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4- amine

[0812]

[0813] To a stirred solution of 2,4-dichloroquinazoline (199 mg, 1.0 mmol), 5-methyl-lH- pyrazol-3-amine (99 mg, 1.02 mmol) and triethylamine (213 mg, 2.1 mmol) in anhydrous ethanol (5 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and the resulting solid was suspended in water-ethanol (v\v=9: 1, 20 mL), filtered and the resulting solid was washed with petroleum ether and dried to give the title compound (240 mg, 92%).

[0814] MS m / z (ESI): 260.1, 262.1 [M+H] + .

[0815] Second Step: Preparation of tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0816]

[0817] To a solution of tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin- 2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.154 mmol) in methanol (3 mL) was added 4 M HC1 in 1,4-dioxane (10 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in anhydrous methanol (10 mL) and stirred at room temperature. Diisopropylethylamine (0.51 mL, 3.08 mmol) and acrylonitrile (10 mg, 0.154 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and reverse phase HPLC to give the title compound (6.0 mg, 10%).

[0818] MS m / z (ESI): 450.2 [M+H] + .

[0819] Third Step: Preparation of 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin- 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0820]

[0821] To a solution of tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin- 2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.154 mmol) in methanol (3 mL) was added 4 M HC1 in 1,4-dioxane (10 mL) at room temperature. The resulting reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. The residue was dissolved in anhydrous methanol (10 mL) and stirred at room temperature. Diisopropylethylamine (0.51 mL, 3.08 mmol) and acrylonitrile (10 mg, 0.154 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography and reverse phase HPLC to give the title compound (6.0 mg, 10%).

[0822] 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.39 (s, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.62 (s, 1H), 4.35 (s, 1H), 3.37 (s, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 2.16 - 1.74 (m, 6H), 1.67 (t, J = 11.7 Hz, 2H).

[0823] MS m / z (ESI): 403.2 [M+H] + .

[0824] Example 80

[0825] 3-((3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0826]

[0827] First Step: Preparation of 2-chloro-7-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinolin-4- amine

[0828]

[0829] To 2,4-dichloro-7-methoxyquinoline (500 mg, 2.18 mmol), 5-methyl-1H-pyrazol-3-amine (223 mg, 2.29 mmol), DIPEA (592 mg, 4.58 mmol) were added separately to anhydrous ethanol (10 mL) and stirred at room temperature for 3 days. The reaction was filtered, the filter cake was washed with acetonitrile (5 mL) and dried under vacuum to give the title compound as a white solid (355 mg, 56%).

[0830] MS m / z (ESI): 290.1 [M+H] + .

[0831] Second Step: Preparation of (3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0832]

[0833] Compound 2-chloro-7-methoxy-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4- amine (355 mg, 1.23 mmol), tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate acetate salt (421 mg, 1.47 mmol) and DIPEA (475 mg, 3.68 mmol) were mixed in n-butanol (7 mL) and the mixture was heated to 150 °C in a microwave and stirred for 4 h. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a white solid (259 mg, 44%).

[0834] MS m / z (ESI): 480.2 [M+H] + .

[0835] Third Step: Preparation of 3-((3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0836]

[0837] Tert-butyl (3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (259 mg, 0.540 mmol) was dissolved in methanol (3 mL) and 4 M HC1 in 1,4-dioxane (4 mL) was added with stirring at room temperature. The reaction was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was re-dissolved in anhydrous methanol (3 mL) and DIPEA (349 mg, 2.70 mmol) and acrylonitrile (43 mg, 0.810 mmol) were added successively. The resulting reaction mixture was stirred at room temperature for 0.5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a white solid (76.8 mg, 33%).

[0838] 1 H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.14 - 6.75 (m, 2H), 6.50 (s, 1H), 4.50 - 4.21 (m, 1H), 3.92 (s, 3H), 3.41 (s, 2H), 2.91 - 2.55 (m, 4H), 2.34 (s, 3H), 2.14 - 1.50 (m, 7H), 1.40 - 1.23 (m, 1H).

[0839] MS m / z (ESI): 433.2 [M+H] + .

[0840] Example 81

[0841] 3-((3-exo)-3-((7-bromo-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0842]

[0843] First Step: Preparation of 7-bromo-2-chloro-N-(5-methyl-lH-pyrazol-3-yl)quinazolin- 4-amine

[0844]

[0845] To a solution of 7-bromo-2,4-dichloroquinazoline (3.36 g, 12.1 mmol), 5-methyl-lH- pyrazol-3-amine (1.29 g, 13.3 mmol), TEA (2.57 g, 25.4 mmol) in anhydrous ethanol (67 mL) was stirred at room temperature for 16 hours. The reaction was filtered, the filter cake was washed with anhydrous ethanol (20 mL) and dried under vacuum to give the title compound as a white solid (4.17 g, 100%).

[0846] Second Step: Preparation of tert-butyl (3-exo)-3-((7-bromo-4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0847]

[0848] To a solution of compound 7-bromo-2-chloro-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4- amine (500 mg, 1.48 mmol), tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8- carboxylate acetate salt (465 mg, 1.62 mmol) and DIPEA (591 mg, 4.58 mmol) in NMP (5 mL) was heated to 130 °C in a microwave and stirred for 4 hours. The reaction was cooled to room temperature and poured into 25 mL of ice water and stirred for 30 minutes. The mixture was filtered, the filter cake was washed with acetonitrile (2 mL) and dried under reduced pressure to give the title compound as a grey solid (877 mg, 100%).

[0849] Step 3: Preparation of 3-((3-exo)-3-((7-bromo-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0850]

[0851] 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 (220 mg, 0.416 mmol) was dissolved in methanol (2 mL), 4M HC1 in 1,4-dioxane (2 mL) was added under stirring at room temperature, the reaction was stirred at room temperature for 2 hours, the reaction was concentrated under reduced pressure, the residue was re-dissolved in anhydrous methanol (2 mL), DIPEA (269 mg, 2.08 mmol) and acrylonitrile (66 mg, 1.25 mmol) were added in turn, the resulting reaction mixture was continuously stirred at room temperature for 1 hour. The reaction was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography to obtain the title compound as a white solid (17.4 mg, 9%).

[0852] 1 H NMR (400 MHz, CD3OD) δ 7.94 (d, J = 8.8 Hz, 1H), 7.74-7.37 (m, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 6.59 (s, 0.8H), 5.92 (s, 0.2H), 4.51-4.12 (m, 1H), 3.42-3.35 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.31 (s, 3H), 2.09-1.61 (m, 8H).

[0853] MS m / z (ESI): 481.1 [M+H] + .

[0854] Example 82

[0855] 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

[0856]

[0857] Step 1: Preparation of 2,7-dichloro-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine

[0858]

[0859] To a solution of 2,4,7-trichloroquinazoline (2.0 g, 8.58 mmol), 5-methyl-lH-pyrazol-3-amine (915 mg, 9.42 mmol), TEA (1.82 g, 18.0 mmol) in anhydrous ethanol (40 mL) was stirred at room temperature for 16 hours. The reaction was filtered, the filter cake was washed with anhydrous ethanol (5 mL) and dried under vacuum to give the title compound as a white solid (2.5 g, 99%).

[0860] MS m / z (ESI): 294.0 [M+H] + .

[0861] Second Step: Preparation of tert-butyl (3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0862]

[0863] To a mixture of compound 2,7-dichloro-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4-amine (500 mg, 1.70 mmol), tert-butyl (3-exo)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate acetate salt (535 mg, 1.87 mmol) and DIPEA (681 mg, 5.27 mmol) in NMP (7 mL) was heated to 180 °C in a microwave and stirred for 2 hours. After the reaction 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 and dried under vacuum, and then purified by silica gel column chromatography to give the title compound as a white solid (405 mg, 49%).

[0864] MS m / z (ESI): 484.2 [M+H] + .

[0865] Third Step: Preparation of 3-((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0866]

[0867] tert-Butyl (3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (405 mg, 0.837 mmol) was dissolved in methanol (4 mL), 4M HC1 in 1,4-dioxane (2.5 mL) was added at room temperature with stirring, the reaction was stirred at room temperature for 1 hour, the reaction was concentrated under reduced pressure, the residue was redissolved in anhydrous methanol (4 mL), DIPEA (486 mg, 3.77 mmol) and acrylonitrile (53 mg, 1.00 mmol) were added in turn, the resulting reaction mixture was continuously stirred at room temperature for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, the residue was separated and purified by silica gel column chromatography, then purified by prep-HPLC to give the title compound as a white solid (40 mg, 11%).

[0868] 1 H NMR (400 MHz, Methanol-d4) δ 8.02 (d, J = 8.8 Hz, 1H), 7.54 - 7.22 (m, 1H), 7.14 - 7.07 (m, 1H), 6.71 - 6.49 (m, 0.6H), 6.05 - 5.76 (m, 0.4H), 4.44 - 4.17 (m, 1H), 3.40 - 3.35 (m, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.46 - 2.12 (m, 3H), 2.07 - 2.00 (m, 2H), 1.96 - 1.75 (m, 4H), 1.71 - 1.61 (m, 2H).

[0869] MS m / z (ESI): 437.2 [M+H] + .

[0870] Example 83

[0871] 3-((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0872]

[0873] 3-((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 82.

[0874] MS m / z (ESI): 437.2 [M+H]+ .

[0875] Example 84

[0876] 3-((3-exo)-3-((5-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0877]

[0878] 3-((3-exo)-3-((5-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 80.

[0879] 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.62 (s, 1H), 7.45 (t, J = 8.0 Hz, 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).

[0880] MS m / z (ESI): 437.2 [M+H] + .

[0881] Example 85

[0882] 3-((3-exo)-3-((8-methyl-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0883]

[0884] 3-((3-exo)-3-((8-methyl-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 80.

[0885] 1H NMR (400 MHz, Methanol-d4) δ 7.86 (d, 1H), 7.44 (d, J = 7.1 Hz, 1H), 7.03 (t, J = 7.7 Hz, 1H), 6.70 - 6.54 (m, 0.6H), 5.96 - 5.84 (m, 0.4H), 4.49 - 4.32 (m, 1H), 3.46 - 3.36 (m, 2H), 2.75 (t, J = 6.9 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H), 2.48 (s, 3H), 2.38 - 2.17 (m, 3H), 2.10 - 1.89 (m, 4H), 1.88 - 1.77 (m, 2H), 1.64 (t, J = 12.0 Hz, 2H).

[0886] MS m / z (ESI): 417.2 [M+H] + .

[0887] Example 86

[0888] 3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0889]

[0890] 3-((3-exo)-3-((8-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 80.

[0891] 1 H NMR (400 MHz, Methanol-d4) δ 8.01 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.83 - 5.77 (m, 1H), 4.52 - 4.26 (m, 1H), 3.57 - 3.36 (m, 2H), 2.94 - 2.71 (m, 2H), 2.71 - 2.53 (m, 2H), 2.32 (s, 3H), 2.19 - 1.49 (m, 8H).

[0892] MS m / z (ESI): 437.2 [M+H] + .

[0893] Example 87

[0894] 3-((3-exo)-3-((6-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0895]

[0896] 3-((3-exo)-3-((6-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 80.

[0897] 1 H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.49 - 7.21 (m, 1H), 6.72 - 6.46 (m, 0.6H), 6.08 - 5.75 (m, 0.4H), 4.46 - 4.20 (m, 1H), 3.41 - 3.36 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.42 - 2.22 (m, 3H), 2.08 - 2.01 (m, 2H), 1.97 - 1.77 (m, 4H), 1.72 - 1.61 (m, 2H).

[0898] MS m / z (ESI): 437.2 [M+H] + .

[0899] Example 87

[0900] 3-((3-exo)-3-((6-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0901]

[0902] 3-((3-exo)-3-((6-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 80.

[0903] 1H NMR (400 MHz, Methanol-d4) δ 8.15 (d, J = 2.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.49 - 7.21 (m, 1H), 6.72 - 6.46 (m, 0.6H), 6.08 - 5.75 (m, 0.4H), 4.46 - 4.20 (m, 1H), 3.41 - 3.36 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.62 (t, J = 7.0 Hz, 2H), 2.42 - 2.22 (m, 3H), 2.08 - 2.01 (m, 2H), 1.97 - 1.77 (m, 4H), 1.72 - 1.61 (m, 2H).

[0904] MS m / z (ESI): 437.2 [M+H] + .

[0905] Example 88

[0906] 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)propanenitrile

[0907]

[0908] First Step: 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

[0909]

[0910] 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 (400 mg, 0.758 mmol), 3-pyridineboronic acid (187 mg, 1.52 mmol), Pd(dppf)Cl2(110 mg, 0.152 mmol), cesium carbonate (740 g, 2.27 mmol) were added into the mixed solvent of dioxane (8 mL) and water (0.8 mL) respectively, and stirred at 100 °C for 1 hour under nitrogen protection. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the title compound as a yellowish gel (160 mg, 40%).

[0911] Step 2: Preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0912]

[0913] 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 (160 mg, 0.302 mmol) was dissolved in methanol (4 mL). 4M HCl in 1,4-dioxane (4 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (2 mL). DIPEA (195 mg, 1.51 mmol) and acrylonitrile (48 mg, 0.906 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for another 2 hours. After the reaction, the mixture was concentrated under reduced pressure and the residue was initially separated and purified by silica gel column chromatography to give a gray solid. The gray solid was slurried with N,N-dimethylformamide / acetonitrile (2 mL / 4 mL). The filtered solid was slurried again with N,N-dimethylformamide / acetonitrile (1.1 mL / 2.2 mL). The solid was filtered and dried in vacuo to give the title compound as a white solid (49 mg, 34%).

[0914] 1 H 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).

[0915] MS m / z(ESI):480.2[M+H] + .

[0916] Example 89

[0917] 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

[0918]

[0919] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(pyridin-4-yl)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 88.

[0920] 1 H NMR (400 MHz, CD3OD) δ 8.73-8.58 (m, 2H), 8.21 (d, J = 8.5 Hz, 1H), 7.95-7.64 (m, 3H), 7.59-7.49 (m, 1H), 6.64 (s, 1H), 4.49-4.22 (m, 1H), 3.45-3.35 (m, 2H), 2.77 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.33 (s, 3H), 2.16-1.58 (m, 8H).

[0921] MS m / z (ESI): 480.2 [M+H] + .

[0922] Example 90

[0923] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(pyridin-2-yl)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0924]

[0925] 3-((3-exo)-3-((7-fluoro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 88.

[0926] MS m / z (ESI): 480.3 [M+H] + .

[0927] Example 91

[0928] 3-((3-exo)-3-((7-(5-methoxypyridin-3-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin- 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0929]

[0930] 3-((3-exo)-3-((7-(5-methoxypyridin-3-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin- 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 88.

[0931] 1 H NMR (400 MHz, CD3OD) δ 8.54 - 8.41 (m, 1H), 8.27 (d, J = 2.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.88 - 7.56 (m, 2H), 7.47 (dd, J = 8.5, 1.8 Hz, 1H), 6.62 (s, 1H), 4.49 - 4.25 (m, 1H), 3.97 (s, 3H), 3.44 - 3.37 (m, 2H), 2.76 (t, J = 7.0 Hz, 2H), 2.63 (t, J = 7.0 Hz, 2H), 2.32 (s, 3H), 2.10 - 1.64 (m, 8H).

[0932] MS m / z (ESI): 510.2 [M+H] + .

[0933] Example 92

[0934] 3-((3-exo)-3-((7-(6-methoxypyridin-3-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin- 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0935]

[0936] 3-((3-exo)-3-((7-(6-methoxypyridin-3-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin- 2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 88.

[0937] MS m / z (ESI): 510.3 [M+H] + .

[0938] Example 93

[0939] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-phenylquinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0940]

[0941] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-phenylquinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 88.

[0942] 1 H NMR (400 MHz, DMSO-d6, small amount of CD3OD) δ 8.47 - 8.23 (m, 1H), 7.88 - 7.69 (m, 2H), 7.67 - 7.25 (m, 5H), 6.92 - 6.62 (m, 0.8H), 5.88 (s, 0.2H), 4.41 - 4.20 (m, 1H), 3.58 (s, 2H), 2.76 - 2.57 (m, 4H), 2.38 - 2.11 (m, 3H), 2.06 - 1.47 (m, 8H).

[0943] MS m / z (ESI): 479.3 [M+H] + .

[0944] Example 94

[0945] 3-((3-exo)-3-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0946]

[0947] First Step: Preparation of tert-butyl (3-exo)-3-((7-(l-cyclopropyl-lH-pyrazol-4-yl)-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[0948]

[0949] 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 (100 mg, 0.189 mmol), (1-cyclopropyl-1H-pyrazol-4-yl)boronic acid (35 mg, 0.227 mmol), cesium carbonate (185 mg, 0.567 mmol), chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (X-Phos Pd G2) (15 mg, 0.0189 mmol) were added to a mixed solvent of dioxane (2 mL) and water (0.4 mL). After nitrogen replacement three times, the temperature was raised to 100°C and stirred for 2 hours. The reaction solution was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound as a brown oil (60 mg, 57%).

[0950] Step 2: Preparation of 3-((3-exo)-3-((7-(1-cyclopropyl-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0951]

[0952] 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 (60 mg, 0.108 mmol) was dissolved in methanol (2 mL), and 4 M HCl in 1,4-dioxane (2 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was redissolved in anhydrous methanol (1 mL). DIPEA (70 mg, 0.542 mmol) and acrylonitrile (17 mg, 0.324 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with DCM (30 mL), washed with water (10 mL), and concentrated under reduced pressure. The residue was initially separated and purified by silica gel chromatography to obtain the title compound as a gray solid (20 mg, 36%).

[0953] 1H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.72 - 7.34 (m, 2H), 6.60 (s, 1H), 4.45 - 4.23 (m, 1H), 3.78 - 3.67 (m, 1H), 3.43 - 3.36 (m, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.09 - 1.64 (m, 8H), 1.24 - 1.00 (m, 4H).

[0954] MS m / z (ESI): 509.2 [M+H] + .

[0955] Example 95

[0956] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(l-methyl-lH-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0957]

[0958] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(l-methyl-lH-pyrazol-4-yl)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 94.

[0959] 1 H NMR (400 MHz, CD3OD) δ 8.20 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.72 - 7.34 (m, 2H), 6.60 (s, 1H), 4.45 - 4.23 (m, 1H), 3.78 - 3.67 (m, 1H), 3.43 - 3.36 (m, 2H), 2.76 (t, J = 6.8 Hz, 2H), 2.63 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.09 - 1.64 (m, 8H), 1.24 - 1.00 (m, 4H).

[0960] MS m / z (ESI): 483.2 [M+H] + .

[0961] Example 96

[0962] 3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0963]

[0964] 3-((3-exo)-3-((7-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 94.

[0965] MS m / z (ESI): 515.3 [M+H] + .

[0966] Example 97

[0967] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazol-4-yl)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[0968]

[0969] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(thiazol-4-yl)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 94.

[0970] MS m / z (ESI): 486.2 [M+H] + .

[0971] Example 98

[0972] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinolin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propanenitrile

[0973]

[0974] Refer to Example 88 for the preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyridin-3-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propionitrile.

[0975] MS m / z(ESI):494.3[M+H] + .

[0976] Example 99

[0977] 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

[0978]

[0979] Refer to Example 88 for the preparation of 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(1-methyl-1H-pyrazol-4-yl)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propionitrile.

[0980] MS m / z(ESI):497.3[M+H] + .

[0981] Example 100

[0982] 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

[0983]

[0984] Step 1: 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

[0985]

[0986] To a solution of tert-butyl (3-exo)-3-((7-bromo-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 0.568 mmol), morpholine (494 mg, 5.68 mmol), Pd2(dba)3(104 mg, 0.114 mmol), DavePhos (90 mg, 0.227 mmol), t-BuONa (109 mg, 1.14 mmol) in dioxane (6 mL) was heated to 100 °C under nitrogen for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), washed with water (20 mL), saturated aqueous sodium chloride solution (10 mL), and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give the title compound as a light yellow oil (66 mg, 22%).

[0987] Second Step: Preparation of 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile

[0988]

[0989] To a solution of tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-morpholinoquinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (66 mg, 0.123 mmol) in methanol (2 mL) was added 4 M HC1 in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous methanol (1 mL). DIPEA (80 mg, 0.617 mmol) and acrylonitrile (20 mg, 0.369 mmol) were added sequentially, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, followed by preparative TLC to give the title compound as a gray solid (12 mg, 20%).

[0990] 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).

[0991] MS m / z(ESI):488.2[M+H] + .

[0992] Example 101

[0993] 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

[0994]

[0995] The 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 was carried out according to Example 100.

[0996] MS m / z(ESI):488.3[M+H] + .

[0997] Example 102

[0998] 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

[0999]

[1000] The preparation of 3-((3-exo)-3-((7-(4-methoxypiperidin-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile was carried out according to Example 100.

[1001] MS m / z(ESI):516.3[M+H] +.

[1002] Example 103

[1003] 3-((3-exo)-3-((7-(4-(dimethylamino)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3- yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1004]

[1005] 3-((3-exo)-3-((7-(4-(dimethylamino)piperidin-1-yl)-4-((5-methyl-1H-pyrazol-3- yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 100.

[1006] MS m / z (ESI): 529.3 [M+H] + .

[1007] Example 104

[1008] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidin-1-yl)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1009]

[1010] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(pyrrolidin-1-yl)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 100.

[1011] MS m / z (ESI): 472.3 [M+H] + .

[1012] Example 105

[1013] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(methylamino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1014]

[1015] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(((l- methylazetidin-3-yl)methyl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 100.

[1016] MS m / z (ESI): 432.3 [M+H] + .

[1017] Example 106

[1018] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(((l- methylazetidin-3-yl)methyl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1019]

[1020] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(((l- methylazetidin-3-yl)methyl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 100.

[1021] MS m / z (ESI): 502.3 [M+H] + .

[1022] Example 107

[1023] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(((l- methylazetidin-3-yl)methyl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1024]

[1025] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(((l- methylazetidin-3-yl)methyl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 100.

[1026] MS m / z (ESI): 501.3 [M+H] + .

[1027] Example 108

[1028] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1029]

[1030] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((tetrahydro-2H-pyran-4- yl)methyl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 100.

[1031] MS m / z (ESI): 516.3 [M+H] + .

[1032] Example 109

[1033] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylpiperidin-4- yl)methyl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1034]

[1035] 3-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)-7-(((1-methylpiperidin-4- yl)methyl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 100.

[1036] MS m / z (ESI): 529.3 [M+H] + .

[1037] Example 110

[1038] 3-((3-exo)-3-((7-(methyl(piperidin-4-yl)methyl)amino)-4-((5-methyl-1H-pyrazol-3- yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1039]

[1040] The preparation of 3-((3-exo)-3-((7-(methyl(pyridin-3-ylmethyl)amino)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile was carried out according to Example 100.

[1041] MS m / z(ESI):523.3[M+H] + .

[1042] Example 111

[1043] 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

[1044]

[1045] The 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 was carried out according to Example 100.

[1046] MS m / z(ESI):502.3[M+H] + .

[1047] Example 112

[1048] 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

[1049]

[1050] The preparation of 3-((3-exo)-3-((7-(1H-imidazol-1-yl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propionitrile was carried out according to Example 100.

[1051] 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.70 (s, 1H), 7.64 - 7.26 (m, 2H), 7.19 (s, 1H), 6.62 (s, 0.8H), 5.93 (s, 0.2H), 4.47 - 4.22 (m, 1H), 3.41 - 3.36 (m, 2H), 2.76 (t, J = 6.9 Hz, 2H), 2.63 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.08 - 2.01 (m, 2H), 2.00 - 1.79 (m, 4H), 1.74 - 1.63 (m, 2H).

[1052] MS m / z (ESI): 469.2 [M+H] + .

[1053] Example 113

[1054] 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)propanenitrile

[1055]

[1056] 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)propanenitrile was prepared according to Reference Example 80.

[1057] MS m / z (ESI): 477.3 [M+H] + .

[1058] Example 114

[1059] 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)propanenitrile

[1060]

[1061] 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)propanenitrile was prepared according to Reference Example 80.

[1062] MS m / z (ESI): 503.3 [M+H] + .

[1063] Example 115

[1064] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l-methylazetidin-3- yl)methoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1065]

[1066] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l-methylazetidin-3- yl)methoxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 80.

[1067] MS m / z (ESI): 502.3 [M+H] + .

[1068] Example 116

[1069] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxy)quinazolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1070]

[1071] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(pyridin-3-ylmethoxy)quinazolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Reference Example 80.

[1072] MS m / z (ESI): 510.3 [M+H] + .

[1073] Example 117

[1074] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l-methylazetidin-3- yl)oxy)quinazolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1075]

[1076] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l- methylpiperidin-4-yl)oxy)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8- yl)propanenitrile

[1077] MS m / z (ESI): 488.3 [M+H] + .

[1078] Example 118

[1079] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l- methylpiperidin-4-yl)oxy)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8- yl)propanenitrile

[1080]

[1081] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-((l- methylpiperidin-4-yl)oxy)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8- yl)propanenitrile

[1082] MS m / z (ESI): 516.3 [M+H] + .

[1083] Example 119

[1084] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinolin- 2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propanenitrile

[1085]

[1086] 3-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)-7-(morpholinomethyl)quinolin- 2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propanenitrile

[1087] MS m / z (ESI): 516.3 [M+H] + .

[1088] Example 120

[1089] 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)propanenitrile

[1090]

[1091] 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)propanenitrile was prepared according to Reference Example 80.

[1092] MS m / z (ESI): 486.3 [M+H] + .

[1093] Example 121

[1094] 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)propanenitrile

[1095]

[1096] 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)propanenitrile was prepared according to Reference Example 80.

[1097] MS m / z (ESI): 473.3 [M+H] + .

[1098] Example 122

[1099] 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

[1100]

[1101] tert-Butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4 M HC1 in 1,4-dioxane (10 mL) and the reaction stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.73 mL, 4.44 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (44 mg, 0.244 mmol) were added sequentially and the reaction mixture stirred at 0 °C for 5 hours. The solvent was removed under reduced pressure and the residue separated by reverse phase HPLC to give the title compound (59.3 mg, 54%).

[1102] 1 H NMR (400 MHz, CD3OD) δ 8.12 (s, 1H), 7.50 (s, 1H), 7.29 (d, J = 44.1 Hz, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.36 (s, 1H), 4.12 (s, 2H), 4.03 (t, J = 8.4 Hz, 2H), 3.90 (t, J = 7.0 Hz, 2H), 3.69-3.57 (m, 1H), 2.20 (s, 3H), 2.10-1.51 (m, 8H).

[1103] MS m / z (ESI): 494.2 [M+H] + .

[1104] Example 123

[1105] 1-(((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile

[1106]

[1107] tert-Butyl (3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (174 mg, 0.36 mmol) was dissolved in a 4 M HC1 solution in 1,4-dioxane (20 mL) and the reaction stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in anhydrous N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (1.19 mL, 7.2 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (78 mg, 0.432 mmol) were added sequentially and the reaction mixture stirred at 0 °C for 16.5 hours. The solvent was removed under reduced pressure and the residue separated by reverse phase HPLC to give the title compound (17.7 mg, 9%).

[1108] 1 H NMR (400 MHz, MeOD-d4) δ 8.02 (s, 1H), 7.42 (s, 1H), 7.20 (s, 1H), 6.57 (s, 1H), 4.51-4.40 (m, 1H), 4.27 (s, 2H), 4.17 (t, J = 8.5 Hz, 2H), 4.13-4.05 (m, 2H), 3.64-3.53 (m, 1H), 2.34 (s, 3H), 2.16 (s, 4H), 1.98 (d, J = 42.2 Hz, 2H), 1.76 (t, J = 11.9 Hz, 2H).

[1109] MS m / z (ESI): 528.2 [M+H] + .

[1110] Example 124

[1111] 1-(((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile

[1112]

[1113] 1-(((3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile was prepared according to Example 122.

[1114] 1H NMR (400 MHz, CD3OD) δ 8.11 (dd, J = 9.1, 6.1 Hz, 1H), 7.21 - 6.82 (m, 2H), 6.56 (s, 0.8H), 5.88 (s, 0.2H), 4.58 - 4.34 (m, 1H), 4.29 - 4.19 (m, 2H), 4.17 - 4.08 (m, 2H), 4.06 - 3.96 (m, 2H), 3.72 - 3.58 (m, 1H), 2.31 (s, 3H), 2.18 - 1.85 (m, 6H), 1.82 - 1.66 (m, 2H).

[1115] MS m / z (ESI): 512.1 [M+H] + .

[1116] Example 125

[1117] 1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile

[1118]

[1119] 1-(((3-exo)-3-((7-cyclopropyl-4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)- 8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile was prepared according to Example 122.

[1120] 1 H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.26 - 6.93 (m, 2H), 6.50 (s, 1H), 4.58 - 4.37 (m, 1H), 4.31 - 4.18 (m, 2H), 4.18 - 4.07 (m, 2H), 4.06 - 3.95 (m, 2H), 3.71 - 3.58 (m, 1H), 2.32 (s, 3H), 2.17 - 1.71 (m, 8H), 1.34 - 1.25 (m, 1H), 1.19 - 1.03 (m, 2H), 0.94 - 0.75 (m, 2H).

[1121] MS m / z (ESI): 534.1 [M+H] + .

[1122] Example 126

[1123] 3-((3-exo)-3-(((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-9- azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile

[1124]

[1125] First Step: Preparation of tert-butyl-(3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1126]

[1127] To a solution of 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)quinolin-4-amine (200 mg, 0.77 mmol) in n-butanol (10 mL), tert-butyl-(3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate (222 mg, 0.92 mmol), DIPEA (199 mg, 1.54 mmol) were added successively, then stirred under microwave condition at 170 °C for 4 h. The reaction was extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride solution (15 mL x 3), the organic phase was collected and dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated under reduced pressure, the resulting product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to give the title compound as a white solid (275 mg, 77%).

[1128] MS m / z (ESI): 464.2 [M+H] + .

[1129] Third Step: Preparation of 3-((3-exo)-3-(((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile

[1130]

[1131] tert-Butyl-(3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9- azabicyclo[3.3.1]nonane-9-carboxylate (100 mg, 0.21 mmol) was dissolved in 1,4-oxane hydrochloric acid solution (4.0 N, 5 mL), after stirring at room temperature for 30 minutes, the reaction was concentrated; then it was dissolved in N,N-dimethylformamide (10 mL), DIPEA (108 mg, 0.84 mmol) was added slowly dropwise, stirred at room temperature for 10 minutes, after adding 3-nitrile azetidine-1-sulfonyl chloride (45 mg, 0.25 mmol), continue to stir at room temperature overnight. The reaction was concentrated under reduced pressure, and the product was obtained by prep-HPLC to obtain the title compound white solid (30.5 mg, 29%).

[1132] 1 H NMR (400 MHz, DMSO) δ = 12.09 (s, 1H), 10.04 (s, 1H), 8.24 (s, 1H), 7.45 (s, 1H), 7.33-6.42 (m, 4H), 4.79 (s, 1H), 4.01-3.79 (m, 6H), 3.74-3.67 (m, 1H), 2.15 (s, 3H), 2.09-1.57 (m, 10H).

[1133] MS m / z (ESI): 508.2 [M+H] + .

[1134] Example 127

[1135] 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8- azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine-3-carbonitrile

[1136]

[1137] First step reaction: Preparation of 2-chloro-7-methoxy-N-(5-methyl-lH-pyrazol-3-yl)quinazoline-4- amine

[1138]

[1139] To a solution of 2,4-dichloro-7-methoxyquinazoline (497 mg, 2.17 mmol), 5-methyl-lH-pyrazol-3-amine (221 mg, 2.28 mmol) and DIPEA (0.75 mL, 4.56 mmol) in anhydrous ethanol (10 mL) was stirred at room temperature for 24 hours and then heated to 50 °C for 5 hours. The solvent was removed by concentration under reduced pressure, the residue was washed with a mixture of ethanol-water (v / v = 1:9, 20 mL), and the filtrate was dried under reduced pressure to give the title compound (509 mg, 81%).

[1140] MS m / z (ESI): 290.0 [M+H] + .

[1141] Second Step Reaction: Preparation of tert-butyl (3-exo)-3-((7-methoxy-4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate

[1142]

[1143] To a solution of 2-chloro-7-methoxy-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4-amine (150 mg, 0.518 mmol), tert-butyl (3-exo)-3-(methylamino)-8-azabicyclo[3.2.1]octane-8- carboxylate (249 mg, 1.036 mmol) and DIPEA (0.43 mL, 2.59 mmol) in n-butanol (3 mL) was heated to 170 °C for 6 hours in a microwave synthesizer. The solvent was removed by concentration under reduced pressure, and the residue was separated by reverse phase column chromatography to give the title compound (193 mg, 75%).

[1144] MS m / z (ESI): 494.2 [M+H] + .

[1145] Third Step Reaction: Preparation of l-(((3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)azetidine- 3-carbonitrile

[1146]

[1147] Tert-butyl (3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (193 mg, 0.39 mmol) was dissolved in 4 M HC1 in 1,4-dioxane (20 mL) and stirred at room temperature for 60 min. The solvent was removed under reduced pressure and the residue was dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (1.93 mL, 11.7 mmol) and 3-cyanoazetidine-1-sulfonyl chloride (71 mg, 0.39 mmol) were added sequentially and the reaction mixture was stirred at 0 °C for 4 h. The solvent was removed under reduced pressure and the residue was separated by prep-HPLC to give the title compound (97 mg, 46%).

[1148] 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 9.77 (s, 1H), 8.23 (d, J = 8.9 Hz, 1H), 6.72 (s, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 5.40-5.25 (m, 1H), 4.18 (s, 2H), 4.06 (t, J = 8.6 Hz, 2H), 4.01-3.92 (m, 2H), 3.87-3.74 (m, 4H), 2.96 (s, 3H), 2.23 (s, 3H), 2.06-1.89 (m, 4H), 1.83 (d, J = 5.8 Hz, 2H), 1.61 (d, J = 11.2 Hz, 2H).

[1149] MS m / z (ESI): 538.2 [M+H] + .

[1150] Example 128

[1151] 1-(((3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-9- azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile

[1152]

[1153] First step reaction: Tert-butyl (3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

[1154]

[1155] To 2-chloro-7-methoxy-N-(5-methyl-lH-pyrazol-3-yl)quinazolin-4-amine (50 mg, 0.173 mmol) and tert-butyl (3-exo)-3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate oxalate (171 mg, 0.518 mmol) in n-butanol (10 mL) was heated to 170 °C in a microwave synthesizer for 8 h. The solvent was removed by concentration under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (68 mg, 80%).

[1156] MS m / z (ESI): 494.2 [M+H] + .

[1157] Second step reaction: l-(((3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)sulfonyl)azetidine-3-carbonitrile

[1158]

[1159] To tert-butyl (3-exo)-3-((7-methoxy-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (68 mg, 0.138 mmol) was dissolved in 4 M HC1 in 1,4-dioxane (15 mL) and stirred at room temperature for 60 min. The solvent was removed by concentration under reduced pressure and the residue was dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.68 mL, 4.14 mmol) and 3-cyanoazetidine-l-sulfonyl chloride (25 mg, 0.138 mmol) were added sequentially and the reaction mixture was stirred at 0 °C for 8 h. The solvent was removed by concentration under reduced pressure and the residue was purified by prep-HPLC to give the title compound (6.9 mg, 9%).

[1160] 1 H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.83 (s, 1H), 8.24 (d, J = 7.3 Hz, 1H), 6.65 (dd, J = 29.7, 20.4 Hz, 4H), 4.83 (s, 1H), 4.02 (t, J = 8.5 Hz, 2H), 3.92 (dd, J = 14.9, 8.4 Hz, 4H), 3.87 - 3.73 (m, 4H), 2.21 (s, 3H), 2.04 (d, J = 4.3 Hz, 3H), 1.92 - 1.68 (m, 7H).

[1161] MS m / z (ESI): 538.2 [M+H] + .

[1162] Example 129

[1163]

[1164] tert-Butyl (3-exo)-3-((7-chloro-4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate was dissolved in dichloromethane (2 mL), 4M HC1 in 1,4-dioxane (20 mL) was added, and the reaction mixture was stirred at room temperature 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 (8 mL), cooled to 0 °C in an ice water bath, and DIPEA (1.2 mL, 7.1 mmol), dimethylglycine (0.31 mL, 4.72 mmol), and HATU (118 mg, 0.31 mmol) were added sequentially with stirring. The resulting reaction mixture was stirred at 0 °C for 60 minutes. The solvent was removed by concentration under reduced pressure, and the crude product was separated by prep-HPLC to give the title compound as a white solid (20.7 mg, 21%).

[1165] 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.33 (s, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 7.13 - 6.86 (m, 2H), 6.60 (s, 1H), 4.52 (s, 1H), 4.42 (d, J=3.4 Hz, 2H), 3.16 (s, 2H), 2.38 - 2.12 (m, 9H), 2.05 - 1.94 (m, 2H), 1.93 - 1.73 (m, 4H), 1.63 - 1.46 (m, 2H).

[1166] MS m / z (ESI): 469.1 [M+H] + .

[1167] Example 130

[1168] 2-(Dimethylamino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one

[1169]

[1170] 2-(dimethylamino)-l-((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2- yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)ethan-l-one was prepared according to Reference Example 129.

[1171] 1 H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.13 (s, 1H), 8.33 (s, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 30.8 Hz, 1H), 7.08 (s, 1H), 6.78 (s, 1H), 6.61 (s, 1H), 4.56 (d, J = 6.1 Hz, 1H), 4.48 (s, 1H), 4.32 (d, J = 5.3 Hz, 1H), 3.65 (dd, J = 32.9, 14.8 Hz, 2H), 2.53 (s, 6H), 2.25 (s, 3H), 1.94 (ddd, J = 36.8, 20.0, 10.6 Hz, 6H), 1.56 (dd, J = 19.2, 9.5 Hz, 2H).

[1172] MS m / z (ESI): 435.2 [M+H] + .

[1173] Example 131

[1174] ((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)(pyridin-2-yl)methanone

[1175]

[1176] ((3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)(pyridin-2-yl)methanone was prepared according to Reference Example 129.

[1177] 1H NMR (400 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.80 (s, 1H), 10.33 (s, 1H), 8.61 (d, J = 4.3 Hz, 1H), 8.52 - 8.24 (m, 1H), 7.96 (td, J = 7.8, 1.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.71 - 7.57 (m, 1H), 7.52 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.39 (d, J = 18.4 Hz, 1H), 7.21 (d, J = 39.2 Hz, 1H), 6.60 (s, 1H), 4.74 (s, 1H), 4.69 - 4.44 (m, 2H), 2.27 (s, 3H), 2.12 - 1.69 (m, 8H).

[1178] MS m / z (ESI): 455.2 [M+H] + .

[1179] Example 132

[1180] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)(pyridin-3-yl)methanone

[1181]

[1182] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)(pyridin-3-yl)methanone was prepared according to Example 129.

[1183] 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 10.36 (s, 1H), 10.05 (s, 1H), 8.78 - 8.62 (m, 2H), 8.34 (d, J = 29.6 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.62 - 7.48 (m, 2H), 7.31 (dd, J = 19.3, 8.1 Hz, 1H), 7.12 (s, 1H), 6.60 (s, 1H), 4.68 (d, J = 4.8 Hz, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.02 (d, J = 3.1 Hz, 1H), 2.25 (s, 3H), 2.16 - 1.48 (m, 8H).

[1184] MS m / z (ESI): 455.2 [M+H]+ .

[1185] Example 133

[1186] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)(pyridin-4-yl)methanone

[1187]

[1188] ((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)(pyridin-4-yl)methanone was prepared according to Reference Example 129.

[1189] 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 10.21 (s, 1H), 8.70 (d, J = 5.5 Hz, 2H), 8.32 (dd, J = 28.3, 8.1 Hz, 1H), 7.59 - 7.51 (m, 1H), 7.45 (d, J = 1.8 Hz, 2H), 7.36 - 7.22 (m, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.86 (s, 1H), 6.59 (s, 1H), 4.67 (d, J = 4.9 Hz, 1H), 4.61 - 4.44 (m, 1H), 3.94 (d, J = 1.9 Hz, 1H), 2.24 (s, 3H), 2.09 - 1.53 (m, 8H).

[1190] MS m / z (ESI): 455.2 [M+H] + .

[1191] Example 134

[1192] 2,2-difluoro-1-((3-exo)-3-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinolin-2-yl)amino)-8- azabicyclo[3.2.1]octan-8-yl)ethan-1-one

[1193]

[1194] tert-Butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.222 mmol) was dissolved in a 4 M solution of HC1 in 1,4-dioxane (10 mL) and the reaction stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue dissolved in dry N,N- dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.73 mL, 4.44 mmol) was added and the mixture stirred until homogeneous before adding a mixture of difluoroacetic acid (0.023 mL, 0.233 mmol) and HATU (169 mg, 4.44 mmol) previously dissolved in 1 mL of dry N,N-dimethylformamide and stirred at 0 °C for 1 hour. The solvent was removed under reduced pressure and the residue separated by reverse phase HPLC to give the title compound (48.9 mg, 52%).

[1195] 1 H NMR (400 MHz, MeOD-d4) δ 7.99 (d, J = 7.7 Hz, 1H), 7.56 - 7.44 (m, 1H), 7.40 - 7.19 (m, 1H), 7.13 - 7.03 (m, 1H), 6.55 (d, J = 4.7 Hz, 1H), 6.33 (t, J = 53.6 Hz, 1H), 4.57 (s, 2H), 4.46 - 4.40 (m, 1H), 2.18 (d, J = 33.6 Hz, 3H), 2.09 - 1.75 (m, 6H), 1.56 (t, J = 12.1 Hz, 2H).

[1196] MS m / z (ESI): 428.1 [M+H] + .

[1197] Example 135

[1198] N4-(5-methyl-lH-pyrazol-3-yl)-N2-((3-exo)-8-(pyridin-3-ylsulfonyl)-8-azabicyclo[3.2.1] octan-3-yl)quinazoline-2,4-diamine

[1199]

[1200] Tert-butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4 M HC1 in 1,4-dioxane (10 mL) and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure and the residue was dissolved in anhydrous N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.73 mL, 4.44 mmol) and 3-pyridinesulfonyl chloride hydrochloride (50 mg, 0.233 mmol) were added sequentially and the reaction mixture was stirred at 0 °C for 0.5 hours. The solvent was removed by concentration under reduced pressure and the residue was separated by reverse phase HPLC to give the title compound (20.5 mg, 19%).

[1201] 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 2.0 Hz, 1H), 8.76 (dd, J = 4.8, 1.4 Hz, 1H), 8.27 - 8.19 (m, 1H), 8.14 - 8.01 (m, 1H), 7.60 - 7.44 (m, 2H), 7.29 (ddd, J = 15.0, 9.9, 4.2 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.58 - 6.39 (m, 1H), 4.30 (dd, J = 6.0, 2.6 Hz, 3H), 2.17 (s, 3H), 2.08 - 1.95 (m, 2H), 1.74 (dd, J = 16.7, 6.2 Hz, 2H), 1.64 (dd, J = 17.3, 6.7 Hz, 2H), 1.43 - 1.32 (m, 2H).

[1202] MS m / z (ESI): 491.1 [M+H] + .

[1203] Example 136

[1204] 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

[1205]

[1206] tert-Butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.222 mmol) was dissolved in a 4 M solution of HC1 in 1,4-dioxane (10 mL) and the reaction stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure and the residue dissolved in dry N,N-dimethylformamide (10 mL) and cooled to 0 °C. DIPEA (0.73 mL, 4.44 mmol) and 2-methoxyethane-l-sulfonyl chloride (37 mg, 0.233 mmol) were added sequentially and the reaction mixture stirred at 0 °C for a further 2 hours. The solvent was removed by concentration under reduced pressure and the residue separated by reverse phase HPLC to give the title compound (25.1 mg, 43%).

[1207] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.24 (dd, J = 23.8, 8.5 Hz, 1H), 6.61 (s, 1H), 4.49 - 4.43 (m, 1H), 4.26 (s, 2H), 3.76 (t, J = 6.2 Hz, 2H), 3.43 - 3.29 (m, 5H), 2.32 (s, 3H), 2.11 - 1.86 (m, 6H), 1.74 (t, J = 13.5 Hz, 2H).

[1208] MS m / z (ESI): 472.2 [M+H] + .

[1209] Example 137

[1210] N2-((3-exo)-8-(2-Fluoroethyl)-8-azabicyclo[3.2.1]octan-3-yl)-N4-(5-methyl-lH-pyrazol-3- yl)quinazoline-2,4-diamine

[1211]

[1212] tert-Butyl (3-exo)-3-((4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (100 mg, 0.222 mmol) was dissolved in 4 M HCI in 1,4-dioxane (10 mL) and stirred at room temperature for 30 minutes. The solvent was removed by concentration under reduced pressure and the residue was dissolved in dry N,N- dimethylformamide (5 mL) and dry potassium carbonate (184 mg, 1.33 mmol) and 1-bromo-2- fluoroethane (50 mg, 0.233 mmol) were added sequentially and the reaction mixture was stirred at 40 °C for 19 hours. The solvent was removed by concentration under reduced pressure and the residue was separated by reverse phase HPLC to give the title compound (27.3 mg, 31%).

[1213] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 17.8 Hz, 1H), 7.56 (s, 1H), 7.35 (d, J = 44.5 Hz, 1H), 7.11 (s, 1H), 6.71 (s, 1H), 4.64 - 4.45 (m, 2H), 4.33 - 4.19 (m, 1H), 3.35 (s, 2H), 2.91 - 2.68 (m, 2H), 2.32 (s, 3H), 2.11 - 1.56 (m, 8H).

[1214] MS m / z (ESI): 396.2 [M+H] + .

[1215] Example 138

[1216] 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonan-9-yl)propanenitrile

[1217]

[1218] First Step: Preparation of (3-((2,7-dichloroquinazolin-4-yl)amino)-lH-pyrazol-5-yl)methanol

[1219]

[1220] To a solution of 2,4,7-trichloroquinazoline (300 mg, 1.29 mmol), (3-amino-lH- pyrazol-5-yl)methanol (180 mg, 1.55 mmol), DIPEA (500 mg, 3.87 mmol) in 1,4- dioxane (5 mL) was stirred at room temperature overnight. The resulting crude was concentrated under reduced pressure, and methanol (5 mL) was added. The solid was dried to give the title compound as a white solid (350 mg, 87%).

[1221] MS m / z (ESI): 310.0 [M+H] + .

[1222] Step 2: Preparation of tert-butyl (3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH-pyrazol-3- yl)amino)quinazolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate

[1223]

[1224] To a solution of (3-((2,7-dichloroquinazolin-4-yl)amino)-lH-pyrazol-5-yl)methanol (150 mg, 0.49 mmol), tert-butyl (3-exo)-3-(methylamino)-9-azabicyclo[3.3.1]nonane-9- carboxylate (150 mg, 0.58 mmol), DIPEA (190 mg, 1.47 mmol) in n-butanol (2 mL) was stirred at 150 °C for 10 h. The resulting crude was concentrated under reduced pressure, and purified by flash silica gel column chromatography to give the title compound as a white solid (140 mg, 55%).

[1225] MS m / z (ESI): 528.2 [M+H] + .

[1226] Step 3: Preparation of 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH-pyrazol-3- yl)amino)quinazolin-2-yl)(methyl)amino)-9-azabicyclo[3.3.1]nonanyl)propanenitrile

[1227]

[1228] To a solution of tert-butyl (3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH- pyrazol-3-yl)amino)quinolin-2-yl)(methyl)amino)-8-azabicyclo[3.2.1]octane-8- carboxylate (140 mg, 0.27 mmol) in methanol (10 mL), hydrochloric acid dioxane (4 N, 2 mL) was added slowly dropwise and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure and the resulting crude was dissolved in methanol (15 mL). DIPEA (0.5 mL) and acrylonitrile (25 mg, 0.46 mmol) were added sequentially at room temperature and the reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure and purified by prep-HPLC to give the title compound as a white solid (22 mg, 20%).

[1229] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 10.02 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.52-6.54 (m, 1H), 5.53-5.55 (m, 1H), 5.25 (s, 1H), 4.46 (t, J = 5.2 Hz, 2H), 3.31-2.87 (m, 7H), 2.66-2.59 (m, 2H), 2.08-1.87 (m, 5H), 1.60-1.41 (m, 5H).

[1230] MS m / z (ESI): 481.2 [M+H] + .

[1231] Example 139

[1232] 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)quinolin-2- yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile

[1233]

[1234] 3-((3-exo)-3-((7-chloro-4-((5-(hydroxymethyl)-lH-pyrazol-3-yl)amino)quinolin-2- yl)(methyl)amino)-8-azabicyclo[3.2.1]octan-8-yl)propanenitrile was prepared according to Example 138.

[1235] H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.08 (d, J = 8.8 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.62 - 6.54 (m, 1H), 5.27 - 5.11 (m, 2H), 4.50 (d, J = 5.6 Hz, 2H), 3.31 - 2.27 (m, 2H), 2.94 (d, J = 16.0 Hz, 3H), 2.67 - 2.58 (m, 4H), 1.92 - 1.81 (m, 4H), 1.71 - 1.62 (m, 2H), 1.39 - 1.23 (m, 2H).

[1236] MS m / z (ESI): 467.2 [M+H] + .

[1237] Example 140

[1238] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propanenitrile

[1239]

[1240] 3-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)piperidin-1-yl)propanenitrile was prepared according to Example 68.

[1241] 1 H NMR (400 MHz, CD3OD:CDCl3, v / v = 1:1) δ 8.03 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.63 (s, 1H), 5.92 (s, 1H), 4.01 - 3.87 (m, 1H), 2.98 (d, J = 11.6 Hz, 2H), 2.77 (t, J = 6.9 Hz, 2H), 2.64 (t, J = 6.9 Hz, 2H), 2.45 - 2.22 (m, 5H), 2.19 - 2.07 (m, 2H), 1.65 (td, J = 14.0, 3.4 Hz, 2H).

[1242] MS m / z (ESI): 377.1 [M+H] + .

[1243] Example 141

[1244] 1 -((4-((4-((5-methyl- 1 H-pyrazol-3 -yl)amino)quinazolin-2-yl)amino)piperidin- 1 - yl)sulfonyl)azetidine-3-carbonitrile

[1245]

[1246] 1 -((4-((4-((5-methyl- 1 H-pyrazol-3 -yl)amino)quinazolin-2-yl)amino)piperidin- 1 - yl)sulfonyl)azetidine-3-carbonitrile was prepared according to Reference Example 122.

[1247] 1 H NMR (400 MHz, CD3OD:CDCl3, v / v = 1 : 1) δ 8.04 (d, J = 8.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.31 (s, 1H), 4.17 (t, J = 8.3 Hz, 2H), 4.12-4.01 (m, 3H), 3.74 (d, J = 12.7 Hz, 2H), 3.61 (ddd, J = 15.1, 8.7, 6.4 Hz, 1H), 3.06 (t, J = 11.3 Hz, 2H), 2.32 (s, 3H), 2.21-2.11 (m, 2H), 1.64 (td, J = 13.6, 3.3 Hz, 2H).

[1248] MS m / z (ESI): 468.1 [M+H] + .

[1249] Example 142

[1250] 3-(endo-6-((4-((5-methyl- 1 H-pyrazol-3 -yl)amino)quinazolin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile

[1251]

[1252] 3-(endo-6-((4-((5-methyl- 1 H-pyrazol-3 -yl)amino)quinazolin-2-yl)amino)-3- azabicyclo[3.1.0]hexan-3-yl)propanenitrile was prepared according to Reference Example 79.

[1253] MS m / z (ESI): 375.2 [M+H] + .

[1254] II. Biological Test Evaluation

[1255] The present application will be further described in conjunction with the following test examples, which are not meant to limit the scope of the present application.

[1256] Test Example 1, Determination of the Inhibitory Effect of the Compound of the Present Invention on JAK Kinase Activity

[1257] Purpose of the Experiment: The purpose of this test example is to test the activity of the compound on the inhibition of JAK kinase activity.

[1258] Experimental Instruments: The centrifuge (5702R) was purchased from Eppendorf, the pipette was purchased from Eppendorf or Rainin, and the microplate reader was purchased from BioTek, USA, model Synergy H1 full-featured microplate reader.

[1259] Experimental Method: In this experiment, the fluorescence resonance energy transfer (TR-FRET) method was used to test the inhibitory effect of the compound on JAK kinase activity, and the half inhibitory concentration IC 50 of the compound on JAK kinase activity was obtained.

[1260] Specific experimental operations are as follows:

[1261] The kinase reaction was carried out in a white 384-well plate (PerkinElmer), 1-5 μL of the compound diluted with DMSO and ddH2O was added to each well, 1-5 μL of the corresponding solvent was added to the positive control well, then 1-5 μL of 0.1-20 nM JAK kinase solution diluted with kinase buffer (HEPES 50-250 mM, MgCl2 5-20 mM, etc.) was added to each well, 1-5 μL of kinase buffer was added to the negative control well, 1-5 μL of substrate mixture containing polypeptide substrate and ATP was added, and incubation was carried out at room temperature for 0.5-5 hours, 10 μL of EDTA and detection solution containing labeled antibody were added, incubation was carried out at room temperature for 1-24 hours, the fluorescence signal values at about 620 nm and 665 nm of each well of the plate were measured by BioTek Synergy H1 microplate reader, and the inhibition rate was calculated by the fluorescence signal values. According to the inhibition rates at different concentrations, the IC 50 of the compound was obtained by curve fitting.

[1262] Experimental Data Processing Method:

[1263] The percentage inhibition data of the well treated with the compound was calculated by the positive control well (DMSO control well) and the negative control well (without adding kinase) on the plate {inhibition rate = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100}. The IC 50 value was calculated by fitting the different concentrations and the corresponding percentage inhibition rate data to the 4-parameter nonlinear logistic formula using GraphPad prism.

[1264] Experimental Conclusion:

[1265] The above scheme shows that the compounds of the embodiments of the present application exhibit the biological activity shown in Table 19 in the JAK1 / 2 / 3 / TYK2 kinase activity test.

[1266] Table 19

[1267]

[1268]

[1269]

[1270]

[1271]

[1272] From the above table, it can be seen that the above example compounds can significantly inhibit the enzymatic activity of JAK1 / 2 / 3 / TYK2 kinase, and some compounds exhibit strong inhibitory effect on JAK1 / 2 / 3 / TYK2 kinase (NA represents undetected).

[1273] Test Example 2, Determination of the Inhibitory Effect of the Compounds of the Present Application on the Cell JAK-STAT Signal Pathway

[1274] Experimental Purpose:

[1275] The purpose of this test example is to test the activity of the compounds on the inhibition of the cell JAK-STAT signal pathway.

[1276] Experimental Instruments:

[1277] Microplate Shaker (88880024) purchased from Thermo Scientific TM Company

[1278] Centrifuge (5702R) purchased from Eppendorf Company

[1279] Pipette purchased from Eppendorf Company

[1280] Microplate Reader purchased from BioTek Company, USA, model SynergyH1 full-featured microplate reader.

[1281] Experimental Method:

[1282] In this experiment, the U266 cell line was used, the JAK-STAT signal pathway was activated by INF-α stimulation, the inhibitory activity of the compounds on the phosphorylation of STAT3 downstream was detected, and the half inhibitory concentration IC 50 of the compounds on the activity of the JAK-STAT signal pathway was obtained.

[1283] The specific experimental operation is as follows:

[1284] U266 cells were plated in 384-well assay plates at 3-12 μL per well with a cell number of 100-300K per well, 2 μL of the gradient-diluted compound solution was added, and incubation was performed at room temperature with shaking at 350 rpm for 2 hours. After 2 hours, 2 μL of INF-α was added, and the final concentration of INF-α was 1000 U / mL, and shaking was performed at room temperature for 15 minutes. 2-5 μL (5X) of LANCE Ultra Lysis Buffer 2 solution was added, and shaking was performed at room temperature for 2 hours. After 2 hours, 5 μL of LANCE Ultra Eu-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 0.5 nM and LANCE Ultra ULight-labeled Anti-STAT3 Antibody (PerkinElmer) with a final concentration of 5 nM were added, and incubation was performed overnight at room temperature. The fluorescence signal value of each well of the plate was measured by a microplate reader at 665 nm, the inhibition rate was calculated by the fluorescence signal value, and the IC 50 .

[1285] Experimental data processing method:

[1286] The percentage inhibition data of the well treated with the compound was calculated by the positive control well (DMSO control well) and the negative control well (without cells) on the plate {the inhibition rate = 100-[(test compound value-negative control value)] / (positive control value-negative control value) x 100}. The IC 50 value was calculated by fitting the different concentrations and the corresponding percentage inhibition rate data to a 4-parameter nonlinear logistic formula using GraphPad prism.

[1287] Experimental conclusion:

[1288] The compounds of the embodiments shown in the present application showed the biological activities in the JAK-STAT signal pathway activity of U266 cells as shown in Table 20 through the above scheme.

[1289] Table 20

[1290]

[1291]

[1292] It can be known from the above table that the compounds of the embodiments have obvious inhibitory effects on the JAK-STAT signal pathway activity of human myeloma cells U266.

[1293] Test 3, Pharmacokinetic determination in Balb / C mice

[1294] 1. Purpose of the study:

[1295] The pharmacokinetic behavior of 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 in Balb / C mice (plasma and colon, ileum tissue) after oral administration at a dose of 5 mg / kg was investigated. The PK excellent compounds were screened for further study by analyzing the drug concentration in colon and ileum, and the ratio of colon / ileum drug concentration, colon / plasma drug concentration.

[1296] 2. Test plan

[1297] 2.1 Test drug:

[1298] 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 self-made.

[1299] 2.2 Test animals:

[1300] Balb / C Mouse, 12 in each group, male, Shanghai Jiesijie Experimental Animal Co., Ltd., Animal Production License No. (SCXK (Shanghai) 2013-0006N0.311620400001794).

[1301] 2.3 Dosing:

[1302] Balb / C Mouse, 12 in each group, male; after fasting overnight, p.o. at a dose of 5 mg / kg, the administration volume was 10 mL / kg.

[1303] 2.4 Sample collection:

[1304] The mice were sacrificed by CO2 before and after administration, and 0.2 mL of blood was collected from the heart and placed in an EDTA-K2 test tube. The blood plasma was separated by centrifugation at 6000 rpm for 6 minutes at 4°C and stored at -80°C. The ileum was taken near the cecum end, with a length of about 4-5 cm. The colon was also taken near the cecum end, with a length of about 2-3 cm. After weighing, the colon was placed in a 2 mL centrifuge tube and stored at -80°C.

[1305] 2.5 Sample processing:

[1306] 1) 40 uL of the plasma sample was added with 160 uL of acetonitrile for precipitation, and then centrifuged at 3500 x g for 5-20 minutes.

[1307] 2) 30 uL of the plasma and intestinal homogenate sample was added with 90 uL of acetonitrile containing an internal standard (100 ng / mL) for precipitation, and then centrifuged at 13000 rpm for 8 minutes.

[1308] 3) 70 uL of the supernatant after treatment was added with 70 uL of water, vortexed for 10 minutes, and then 20 uL was taken for LC / MS / MS analysis of the concentration of the test compound. The LC / MS / MS analyzer was an AB Sciex API 4000 Qtrap.

[1309] 2.6 Liquid analysis

[1310] • Liquid condition: Shimadzu LC-20AD pump

[1311] • Column: Agilent ZORBAX XDB-C18 (50 x 2.1 mm, 3.5 μm)

[1312] A liquid was 0.1% formic acid aqueous solution, and B liquid was acetonitrile

[1313] • Flow rate: 0.4 mL / min

[1314] • Elution time: 0-4.0 minutes, and the eluent was as follows:

[1315]

[1316] 3. Test results and analysis

[1317] The main pharmacokinetic parameters were calculated by WinNonlin 6.1, and the results of the mouse pharmacokinetic experiment are shown in Table 21:

[1318] Table 21

[1319]

[1320]

[1321]

[1322] NA means not detected or not detected (the detection limit of blood concentration is 1 ng / ml, and C max When NA, NA in the blood test index means not detected; when C max higher than the limit of quantification 1 ng / ml, NA in the blood test index means not detected; NA in the tissue (colon and ileum) means not detected.

[1323] Experimental conclusion:

[1324] From the results of the mouse pharmacokinetics (PK) experiment in the table, it can be seen that the compound of the embodiment of the application shows good exposure level in the colon and ileum, the area under the blood concentration-time curve (AUC) and the maximum blood concentration (C max ) all meet the screening standard; and the colon / ileum drug concentration, colon / plasma drug concentration ratio of the compound is high, showing good selectivity.

[1325] Test 4, in-vivo pharmacodynamic test steps and results

[1326] 4.1 Purpose of the experiment:

[1327] To evaluate the pharmacodynamics of the compound of the embodiment on the DSS (dextran sulfate sodium) induced C57BL / 6 mouse colitis model.

[1328] 4.2. Main materials for the experiment

[1329] 4.2.1 Instruments

[1330] 1. Balance Mettler toledo AL104

[1331] 2. Balance TP-602

[1332] 4.2.2 Reagents

[1333] 1. Dextran sulfate sodium (DSS): MP Biomedicals, LLC, Solon, Ohio, Catalog No.: 160110

[1335] 2. Cyclosporine (CsA): Novartis, Switzerland, Batch No. S0033A

[1336] 3. Sodium carboxymethylcellulose: National Pharmaceutical Group Chemical Reagent Co., Ltd.

[1337] 4. Tween 80: Sigma, Catalog No. 8CBM 513V

[1338] 4.2.3 Experimental animals

[1339] Table 22

[1340] Animal species and strain: C57BL / 6 Gender, age / weight: Female, 6-8 weeks old / 18-20 grams Supplier: Shanghai Slake Experimental Animal Co., Ltd.

[1341] 4.3. Experimental procedure

[1342] 4.3.1 Grouping

[1343] According to the body weight of the animals, the animals were randomly grouped on day-1 using BioBook software to ensure that the body weight values of the animals in each group were similar to reduce bias. The grouping and dosing schedule are shown in the table below.

[1344] Grouping and dosing schedule

[1345] Table 23

[1346]

[1347] a: Solvent is 0.5% CMC-Na + 1% Tween 80

[1348] b: With an interval of 8 hours

[1349] 4.3.2 Experimental procedure

[1350] 1. Preparation of reagents

[1351] DSS-containing drinking water: An appropriate amount of DSS powder was dissolved in autoclaved drinking water to prepare a 2% DSS solution.

[1352] 2. Induction of enteritis

[1353] On day-1, the animals were evenly divided into 12 groups, with 10 animals in each group. (Refer to Table 1 for the specific grouping scheme)

[1354] From 9:00 on day 0 to 9:00 on day 6, the mice in groups 2 to 9 drank a 2% DSS solution for 6 days (from day 0 to day 6), after which the mice were allowed to drink normal water freely for 3 days (from 9:00 on day 6 to the day of autopsy before day 9). The day of modeling was counted as day 0. The DSS solution was wrapped in tin foil to ensure that it was protected from light. The DSS solution was replaced every 2 days.

[1355] The mice in group 1 drank normal water freely for 9 days (from 9:00 on day 0 to the day of autopsy before day 9).

[1356] 3. Dosing

[1357] The specific dosing amount, dosing route, and dosing time are shown in the table above.

[1358] 4.4 Measurement

[1359] 1) Body weight

[1360] The recording frequency is once a day.

[1361] 2) Daily disease index (DAI)

[1362] The recording frequency is once a day, and is evaluated as 4 grades according to the following criteria:

[1363] Body weight change (0, ≤1%; 1, 1-5%; 2, 5-10%; 3, 10-15%; 4, >15%);

[1364] Blood stool (0, negative; 4, positive);

[1365] Stool score (0, normal; 2, loose stool; 4, diarrhea)

[1366] The scores of the above 3 parts are added and divided by 3 to obtain the daily disease index value (DAI). The DAI-time (day) curve is plotted according to the DAI score of each day, and the peak area under the curve (AUC) is calculated. The DAI AUC reduction ratio is calculated compared with the Vehicle group, and the calculation formula is (DAI AUC 给药组 -DAI AUC Vehicle ) / DAI AUC Vehicle ×100%

[1367] 4.5. Experimental results:

[1368] Table 24

[1369]

[1370] 4.6. Experimental conclusion

[1371] In the DSS-induced C57BL / 6 mouse colitis model, the above example compounds can significantly reduce the daily disease index (DAI), and have obvious efficacy.

[1372] III. Crystal form study

[1373] 1.1 Experimental instruments

[1374] 1.1.1 Some parameters of physical and chemical detection instruments

[1375] Table 25

[1376]

[1377]

[1378] 1.2 Instruments and liquid phase analysis conditions

[1379] 1.2.1 Instruments and equipment

[1380] Table 26

[1381] Instrument name Model Analytical balance Sartorius BSA224S-CW Milli-Q Plus, Millipore High performance liquid chromatograph Agilent 1260 Pump Agilent G1311B Sampler G1329B Column oven G1316A Detector G1315D T(min)

[1382] 1.2.2 Chromatographic conditions

[1383] Chromatographic column: ZORBAX (SB-C8, 3.5 μm, 4.6*75 mm)

[1384] Flow rate: 1.5 mL / min

[1385] Column temperature: 40°C

[1386] Detection wavelength: 242nm

[1387] Injection volume: 5.0 μL

[1388] Run time: 15 minutes

[1389] Diluent: ACN-water (v / v, 1:1)

[1390] Mobile phase: A: water (0.05% trifluoroacetic acid); B: acetonitrile (0.05% trifluoroacetic acid)

[1391] Table 27

[1392] Figure 1 A(％) B(％) 0.00 95 5 8.00 60 40 12.00 10 90 12.10 95 5 15.00 95 5

[1393] 1. Preparation of different crystal forms

[1394] 1.1 Preparation of Compound III Free Base Form A

[1395] Weigh 1000 mg of the hydrochloride salt of the free base of compound III into a 40 mL glass bottle, add 7 mL of methanol, heat and stir at 50 ° C, add 1 M HCl solution to dissolve it and filter it, add 1 M NaOH solution until it precipitates (pH about 10), stir at room temperature overnight, filter and wash with water, and dry the solid at 50 ° C in vacuum to obtain the free base crystal form A. After detection and analysis, it has the following characteristics: Figure 2 The XRPD pattern shown.

[1396] 1.2 Preparation of Compound III Free Base Form B

[1397] Weigh 1000 mg of the hydrochloride salt of the free base of compound III into a 40 mL glass bottle, add 6.67 mL of methanol, heat and stir at 50°C, add 1 M HCl solution to dissolve it and filter it, add 1 M NaOH solution until a precipitate is precipitated (pH about 10), stir at room temperature overnight, filter and wash with water, and dry the solid at 50°C in vacuum to obtain the free base crystal form B. After testing and analysis, it has the following characteristics: Figure 3 The XRPD pattern shown.

[1398] 1.3 Preparation of Compound III Free Base Form C

[1399] Weigh 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μl of acetonitrile, slurry at 50°C for 1 week, centrifuge, remove the supernatant, and dry the remaining solid in a 50°C vacuum drying oven to constant weight to obtain free base crystal form C. After detection and analysis, it has the following characteristics: Figure 4 The XRPD pattern shown, Figure 5 The DSC diagram shown and Figure 6 TGA graph shown.

[1400] 1.4 Preparation of Compound III Free Base Form D

[1401] Weigh 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μl of ethyl acetate, slurry at 50°C for 1 week, centrifuge, remove the supernatant, and dry the remaining solid in a 50°C vacuum drying oven to constant weight to obtain free base crystal form D. After detection and analysis, it has the following characteristics: Figure 7 The XRPD pattern shown in Figure 8 The DSC diagram shown and Figure 9 TGA graph shown.

[1402] 1.5 Preparation of Compound III Free Base Form E

[1403] Weigh 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μl of ethanol, slurry at 50°C for 1 week, centrifuge, remove the supernatant, and dry the remaining solid in a 50°C vacuum drying oven to constant weight to obtain free base crystal form E. After testing and analysis, it has the following characteristics: Figure 10 The XRPD pattern shown, Figure 11 The DSC diagram shown and Figure 12 TGA graph shown.

[1404] 1.6 Preparation of Compound III Free Base Form F

[1405] Weigh 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μl of 3-pentanone, slurry at 50°C for 1 week, centrifuge, remove the supernatant, and dry the remaining solid in a 50°C vacuum drying oven to constant weight to obtain free base crystal form F. After testing and analysis, it has the following characteristics: Figure 14 The XRPD pattern shown in FIG13 , the DSC pattern shown in FIG14 and the Figure 15 TGA graph shown.

[1406] 1.7 Preparation of Compound III Free Base Form G

[1407] Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μΐ of toluene, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum drying oven to dry to constant weight to obtain free base crystal form G. The analysis shows that it has the XRPD pattern as shown in Figure 17, the DSC pattern as shown in Figure 18, and the TGA pattern as shown in Figure 19. Figure 16

[1408] 1.8 Preparation of compound III free base crystal form H

[1409] Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μΐ of isopropanol, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum drying oven to dry to constant weight to obtain free base crystal form H. The analysis shows that it has the XRPD pattern as shown in Figure 21, the DSC pattern as shown in Figure 22, and the TGA pattern as shown in Figure 23. Figure 17 Figure 18 Figure 19

[1410] 1.9 Preparation of compound III free base crystal form I

[1411] Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μΐ of 2-butanol, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum drying oven to dry to constant weight to obtain free base crystal form I. The analysis shows that it has the XRPD pattern as shown in Figure 20, the DSC pattern as shown in Figure 21, and the TGA pattern as shown in Figure 22. Figure 21 Figure 22

[1412] 1.10 Preparation of compound III free base crystal form J

[1413] Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μΐ of 2-butanone, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum drying oven to dry to constant weight to obtain free base crystal form J. The analysis shows that it has the XRPD pattern as shown in Figure 23, the DSC pattern as shown in Figure 24, and the TGA pattern as shown in Figure 25. Figure 24 Figure 25

[1414] 1.11 Preparation of compound III free base crystal form K

[1415] Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μΐ of 2-methyl-tetrahydrofuran, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum drying oven to dry to constant weight to obtain free base crystal form K. The analysis shows that it has the XRPD pattern as shown in Figure 25, the DSC pattern as shown in Figure 26, and the TGA pattern as shown in Figure 27. Figure 26 ​​​​​​​​The XRPD pattern shown.

[1416] 1.12 Preparation of Compound III free base Form L

[1417] Take 10 mg of Compound III free base Form B into a 2 mL glass bottle, add 200 μΐ of 1-propanol, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum oven to dry to constant weight to obtain free base Form L. It is analyzed to have the following XRPD pattern shown, DSC pattern shown in Figure 27, and TGA pattern shown in Figure 28. Figure 28 Figure 29

[1418] 1.13 Preparation of Compound III free base Form M

[1419] Take 10 mg of Compound III free base Form B into a 2 mL glass bottle, add 200 μΐ of isopropyl acetate, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum oven to dry to constant weight to obtain free base Form M. It is analyzed to have the following XRPD pattern shown, DSC pattern shown in Figure 29, and TGA pattern shown in Figure 30. Figure 30 Figure 31 Figure 32

[1420] 1.14 Preparation of Compound III free base Form N

[1421] Take 10 mg of Compound III free base Form B into a 2 mL glass bottle, add 200 μΐ of chlorobenzene, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum oven to dry to constant weight to obtain free base Form N. It is analyzed to have the following XRPD pattern shown. Figure 33

[1422] 1.15 Preparation of Compound III free base Form O

[1423] Take 10 mg of Compound III free base Form B into a 2 mL glass bottle, add 200 μΐ of ethyl formate, centrifuge after slurry at 50 °C for 1 week, remove supernatant, and the remaining solid is placed into a 50 °C vacuum oven to dry to constant weight to obtain free base Form O. It is analyzed to have the following XRPD pattern shown, DSC pattern shown in Figure 31, and TGA pattern shown in Figure 32. Figure 34 Figure 35 Figure 36

[1424] 1.16 Preparation of Compound III free base Form P

[1425] ​​​​​​​​​Take 10 mg of compound III free base crystal form B into a 2 mL glass bottle, add 200 μl of methanol, centrifuge after slurry at 50 °C for 1 week, remove the supernatant, and the remaining solid is placed in a 50 °C vacuum drying oven to dry to constant weight to obtain the free base crystal form P. The detection analysis has the following XRPD pattern as shown in Figure 38 , the DSC pattern as shown in Figure 39 , and the TGA pattern as shown in .

[1426] 1.17 Preparation of compound III free base crystal form Q

[1427] Take 10 mg of compound III free base crystal form A into a 2 mL glass bottle, add 200 μl of methanol, centrifuge after slurry at 50 °C overnight, remove the supernatant, and the remaining solid is placed in a 50 °C vacuum drying oven to dry to constant weight to obtain the free base crystal form Q. The detection analysis has the following XRPD pattern as shown in Figure 41 , the DSC pattern as shown in Figure 43 , and the TGA pattern as shown in .

[1428] 1.18 Preparation of compound IV free base crystal form A

[1429] Take 9.4 g of (3-exo)-3-((7-methoxy-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-2-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester dissolved in methanol (47 mL), add 4M HCl in 1,4-dioxane (94 mL) under stirring at a temperature of 10-20 °C, stir the reaction at 20-30 °C for 1-2 hours, after the reaction is completed, filter the reaction solution, wash the filter cake with methanol (20 mL), and directly use the solid for the next step reaction, dissolve the solid in methanol (56 mL), at a temperature of 10-20 °C, dropwise add DIPEA (10 g, 0.0784 mol), after the dropwise addition is completed, adjust the temperature of the reaction solution to 20-30 °C, and dropwise add acrylonitrile (3.1 g, 0.0588 mol) into the reaction solution, react at a temperature of 20-30 °C for 2 hours. Filter the reaction solution, wash the filter cake with 15 mL of methanol, and dry to obtain the compound IV white solid (7.6 g). The detection analysis has the following XRPD pattern as shown in Figure 44 , the DSC pattern as shown in ​ , and the TGA pattern as shown in .

[1430] 2. Solid stability experiment

[1431] 2.1 Purpose of the experiment:

[1432] The physical and chemical stability of compound III crystal form A and compound III crystal form C, compound III crystal form D, compound III crystal form Q and compound IV crystal form A under the conditions of light 5000 lx, high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH is investigated, so as to provide a basis for crystal screening and compound storage.

[1433] 2.2 Experimental scheme:

[1434] About 2 mg of compound III crystal form A, compound III crystal form C, compound III crystal form D, compound III crystal form Q and compound IV crystal form A are taken, and the content is determined by HPLC and external standard method under the conditions of light 5000 lx, high temperature 60℃, high humidity 92.5% RH, high temperature and high humidity 50℃ 75% RH for 5 days and 10 days, and the change of related substances is calculated by chromatographic peak area normalization method.

[1435] 2.3 Experimental results:

[1436] The results of physical and chemical stability of free bases of different crystal forms:

[1437] Table 28

[1438]

[1439] The above data show that compound III crystal form C is relatively stable under the conditions of high temperature, high humidity and high temperature and high humidity.

[1440] 3 Hygroscopicity experiment

[1441] 3.1 Purpose of experiment

[1442] The hygroscopicity of compound III free base crystal form A, compound III free base crystal form C and compound IV free base crystal form A under different relative humidity conditions is investigated, so as to provide a basis for crystal screening and storage of the compounds.

[1443] 3.2 Experimental scheme:

[1444] Compound III free base crystal form A, compound III free base crystal form C and compound IV free base crystal form A are placed in saturated water vapor of different relative humidity, so that the compound and water vapor reach dynamic equilibrium, and the percentage of weight gain of the compound after equilibrium is calculated.

[1445] 3.3 Experimental results:

[1446] Compound III free base crystal form A is subjected to hygroscopicity and desorption of moisture cycles 2 times under the conditions of 0-95% relative humidity, and the XRPD spectrum of free base crystal form A does not change, i.e. the crystal form does not change.

[1447] Compound III free base Form C absorbed moisture and gained approximately 0.717% weight at 80% relative humidity, indicating slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD pattern of free base Form C remained unchanged, indicating no crystal transformation.

[1448] Compound IV free base Form A absorbs moisture at 80% relative humidity and gains weight by approximately 0.5354%, indicating slight hygroscopicity. After two cycles of moisture absorption and desorption at 0-95% relative humidity, the XRPD spectrum of free base Form A remains unchanged, indicating no crystal transformation.

[1449] 4. Solubility experiments in different media

[1450] 4.1 Experimental Purpose

[1451] The solubility of compound III free base form A and compound IV free base form A in different pH media, 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 was compared to provide a basis for druggability evaluation.

[1452] 4.2 Experimental plan:

[1453] About 1 mg of Compound III free base Form A and about 1 mg of Compound IV free base Form A were suspended in different media for 6 hours, and the thermodynamic solubility of the compounds at 37° C. was determined by HPLC using an external standard method.

[1454] 4.3 Experimental results: as shown in Table 29

[1455] Table 29

[1456]

[1457] From the above experimental results, it can be seen that the solubility of this crystal form meets the drug concentration required for local treatment.

[1458] 5. Polycrystalline screening and stable crystal form confirmation experiments

[1459] 5.1 Experimental Purpose:

[1460] Through polycrystalline screening, a relatively stable compound crystal form is found.

[1461] 5.2 Experimental plan:

[1462] The organic solvent with certain solubility, water were selected, different crystal forms were suspended in the solvent system, stirred and slurried at room temperature for 1 week, centrifuged, the supernatant was discarded, the solid was dried at 50°C under vacuum (-0.1 Mpa) overnight, then the XRPD, DSC and TGA of the solid were determined and compared.

[1463] 5.3 Experimental results:

[1464] Through slurry, changing the crystallization solvent, crystallization method, etc., 17 crystal forms were obtained, which were compound III crystal form A, compound III crystal form B, compound III crystal form C, compound III crystal form D, compound III crystal form E, compound III crystal form F, compound III crystal form G, compound III crystal form H, compound III crystal form I, compound III crystal form J, compound III crystal form K, compound III crystal form L, compound III crystal form M, compound III crystal form N, compound III crystal form O, compound III crystal form P and compound IV free base crystal form A. By comparing the DSC patterns of different crystal forms, it can be judged that the thermodynamic stability of compound III crystal form C and compound III crystal form I is better.

Claims

1. Crystalline forms of 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)-ethan-1-one, including crystal forms A to Q, wherein: The X-ray powder diffraction pattern of the crystalline form A has characteristic peaks at 2θ of 19.7±0.2°, 7.0±0.2°, 16.1±0.2°, 13.9±0.2°, 16.6±0.2°, 20.9±0.2° and 22.8±0.2°; The X-ray powder diffraction pattern of the crystalline form B has characteristic peaks at 2θ of 17.4±0.2°, 20.9±0.2°, 26.5±0.2°, 14.4±0.2°, 16.7±0.2°, 19.2±0.2° and 20.3±0.2°; The X-ray powder diffraction pattern of the crystalline form C has characteristic peaks at 2θ of 20.2±0.2°, 14.3±0.2°, 15.5±0.2°, 19.2±0.2°, 21.5±0.2°, 25.3±0.2° and 27.5±0.2°; The X-ray powder diffraction pattern of the crystalline form D has characteristic peaks at 2θ of 23.3±0.2°, 16.1±0.2°, 17.6±0.2°, 7.4±0.2°, 20.4±0.2°, 22.0±0.2° and 22.4±0.2°; The X-ray powder diffraction pattern of the crystalline form E has characteristic peaks at 2θ of 7.3±0.2°, 20.5±0.2°, 21.7±0.2°, 8.5±0.2°, 17.2±0.2°, 22.1±0.2° and 22.8±0.2°; The X-ray powder diffraction pattern of the crystalline form F has characteristic peaks at 2θ of 22.9±0.2°, 12.3±0.2°, 20.2±0.2°, 12.6±0.2°, 14.6±0.2°, 18.4±0.2° and 24.6±0.2°; The X-ray powder diffraction pattern of the crystalline form G has characteristic peaks at 2θ of 19.6±0.2°, 15.4±0.2°, 19.0±0.2°, 6.9±0.2°, 7.7±0.2°, 11.0±0.2° and 22.7±0.2°; The X-ray powder diffraction pattern of the crystalline form H has characteristic peaks at 2θ of 7.2±0.2°, 16.0±0.2°, 20.8±0.2°, 16.4±0.2°, 17.6±0.2°, 19.7±0.2° and 21.9±0.2°; The X-ray powder diffraction pattern of the crystalline form I has characteristic peaks at 2θ of 6.8±0.2°, 13.7±0.2°, 18.6±0.2°, 15.1±0.2°, 15.5±0.2°, 20.5±0.2° and 20.7±0.2°; The X-ray powder diffraction pattern of the crystalline form J has characteristic peaks at 2θ of 20.5±0.2°, 18.7±0.2°, 20.2±0.2°, 6.8±0.2°, 12.2±0.2°, 12.6±0.2° and 22.8±0.2°; The X-ray powder diffraction pattern of the crystalline form K has characteristic peaks at 2θ of 19.5±0.2°, 6.7±0.2°, 15.9±0.2°, 10.3±0.2°, 13.7±0.2°, 16.3±0.2° and 22.5±0.2°; The X-ray powder diffraction pattern of the crystalline form L has characteristic peaks at 2θ of 7.2±0.2°, 21.3±0.2°, 22.5±0.2°, 16.0±0.2°, 21.9±0.2°, 22.2±0.2° and 27.3±0.2°; The X-ray powder diffraction pattern of the crystalline form M has characteristic peaks at 2θ of 18.6±0.2°, 15.7±0.2°, 25.1±0.2°, 21.7±0.2°, 23.4±0.2°, 24.0±0.2° and 28.1±0.2°; The X-ray powder diffraction pattern of the crystalline form N has characteristic peaks at 2θ of 19.1±0.2°, 15.4±0.2°, 19.7±0.2°, 7.6±0.2°, 10.9±0.2°, 21.0±0.2° and 21.3±0.2°; The X-ray powder diffraction pattern of the crystalline form O has characteristic peaks at 2θ of 23.8±0.2°, 12.7±0.2°, 17.9±0.2°, 14.4±0.2°, 17.6±0.2°, 21.0±0.2° and 24.7±0.2°; The X-ray powder diffraction pattern of the crystalline form P has characteristic peaks at 2θ of 23.2±0.2°, 14.9±0.2°, 16.5±0.2°, 8.3±0.2°, 13.4±0.2°, 19.2±0.2° and 20.2±0.2°; The X-ray powder diffraction pattern of the crystalline form Q has characteristic peaks at 2θ of 16.4±0.2°, 13.5±0.2°, 20.0±0.2°, 9.1±0.2°, 14.7±0.2°, 15.9±0.2° and 27.9±0.2°.

2. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form A further comprises characteristic peaks at 2θ of 10.5±0.2°, 15.1±0.2°, 19.3±0.2°, 19.7±0.2°, 20.4±0.2°, 24.0±0.2°, 24.5±0.2° and 29.2±0.2°; The X-ray powder diffraction pattern of the crystalline form B further comprises characteristic peaks at 2θ of 15.2±0.2°, 15.9±0.2°, 19.6±0.2°, 21.6±0.2°, 23.0±0.2°, 23.6±0.2°, 26.1±0.2° and 28.3±0.2°; The X-ray powder diffraction pattern of the crystalline form C further comprises characteristic peaks at 2θ of 16.9±0.2°, 18.3±0.2°, 23.0±0.2° and 24.5±0.2°; The X-ray powder diffraction pattern of the crystalline form D further comprises characteristic peaks at 2θ of 11.6±0.2°, 11.8±0.2°, 14.4±0.2°, 16.6±0.2°, 18.8±0.2°, 19.6±0.2°, 23.8±0.2° and 28.9±0.2°; The X-ray powder diffraction pattern of the crystalline form E further comprises characteristic peaks at 2θ of 10.8±0.2°, 11.6±0.2°, 14.4±0.2°, 16.2±0.2°, 16.5±0.2°, 17.7±0.2°, 23.8±0.2° and 28.3±0.2°; The X-ray powder diffraction pattern of the crystalline form F further comprises characteristic peaks at 2θ of 8.1±0.2°, 16.1±0.2°, 16.6±0.2°, 17.8±0.2°, 22.0±0.2°, 23.1±0.2°, 29.5±0.2° and 30.2±0.2°; The X-ray powder diffraction pattern of the crystalline form G further comprises characteristic peaks at 2θ of 13.6±0.2°, 13.8±0.2°, 16.0±0.2°, 17.6±0.2°, 18.1±0.2°, 20.7±0.2°, 21.3±0.2° and 27.3±0.2°; The X-ray powder diffraction pattern of the crystalline form H further comprises characteristic peaks at 2θ of 8.3±0.2°, 11.7±0.2°, 14.6±0.2°, 15.2±0.2°, 19.1±0.2°, 20.3±0.2°, 23.6±0.2° and 27.3±0.2°; The X-ray powder diffraction pattern of the crystalline form I further comprises characteristic peaks at 2θ of 8.2±0.2°, 11.8±0.2°, 17.7±0.2°, 20.2±0.2°, 22.4±0.2°, 23.1±0.2°, 23.5±0.2° and 27.0±0.2°; The X-ray powder diffraction pattern of the crystalline form J further comprises characteristic peaks at 2θ of 14.5±0.2°, 15.5±0.2°, 16.0±0.2°, 16.5±0.2°, 18.4±0.2°, 21.9±0.2°, 23.1±0.2° and 24.6±0.2°; The X-ray powder diffraction pattern of the crystalline form K further comprises characteristic peaks at 2θ of 10.0±0.2°, 12.2±0.2°, 14.9±0.2°, 19.1±0.2°, 20.2±0.2°, 20.7±0.2°, 23.7±0.2°, 26.2±0.2° and 29.0±0.2°; The X-ray powder diffraction pattern of the crystalline form L further comprises characteristic peaks at 2θ of 8.4±0.2°, 16.9±0.2°, 17.5±0.2°, 19.5±0.2°, 20.3±0.2°, 23.6±0.2°, 24.1±0.2° and 27.9±0.2°; The X-ray powder diffraction pattern of the crystalline form M further comprises characteristic peaks at 2θ of 10.5±0.2°, 12.9±0.2°, 14.2±0.2°, 16.0±0.2°, 16.8±0.2°, 17.4±0.2°, 19.6±0.2° and 22.3±0.2°; The X-ray powder diffraction pattern of the crystalline form N further comprises characteristic peaks at 2θ of 13.5±0.2°, 18.0±0.2°, 18.8±0.2°, 22.6±0.2°, 25.4±0.2°, 26.2±0.2° and 27.3±0.2°; The X-ray powder diffraction pattern of the crystalline form O further comprises characteristic peaks at 2θ of 8.4±0.2°, 13.0±0.2°, 19.6±0.2°, 20.7±0.2°, 22.7±0.2°, 26.6±0.2°, 28.7±0.2° and 30.9±0.2°; The X-ray powder diffraction pattern of the crystalline form P further comprises characteristic peaks at 2θ of 7.8±0.2°, 9.3±0.2°, 11.6±0.2°, 12.6±0.2°, 16.0±0.2°, 18.5±0.2°, 19.6±0.2° and 27.4±0.2°; The X-ray powder diffraction pattern of the crystalline form Q also includes characteristic peaks at 2θ of 7.7±0.2°, 11.7±0.2°, 11.9±0.2°, 18.4±0.2°, 19.5±0.2°, 22.3±0.2°, 26.4±0.2° and 27.3±0.2°.

3. The crystal form according to claim 1, characterized in that The X-ray powder diffraction pattern of the crystalline form A is substantially as shown in FIG1 ; The X-ray powder diffraction pattern of the crystalline form B is substantially as shown in FIG2 ; The X-ray powder diffraction pattern of the crystalline form C is substantially as shown in FIG3 ; The X-ray powder diffraction pattern of the crystalline form D is substantially as shown in FIG6 ; The X-ray powder diffraction pattern of the crystalline form E is substantially as shown in FIG9 ; The X-ray powder diffraction pattern of the crystalline form F is substantially as shown in FIG12 ; The X-ray powder diffraction pattern of the crystalline form G is substantially as shown in FIG15 ; The X-ray powder diffraction pattern of the crystalline form H is substantially as shown in FIG16 ; The X-ray powder diffraction pattern of the crystalline form I is substantially as shown in FIG19 ; The X-ray powder diffraction pattern of the crystal form J is substantially as shown in FIG22 ; The X-ray powder diffraction pattern of the crystal form K is substantially as shown in FIG25 ; The X-ray powder diffraction pattern of the crystalline form L is substantially as shown in FIG26 ; The X-ray powder diffraction pattern of the crystalline form M is substantially as shown in FIG29 ; The X-ray powder diffraction pattern of the crystalline form N is substantially as shown in FIG32 ; The X-ray powder diffraction pattern of the crystalline form O is substantially as shown in FIG33 ; The X-ray powder diffraction pattern of the crystalline form P is substantially as shown in FIG36 ; The X-ray powder diffraction pattern of the crystalline form Q is basically shown in Figure 39. The crystalline form A of 4.3-((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 having diffraction peaks at 2θ of 8.2±0.2°, 9.7±0.2°, 20.4±0.2°, 13.5±0.2°, 17.4±0.2°, 21.1±0.2° and 26.6±0.2°.

5. The crystal form according to claim 4, characterized in that The X-ray powder diffraction pattern of the crystalline form A also includes diffraction peaks at 2θ of 16.5±0.2°, 16.8±0.2°, 14.1±0.2°, 19.1±0.2°, 19.4±0.2°, 22.8±0.2°, 27.1±0.2° and 28.5±0.2°.

6. The crystal form according to claim 4, characterized in that The X-ray powder diffraction pattern of the crystalline form A is basically shown in Figure 42, its DSC pattern is basically shown in Figure 43, and its TGA pattern is basically shown in Figure 44.

7. A method for preparing the crystal form according to any one of claims 1 to 6, comprising the following steps: 1) Weigh an appropriate amount of compound and suspend it in a poor solvent; 2) shaking the suspension obtained above at a certain temperature for a certain time; 3) The suspension was centrifuged quickly, the supernatant was removed, and the suspension was dried to a constant weight to obtain the target product; in: The poor solvent is selected from one or more of methanol, acetone, ethyl formate, ethyl acetate, acetonitrile, ethanol, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, chlorobenzene, isopropyl alcohol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, isopropyl acetate, tert-butanol, 2-butanone or 3-pentanone; or, i) Weigh an appropriate amount of compound and dissolve it in a good solvent; ii) adding an anti-solvent to the above solution at a certain temperature and stirring until a solid precipitates; iii) rapidly centrifuging the suspension, removing the supernatant, and drying the remaining solid to a constant weight to obtain the target product; in: The benign solvent is selected from one or more of methanol, acetone, ethyl acetate, acetonitrile, ethanol, 2-methyltetrahydrofuran, dichloromethane, 1,4-dioxane, benzene, toluene, isopropanol, n-butanol, isobutanol, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, n-propanol, tert-butanol, 2-butanone or 3-pentanone; The anti-solvent is selected from one or more of dichloromethane, toluene, ethyl formate, ethyl acetate, 2-methyltetrahydrofuran, ethanol, n-heptane, 1,4-dioxane, water, isopropyl acetate, cyclohexane, methyl tert-butyl ether, toluene or isopropyl ether.

8. The method according to claim 7, characterized in that In step 1), the suspension density is 50 to 200 mg / mL; in step 2), the temperature is 0 to 50° C., and the time is 1 to 10 days; The certain temperature in step ii) is 0-50°C.

9. The method according to claim 7, characterized in that The poor solvent is selected from one or more of ethyl formate, ethyl acetate, 2-methyltetrahydrofuran, acetone, acetonitrile, methanol, ethanol, dichloromethane, isopropyl acetate or isopropyl alcohol; The benign solvent is selected from one or two of methanol, dimethyl sulfoxide or isobutanol; The anti-solvent is selected from one or more of water, n-heptane, cyclohexane or methyl tert-butyl ether.

10. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 6, and one or more pharmaceutically acceptable carriers or diluents.

11. A pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the compound according to any one of claims 1 to 6, and one or more pharmaceutically acceptable excipients.

12. Use of the crystalline form according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 10 or 11 in the preparation of a drug for preventing and / or treating a JAK kinase-related disease, wherein the JAK kinase-related disease is an inflammatory disease and / or a tumor disease, wherein: The tumor disease is selected from myelofibrosis, polycythemia vera, essential thrombocythemia, myelocytic leukemia, and acute lymphocytic leukemia.

13. The use according to claim 12, characterized in that The inflammatory disease is selected from rheumatoid arthritis, dermatitis, psoriasis, and inflammatory bowel disease.

14. The use according to claim 13, characterized in that The inflammatory bowel disease is a chronic intestinal inflammatory disease.

15. The use according to claim 13, characterized in that The inflammatory bowel diseases are ulcerative colitis and Crohn's disease.

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