Salts of pyrazolo[1,5-a]pyridine derivative and use thereof

Abstract

The present invention provides salts of pyrazolo[1,5-α]pyridine derivative and use thereof. The invention also relates to a pharmaceutically acceptable composition comprising such salts and a method of using the salts and the pharmaceutically acceptable composition to prevent or treat a proliferative disorder or pulmonary fibrosis in a patient.

Claims

1. A pharmaceutically acceptable base addition salt of a compound of Formula (I): ##STR00003## wherein, the base addition salt is crystalline form A of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 14.73°±0.2°, 14.93°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2° and 24.87°±0.2°; or the base addition salt is crystalline form B of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 20.46°±0.2°, 23.64°±0.2°, 25.14°±0.2° and 25.89°±0.2°; or the base addition salt is crystalline form C of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2° and 24.68°±0.2°; or the base addition salt is an amorphous form of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 4; or the base addition salt is crystalline form A of mono-lithium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 9.98°±0.2°, 13.82°±0.2°, 21.74°±0.2°, 23.70°±0.2°, 25.03°±0.2°, 26.82°±0.2° and 32.96°±0.2°; or the base addition salt is crystalline form A of mono-potassium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 11.04°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 21.26°±0.2°, 22.22°±0.2° and 23.33°±0.2°; or the base addition salt is crystalline form A of mono-choline salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 8.31°±0.2°, 16.94°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2° and 22.85°±0.2°.

2. The base addition salt according to claim 1, wherein the mono-sodium salt is crystalline form A of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 10.71°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.87°±0.2°, 28.36°±0.2° and 30.18°±0.2°; or the mono-sodium salt is crystalline form B of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 8.75°±0.2°, 12.27°±0.2°, 14.42°±0.2°, 15.62°±0.2°, 20.46°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 25.14°±0.2°, 25.89°±0.2°, 26.87°±0.2°, 27.43°±0.2°, 28.09°±0.2°, 32.95°±0.2° and 36.47°±0.2°; or the mono-sodium salt is crystalline form C of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 15.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 21.16°±0.2°, 23.94°±0.2°, 24.68°±0.2°, 26.21°±0.2° and 29.03°±0.2°; or the lithium salt is crystalline form A of mono-lithium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 9.98°±0.2°, 13.82°±0.2°, 15.83°±0.2°, 16.25°±0.2°, 19.64°±0.2°, 20.02°±0.2°, 21.74°±0.2°, 22.16°±0.2°, 23.70°±0.2°, 25.03°±0.2°, 26.38°±0.2°, 26.82°±0.2°, 30.27°±0.2° and 32.96°±0.2°; or the potassium salt is crystalline form A of mono-potassium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 11.04°±0.2°, 14.28°±0.2°, 16.29°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 22.22°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.87°±0.2°, 27.83°±0.2° and 32.47°±0.2°; or the choline salt is crystalline form A of mono-choline salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 5.65°±0.2°, 8.31°±0.2°, 10.31°±0.2°, 16.53°±0.2°, 16.94°±0.2°, 17.27°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.97°±0.2°, 24.81°±0.2° and 29.07°±0.2°.

3. The base addition salt according to claim 2, wherein the mono-sodium salt is crystalline form A of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 5.59°±0.2°, 9.33°±0.2°, 10.71°±0.2°, 11.21°±0.2°, 14.73°±0.2°, 14.93°±0.2°, 15.39°±0.2°, 16.55°±0.2°, 17.36°±0.2°, 17.64°±0.2°, 18.42°±0.2°, 19.01°±0.2°, 19.41°±0.2°, 19.66°±0.2°, 19.84°±0.2°, 20.26°±0.2°, 21.57°±0.2°, 21.77°±0.2°, 22.34°±0.2°, 22.59°±0.2°, 23.29°±0.2°, 24.15°±0.2°, 24.87°±0.2°, 25.59°±0.2°, 26.26°±0.2°, 26.75°±0.2°, 27.32°±0.2°, 27.87°±0.2°, 28.36°±0.2°, 28.71°±0.2°, 29.08°±0.2°, 29.59°±0.2°, 30.18°±0.2°, 30.56°±0.2°, 31.01°±0.2°, 31.61°±0.2°, 31.81°±0.2°, 32.14°±0.2°, 32.72°±0.2°, 33.26°±0.2°, 34.14°±0.2°, 35.97°±0.2°, 36.46°±0.2°, 38.40°±0.2°, 38.83°±0.2°, 39.49°±0.2°, 40.04°±0.2°, 41.32°±0.2°, 42.80°±0.2°, 43.89°±0.2° and 45.77°±0.2°; or the mono-sodium salt is crystalline form B of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 7.23°±0.2°, 8.75°±0.2°, 12.27°±0.2°, 12.88°±0.2°, 13.94°±0.2°, 14.42°±0.2°, 14.87°±0.2°, 15.62°±0.2°, 17.85°±0.2°, 18.51°±0.2°, 18.94°±0.2°, 19.33°±0.2°, 19.79°±0.2°, 20.46°±0.2°, 21.50°±0.2°, 22.23°±0.2°, 22.79°±0.2°, 23.32°±0.2°, 23.64°±0.2°, 24.67°±0.2°, 25.14°±0.2°, 25.89°±0.2°, 26.87°±0.2°, 27.43°±0.2°, 28.09°±0.2°, 28.54°±0.2°, 29.02°±0.2°, 29.48°±0.2°, 29.96°±0.2°, 30.74°±0.2°, 31.56°±0.2°, 32.95°±0.2°, 33.50°±0.2°, 35.86°±0.2°, 36.47°±0.2°, 37.32°±0.2°, 39.11°±0.2°, 39.84°±0.2°, 42.23°±0.2°, 42.93°±0.2° and 44.44°±0.2°; or the mono-sodium salt is crystalline form C of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 5.24°±0.2°, 5.61°±0.2°, 8.88°±0.2°, 9.54°±0.2°, 10.52°±0.2°, 13.64°±0.2°, 14.40°±0.2°, 14.78°±0.2°, 15.86°±0.2°, 16.46°±0.2°, 16.95°±0.2°, 17.86°±0.2°, 18.72°±0.2°, 19.14°±0.2°, 19.47°±0.2°, 20.31°±0.2°, 20.74°±0.2°, 21.16°±0.2°, 22.09°±0.2°, 22.61°±0.2°, 23.94°±0.2°, 24.29°±0.2°, 24.68°±0.2°, 26.21°±0.2°, 27.03°±0.2°, 27.60°±0.2°, 28.32°±0.2°, 29.03°±0.2°, 30.10°±0.2°, 31.73°±0.2°, 31.94°±0.2°, 33.86°±0.2°, 34.33°±0.2°, 35.60°±0.2°, 36.01°±0.2°, 36.95°±0.2°, 38.02°±0.2°, 38.86°±0.2°, 40.32°±0.2°, 41.00°±0.2°, 42.08°±0.2° and 44.21°±0.2°; or the lithium salt is crystalline form A of mono-lithium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 3.60°±0.2°, 8.33°±0.2°, 8.97°±0.2°, 9.58°±0.2°, 9.98°±0.2°, 11.25°±0.2°, 12.24°±0.2°, 13.26°±0.2°, 13.82°±0.2°, 15.34°±0.2°, 15.83°±0.2°, 16.25°±0.2°, 16.61°±0.2°, 17.31°±0.2°, 18.06°±0.2°, 18.90°±0.2°, 19.64°±0.2°, 20.02°±0.2°, 21.02°±0.2°, 21.28°±0.2°, 21.74°±0.2°, 22.16°±0.2°, 23.70°±0.2°, 24.37°±0.2°, 25.03°±0.2°, 25.52°±0.2°, 26.38°±0.2°, 26.82°±0.2°, 27.59°±0.2°, 28.15°±0.2°, 28.74°±0.2°, 29.30°±0.2°, 29.69°±0.2°, 30.27°±0.2°, 30.82°±0.2°, 31.45°±0.2°, 32.60°±0.2°, 32.96°±0.2°, 33.96°±0.2°, 36.26°±0.2°, 37.86°±0.2°, 38.76°±0.2°, 39.40°±0.2°, 41.02°±0.2°, 41.98°±0.2°, 42.73°±0.2° and 43.64°±0.2°; or the potassium salt is crystalline form A of mono-potassium salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 5.53°±0.2°, 11.04°±0.2°, 14.28°±0.2°, 14.67°±0.2°, 16.29°±0.2°, 17.19°±0.2°, 19.18°±0.2°, 19.75°±0.2°, 20.01°±0.2°, 21.26°±0.2°, 21.61°±0.2°, 22.22°±0.2°, 23.33°±0.2°, 24.02°±0.2°, 25.47°±0.2°, 25.87°±0.2°, 26.46°±0.2°, 27.07°±0.2°, 27.83°±0.2°, 28.76°±0.2°, 29.49°±0.2°, 30.37°±0.2°, 31.01°±0.2°, 32.47°±0.2°, 32.96°±0.2°, 33.64°±0.2°, 33.98°±0.2°, 36.27°±0.2°, 38.87°±0.2°, 39.22°±0.2°, 40.59°±0.2°, 41.36°±0.2°, 41.77°±0.2°, 43.03°±0.2°, 44.51°±0.2°, 46.39°±0.2°, 47.48°±0.2°, 48.26°±0.2°, 50.58°±0.2°, 51.71°±0.2° and 54.23°±0.2°; or the choline salt is crystalline form A of mono-choline salt of compound of formula (I) having an X-ray powder diffraction pattern comprising 2θ values at 5.65°±0.2°, 7.12°±0.2°, 7.52°±0.2°, 8.31°±0.2°, 9.40°±0.2°, 10.31°±0.2°, 11.29°±0.2°, 13.51°±0.2°, 14.92°±0.2°, 15.29°±0.2°, 16.53°±0.2°, 16.94°±0.2°, 17.27°±0.2°, 17.50°±0.2°, 18.80°±0.2°, 19.82°±0.2°, 22.20°±0.2°, 22.63°±0.2°, 22.85°±0.2°, 23.42°±0.2°, 23.97°±0.2°, 24.39°±0.2°, 24.81°±0.2°, 25.11°±0.2°, 25.45°±0.2°, 26.19°±0.2°, 26.95°±0.2°, 27.70°±0.2°, 28.52°±0.2°, 29.07°±0.2°, 30.15°±0.2°, 31.21°±0.2°, 32.12°±0.2°, 32.95°±0.2°, 33.33°±0.2°, 34.15°±0.2°, 35.49°±0.2°, 36.11°±0.2°, 38.57°±0.2°, 40.18°±0.2°, 41.92°±0.2° and 42.99°±0.2°.

4. The base addition salt according to claim 2, wherein the mono-sodium salt is crystalline form A of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 1; or the mono-sodium salt is crystalline form B of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 2; or the mono-sodium salt is crystalline form C of mono-sodium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 3; or the lithium salt is crystalline form A of mono-lithium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 5; or the potassium salt is crystalline form A of mono-potassium salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 6; or the choline salt is crystalline form A of mono-choline salt of compound of formula (I) having an X-ray powder diffraction (XRPD) pattern substantially in accordance with the pattern shown in FIG. 7.

5. A pharmaceutical composition comprising the base addition salt of claim 1 and a pharmaceutically acceptable carrier, excipient, diluents, adjuvant, or a combination thereof.

6. The pharmaceutical composition according to claim 5 further comprising an additional therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis or a combination thereof.

7. The pharmaceutical composition according to claim 6, wherein the additional therapeutic agent is chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin, ixabepilone, tamoxifen, flutamide, gonadorelin analogues, megestrol, prednidone, dexamethasone, methylprednisolone, thalidomide, interferon alfa, leucovorin, sirolimus, temsirolimus, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, danusertib, dasatinib, erlotinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, lmasitinib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, ramucirumab, rituximab, trastuzumab, or a combination thereof.

8. The base addition salt according to claim 1, wherein the base addition salt is not hygroscopic.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 depicts an X-ray powder diffraction pattern of the crystalline form A of mono-sodium salt of compound of formula (I).

(2) FIG. 2 depicts an X-ray powder diffraction pattern of the crystalline form B of mono-sodium salt of compound of formula (I).

(3) FIG. 3 depicts an X-ray powder diffraction pattern of the crystalline form C of mono-sodium salt of compound of formula (I).

(4) FIG. 4 depicts an X-ray powder diffraction pattern of the amorphous form of mono-sodium salt of compound of formula (I).

(5) FIG. 5 depicts an X-ray powder diffraction pattern of the crystalline form A of mono-lithium salt of compound of formula (I).

(6) FIG. 6 depicts an X-ray powder diffraction pattern of the crystalline form A of mono-potassium salt of compound of formula (I).

(7) FIG. 7 depicts an X-ray powder diffraction pattern of the crystalline form A of mono-choline salt of compound of formula (I).

(8) FIG. 8 depicts a differential scanning calorimetry thermogram of the crystalline form A of mono-sodium salt of compound of formula (I).

(9) FIG. 9 depicts a differential scanning calorimetry thermogram of the crystalline form B of mono-sodium salt of compound of formula (I).

(10) FIG. 10 depicts a differential scanning calorimetry thermogram of the crystalline form C of mono-sodium salt of compound of formula (I).

(11) FIG. 11 depicts a differential scanning calorimetry thermogram of the amorphous form of mono-sodium salt of compound of formula (I).

(12) FIG. 12 depicts a differential scanning calorimetry thermogram of the crystalline form A of mono-lithium salt of compound of formula (I).

(13) FIG. 13 depicts a differential scanning calorimetry thermogram of the crystalline form A of mono-potassium salt of compound of formula (I).

(14) FIG. 14 depicts a differential scanning calorimetry thermogram of the crystalline form A of mono-choline salt of compound of formula (I).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

(15) The invention is further illustrated by the following examples, which are not be construed as limiting the invention in scope.

(16) N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide can be prepared according to the synthetic method of example 3 disclosed in WO2014130375 A1.

EXAMPLES

Example 1 Crystalline Form A of Mono-Sodium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Method I for Preparation of Crystalline Form A of Mono-Sodium Salt

(17) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (600.00 g, 1359 mmol) in acetone (5400 mL) was added a aqueous sodium hydroxide solution (59.81 g, 1495 mmol, 600 mL) at room temperature. The mixture was heated to 60±5° C. and stirred for 0.5 h, then cooled to 25±5° C. and filtered. The filtrate was added to the reaction kettle. The temperature was controlled at 25±5° C., and then isopropanol (12000 mL) was added. The mixture was cooled to 0±5° C. and stirred for 1 h, filtered to give the filter cake which was dried at 60° C. for 24 h to obtain the crude sodium salt. The mixture of the crude sodium salt in absolute ethanol (5500 mL) was heated to 78±5° C. and stirred for 4 h, then cooled to 0±5° C. and stirred for 1 h, filtered, the filter cake was dried at 60° C. for 24 h to obtain a light yellow solid (475 g, 86.4%).

Method II for Preparation of Crystalline Form A of Mono-Sodium Salt

(18) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (500 mg, 1.13 mmol) in ethanol (8 mL) was added a solution of sodium hydroxide (50 mg, 1.25 mmol) in ethanol (2 mL) at room temperature. The mixture was heated to 80±5° C. and stirred for 0.5 h, then cooled to 25±5° C. and filtered to give the filter cake which was dried at 60° C. for 24 h to obtain a yellow solid (446 mg, 84.97%).

Identification of Crystalline Form A of Mono-Sodium Salt

(19) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(20) (2) The X-ray powder diffraction pattern of crystalline form A of mono-sodium salt is shown in FIG. 1. The error margin in 2θ of the characteristic peaks was ±0.2°.

(21) (3) The differential scanning calorimetry thermogram of crystalline form A of mono-sodium salt is shown in FIG. 8 which contains the endothermic peak of 307.72° C. The error margin was ±3° C.

Example 2 Crystalline Form B of Mono-Sodium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Crystalline Form B of Mono-Sodium Salt

(22) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in acetone (40 mL) was added a aqueous sodium hydroxide solution (190 mg, 4.75 mmol, 2 mL) at room temperature. The mixture was heated to 60±5° C. and stirred for 0.5 h, then cooled to 25±5° C. and filtered. The temperature of the filtrate was controlled at 25±5° C. and then isopropanol (40 mL) was added. The mixture was stirred for 1 h and filtered to give the filter cake which was dried at 60° C. for 24 h to obtain a yellow solid (1.27 g, 60.5%).

Identification of Crystalline Form B of Mono-Sodium Salt

(23) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(24) (2) The X-ray powder diffraction pattern of crystalline form B of mono-sodium salt is shown in FIG. 2. The error margin in 2θ of the characteristic peaks was ±0.2°.

(25) (3) The differential scanning calorimetry thermogram of crystalline form B of mono-sodium salt is shown in FIG. 9 which contains the endothermic peak of 181.60° C. The error margin was ±3° C.

Example 3 Crystalline Form C of Mono-Sodium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Crystalline Form C of Mono-Sodium Salt

(26) A mixture of sodium salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (1.00 g, 2.16 mmol) in water (2 mL) and absolute ethanol (8 mL) was heated to reflux till the solid was completely dissolved, then cooled to 44° C. and filtered. The filter cake was dried at 60° C. for 24 h to obtain a light yellow solid (0.35 g, 35.0%).

Identification of Crystalline Form C of Mono-Sodium Salt

(27) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(28) (2) The X-ray powder diffraction pattern of crystalline form C of mono-sodium salt is shown in FIG. 3. The error margin in 2θ of the characteristic peaks was ±0.2°.

(29) (3) The differential scanning calorimetry thermogram of crystalline form C of mono-sodium salt is shown in FIG. 10 which contains the endothermic peak of 215.76° C. The error margin was ±3° C.

Example 4 Amorphous Form of Mono-Sodium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Amorphous Form of Mono-Sodium Salt

(30) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (1.00 g, 2.27 mmol) in dichloromethane (75 mL) and methanol (20 mL) was added a solution of sodium hydroxide (90 mg, 2.25 mmol) in methanol (5 mL) at room temperature. The mixture was heated to 80±5° C. and stirred for 0.5 h, then cooled to 25±5° C. and filtered. The filtrate was concentrated under reduced pressure to give a solid which was dried at 60° C. for 24 h to obtain a light yellow solid (1.05 g, 100%).

Identification of Amorphous Form of Mono-Sodium Salt

(31) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(32) (2) The X-ray powder diffraction pattern of amorphous form of mono-sodium salt is shown in FIG. 4. The error margin in 2θ of the characteristic peaks was ±0.2°

(33) (3) The differential scanning calorimetry thermogram of amorphous form of mono-sodium salt is shown in FIG. 11 which contains the exothermic peak of 214.79° C. The error margin was ±3° C.

Example 5 Crystalline Form A of Mono-Lithium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Crystalline Form A of Mono-Lithium Salt

(34) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (30 mL) was added a solution of lithium hydroxide (141 mg, 5.89 mmol) in ethanol (10 mL) at rt. The mixture was heated to reflux and stirred for 1 h, cooled to room temperature and stirred for 0.5 h, filtered to give the filter cake which was dried at 60° C. for 24 h to obtain a light yellow solid (1.84 g, 90.8%).

Identification of Crystalline Form A of Mono-Lithium Salt

(35) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(36) (2) The X-ray powder diffraction pattern of crystalline form A of mono-lithium salt is shown in FIG. 5. The error margin in 2θ of the characteristic peaks was ±0.2°

(37) (3) The differential scanning calorimetry thermogram of crystalline form A of mono-lithium salt is shown in FIG. 12 which contains the endothermic peak of 209.24° C. The error margin was ±3° C.

Example 6 Crystalline Form A of Mono-Potassium Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Crystalline Form A of Mono-Potassium Salt

(38) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (30 mL) was added a solution of potassium hydroxide (280 mg, 4.99 mmol) in ethanol (10 mL) at room temperature. The mixture was heated to reflux and stirred for 1 h, then cooled to room temperature and stirred for 0.5 h, filtered to give the filter cake which was dried at 60° C. for 24 h to obtain a light yellow solid (2.11 g, 97.1%).

Identification of Crystalline Form A of Mono-Potassium Salt

(39) (1) The salt-forming ratio was 1:1 determined by ICP-MS.

(40) (2) The X-ray powder diffraction pattern of crystalline form A of mono-potassium salt is shown in FIG. 6. The error margin in 2θ of the characteristic peaks was ±0.2°

(41) (3) The differential scanning calorimetry thermogram of crystalline form A of mono-potassium salt is shown in FIG. 13 which contains the endothermic peak of 301.12° C. The error margin was ±3° C.

Example 7 Crystalline Form A of Mono-Choline Salt of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide

Preparation of Crystalline Form A of Mono-Choline Salt

(42) To a mixture of N-(5-(3-cyanopyrazolo[1,5-α]pyridin-5-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (2.00 g, 4.53 mmol) in ethanol (40 mL) was added a solution of choline in water (1.56 g, 46% w/w, 5.89 mmol) at rt. The mixture was heated to reflux and stirred for 1 h, then cooled to room temperature and stirred for 0.5 h, filtered to give the filter cake which was dried at 60° C. for 24 h to obtain a yellow solid (1.91 g, 77.4%).

Identification of Crystalline Form A of Mono-Choline Salt

(43) (1) The salt-forming ratio was 1:1 determined by .sup.1H NMR.

(44) (2) The X-ray powder diffraction pattern of crystalline form A of mono-choline salt is shown in FIG. 7. The error margin in 2θ of the characteristic peaks was ±0.2°.

(45) (3) The differential scanning calorimetry thermogram of crystalline form A of mono-choline salt is shown in FIG. 14 which contains the endothermic peak of 215.43° C. The error margin was ±3° C.

Example 8 Pharmacokinetics Test

(46) The pharmacokinetic properties of amorphous forms or the crystalline forms of base addition salt of Compound (I) disclosed herein were assessed in beagle dogs. The LC/MS/MS system used in the analysis consists of an Agilent 1200 Series vacuum degasser, binary pump, well-plate autosampler, thermostated column compartment, the Agilent G6430 Triple Quadrupole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.

(47) TABLE-US-00001 TABLE A MRM 490.2.fwdarw.383.1 Fragmentor  .sup. 230 V CE   .sup. 55 V Drying Gas Temp  350° C. Nebulize .sup. 0.28 MPa Drying Gas Flow   .sup. 10 L/min

(48) An Agilent XDB-C18, 2.1×30 mm, 3.5 μM column was used for the analysis. 5 μL of the samples were injected. Analysis condition: The mobile phase was 0.1% formic acid in water (A) and 0.1% formic acid in methanol (B). The flow rate was 0.4 mL/min. And the gradient of Mobile phase was in the Table B.

(49) TABLE-US-00002 TABLE B Time Gradient of Mobile Phase B 0.5 min  5% 1.0 min 95% 2.2 min 95% 2.3 min  5% 5.0 min stop

(50) Alternatively, an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis. An ESI source was used on the LC/MS/MS spectrometer. The analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution. A Capcell MP-C18 100×4.6 mm I.D., 5 μM column (Phenomenex, Torrance, Calif., USA) was used during the analysis. The mobile phase was 5 mM ammonia acetate, 0.1% MeOH in water (A): 5 mM ammonia acetate, 0.1% MeOH in acetonitrile (B) (70/30, v/v). The flow rate was 0.6 mL/min. Column was maintained at ambient temperature. 20 μL of the samples were injected.

(51) The capsule of amorphous forms or the crystalline forms of base addition salt of Compound (I) mixed with adjuvants respectively was administered by gavage to beagle dogs in a dose of 2.5 mg/kg, 5.0 mg/kg, 7 mg/kg or 10 mg/kg. The blood samples (0.3 mL) were drawn at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hour time points or 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hour time points and centrifuged at 3,000 or 4000 rpm for 2 to 10 min. The plasma solutions were collected, and analyzed by LC/MS/MS as described above. The pharmacokinetic parameters were calculated according to non-compartment model using WinNonlin procedure. The pharmacokinetic parameters are shown in Table 1.

(52) TABLE-US-00003 TABLE 1 Pharmacokinetic profile in beagle dogs Dose T.sub.max C.sub.max AUC.sub.last Example (mg/kg) (h) (ng/mL) (ng .Math. h/mL) crystalline form A of 2.5 2.5 2820 8730 mono-sodium salt crystalline form B of 2.5 0.583 4530 9370 mono-sodium salt crystalline form C of 2.5 2.33 1410 5700 mono-sodium salt amorphous form of 2.5 1.33 2180 7290 mono-sodium salt crystalline form A of 2.5 1.5 1640 4290 mono-lithium salt crystalline form A of 2.5 0.667 3050 8420 mono-potassium salt crystalline form A of 2.5 1.08 3220 9130 mono-choline salt Compound of formula (I) 2.5 1.67 482 1550

(53) The results listed in Table 1 above show that the values of C.sub.max and AUC.sub.last of crystalline form A of mono-sodium salt, crystalline form B of mono-sodium salt, crystalline form C of mono-sodium salt, amorphous form of mono-sodium salt, crystalline form A of mono-lithium salt, crystalline form A of mono-potassium salt and crystalline form A of mono-choline salt are much larger than those of compound of formula (I), which indicates that crystalline form A of mono-sodium salt, crystalline form B of mono-sodium salt, crystalline form C of mono-sodium salt, amorphous form of mono-sodium salt, crystalline form A of mono-lithium salt, crystalline form A of mono-potassium salt and crystalline form A of mono-choline salt have good exposure and bioavailability in vivo in beagle dogs.

Example 9 Stability Test

(54) Appropriate amount of sample (100˜200 mg) was placed on a watching glass in the form of a thin layer (thickness≤5 mm). The samples were exposed to the following conditions: high temperature (60±2° C.) for 10 days; high humidity (25±2° C., 90%±5% relative humidity) for 10 days; illumination condition (visible light 45001×±5001× with ultraviolet light not lower than 0.7 W.Math.h/m.sup.2, 25±2° C., 60%±5% relative humidity) for 10 days; and room temperature (30±2° C., 65%±5% relative humidity) for 10 days, respectively. The impurity contents in the samples were determined at different time points (0, 5 and 10 days) by high performance liquid chromatography (HPLC), and the absorption peaks were normalized relative to the highest peak (corresponds to compound I) which is set to 100%. The instrument and conditions for HPLC are showed in Table 2.

(55) TABLE-US-00004 TABLE 2 Instrument and Instrument: Agilent 1200 or 1260, One over one reagent hundred thousand of electronic balance, Volumetric flask, 0.45 μm nylon membrane filter; Reagent: Acetonitrile (HPLC), Monopotassium phosphate (AR), Potassium hydroxide (AR), Water (Millipore). Solution Blank Solution/Diluent: Mix acetonitrile and Preparation water at the ratio of 45/55 (v/v); Sample Solution: Transfer about 33 mg of crystalline form A of compound (I), accurately weighed, to a 100 mL volumetric flask and add diluent to dissolve. Dilute to volume with Diluent and mix well. Chromatographic Column: Octadecyl silane bonded silica gel column, Conditions 4.6 × 150 mm, 5 μm; Column temperature: 30° C.; Detection wavelength: 235 nm; Flow rate: 1.0 mL/min; Injection volume: 20 μL; Buffer solution: Dissolve 1.361 g of monopotassium phosphate in 1 L of water and mix well. Adjust with potassium hydroxide to a pH of 6.0. Filter the solution and sonicate to obtain buffer Solution; Mobile Phase: Mix Buffer and acetonitrile at the ratio of 55/45 (v/v); Run time: 30 min.

(56) The results indicated that crystalline forms and amorphous forms of base addition salts of compound of formula (I) had no obvious change in term of appearance and purity under the condition of high temperature (60° C.) and high humidity (25° C., RH 90%±5%). They were steady and suitable for pharmaceutical use.

Example 10 Hygroscopicity Test

(57) A glass weighing bottle equipped with a stopper was tarred and the weight was recorded as m.sub.1. Base addition salts of compound (I) in different crystalline forms or amorphous form (about 1.0 g) were placed in the tared weighing bottle and capped with the stopper. The total weight was then recorded as m.sub.2. The weighing bottle (without its stopper) was placed in a desiccator containing a saturated solution of ammonium chloride (80%±2% RH (relative humidity)) at 25±1° C. The weighing bottle capped with its stopper was weighed on day 5 and day 10 and the weight was recorded as m.sub.3. The hygroscopic capacity was calculate according to the following formula.

(58) $\left(\mathrm{Hygroscopic}\mathrm{capacity}\right)=\frac{m_3-m_2}{m_2-m_1}\times 100\%$

(59) The experimental results showed that the base addition salts of compound (I) in different crystalline forms and amorphous form in this invention were not hygroscopic.

Example 11 Solubility Test

(60) 0.5 mg of the crystalline forms of base addition salt of Compound (I) was weighed and placed in a 30 mL penicillin bottle, and then 15 mL of purified water was added. The bottle was shook in a 37° C. water bath to observe the dissolution of the sample. If the sample in the bottle was dissolved completely, a little additional sample was added to the solution several times until the solution was saturated and the sample in the bottle was unable to be further dissolved. After the bottle was shook for additional 24 h/48 h, an appropriate amount of 37° C. saturated solution was took from the penicillin bottle and filtered through a membrane filtration (Polyethersulfone, 0.45 m, 13 mm, JINTENG), 2 mL of primary filtrate was discarded, and 600 μL of filtrate and 600 μL of acetonitrile were measured precisely and rapidly, respectively, and then mixed uniformly to obtain the test solution at equilibrium. The solubility of the sample was detected by external standard method.

(61) The chromatographic column used in the analysis was Agilent ZORBAX SB-C18, 4.6×50 mm, 5 μM (or other suitable chromatographic column), the detector was UV detector with detection wavelength of 264 nm, the flow rate was 1.0 mL/min, the column temperature was 35° C., the injection volume was 10 μL, the mobile phases were 10 mM sodium dihydrogen phosphate buffer (pH 3.0) and acetonitrile (V:V=50:50), the running time was 7 min.

(62) Conclusion: The experimental results showed that all the crystalline forms of base addition salt of Compound (I) have good solubility.

(63) The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.