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WO 2016/123581 Al 4 August 2016 (04.08.2016) P O P C T

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WO 2016/123581 Al 4 August 2016 (04.08.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2016/123581 Al 4 August 2016 (04.08.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61P 37/00 (2006.01) A61P 25/00 (2006.01) kind of national protection available): AE, AG, AL, AM, C07F 9/58 (2006.01) C07F 9/6558 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US2016/015843 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 29 January 2016 (29.01 .2016) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/1 10,446 30 January 2015 (30.01.2015) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant: BIOMED VALLEY DISCOVERIES, INC. TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, [US/US]; 4520 Main Street, 16th FL, Kansas City, Mis TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, souri 64 111 (US). DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (72) Inventors: DECRESCENZO, Gary; 6135 Westwood SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Court, Parkville, Missouri 641 52 (US). WELSCH, Dean; GW, KM, ML, MR, NE, SN, TD, TG). 10427 NW River Hills Place, Parkville, Missouri 64152 (US). SELBO, Jon G.; 5798 Augusta Blvd., West Lafay Published: ette, Indiana 47906 (US). ALBERT, Ekaterina V.; 821 — with international search report (Art. 21(3)) Lagrange Street, West Lafayette, Indiana 47906 (US). RIGSBEE, Emily M.; 8857 Traders Landing, Browns- — with amended claims (Art. 19(1)) burg, Indiana 461 12 (US). (74) Agent: HOOPER, Kevin C ; Bryan Cave LLP, 1290 Av enue of the Americas, New York, New York 10104 (US). (54) Title: CRYSTALLINE C2iH22Ci2N 0 2MALONATE - (57) Abstract: The present invention provides a malonate salt of a compound of formula (I), which is a crystalline salt. Also provided are pharmaceutical compositions that include the provided malonate salt and methods of using the provided crystalline o forms and pharmaceutical compositions for the treatment of cancer. CRYSTALLINE C 2 H22CI2N4O2 MALONATE CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This patent application claims the benefit of U.S. Provisional Patent Application No. 62/1 10,446, filed January 30, 201 5 , which is incorporated by reference herein in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate, which is useful as an inhibitor of ERK protein kinase. BACKGROUND OF THE INVENTION [0003] Mitogen-activated protein kinase (MAPK) pathways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation and apoptosis. One MAPK pathway, the extracellular signal-regulated kinase (ERK) signaling pathway, is often found to be up-regulated in tumors. Pathway members, therefore, represent attractive blockade targets in the development of cancer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Patent No. 7,354,939 B2 discloses, inter alia, compounds effective as inhibitors of ERK protein kinase. One of these compounds, 4-(5-Chloro-2-isopropylaminopyridin- 4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide, is a compound according to formula (I): [0004] Pharmaceutical compositions are often formulated with a crystalline solid of the active pharmaceutical ingredient (API). The specific crystalline form of the API can have significant effects on properties such as stability and solubility / bioavailability. Instability and solubility characteristics can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount of a drug over a given time frame. One strategy used to achieve the desired physical parameters is the practice of salt selection. (Peterson et al., 2006). [0005] There exists an unmet need for crystalline forms of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide which exhibit improved properties for formulation of pharmaceutical compositions. The present application is directed to meeting this and other needs. SUMMARY OF THE INVENTION [0006] It has been discovered that crystalline forms of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonalte can be prepared which exhibit improved properties, e.g. surprisingly improved stability and improved solubility characteristics. Thus, the present invention provides a malonate salt of a compound of which is a crystalline salt. [0008] The present invention also provides a malonate salt of a compound of formula (I): having an XRPD pattern substantially as shown in FIG. 7 . [0009] The present invention also provides Form A crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate having an infrared spectroscopy (IR) spectrum comprising one or more peaks at about 1573, 1504, 1475, 1253, 1033, and 883 cm 1 . [0010] The present invention also provides Form A crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate having an IR spectrum substantially as shown in FIG. 8 . [0011] The present invention also provides Form A crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate having (i) an XRPD pattern comprising one or more peaks at about 3.0. 5.2, 8.0, and 10.9° 2Θ; and (ii) an IR spectrum comprising one or more peaks at about 1573, 1504, 1475, 1253, 1033, and 883 cm 1 . [0012] The present invention also provides Form A crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate having having a DSC thermogram with an endotherm having an onset temperature of approximately 142.1°C. [0013] The present invention also provides Form A crystalline 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide malonate having a DSC thermogram substantially as shown in FIG. 9 . [0014] The present invention also provides a pharmaceutical composition comprising a crystalline compound of the present invention and a pharmaceutically acceptable carrier. [0015] The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a crystalline compound of the present invention. [0016] The present invention also provides a method of treating a cancer in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition of the present invention. [0017] The present invention also provides a method of making Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1- (3-chlorophenyl)-2-hydroxyethyl]amide malonate comprising reacting malonic acid and 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3- chlorophenyl)-2-hydroxyethyl]amide under conditions suitable to form Form A crystalline 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1- (3-chlorophenyl)-2-hydroxyethyl]amide malonate. BRIEF DESCRIPTION OF THE DRAWINGS [0018] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. [0019] FIG. 1 shows the XRPD of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)- 1H-pyrrole-2-carboxylic acid [ 1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base acquired in transmission mode. [0020] FIG. 2 shows the FT-IR spectrum of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide free base. [0021] FIG. 3 shows the DSC thermogram of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide free base. [0022] FIG. 4 shows the XRPD of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)- 1H-pyrrole-2-carboxylic acid [ 1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C acquired in transmission mode. [0023] FIG. 5 shows the FT-IR spectrum of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide Form C. [0024] FIG. 6 shows the DSC thermogram of 4-(5-Chloro-2- isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2- hydroxyethyl]amide Form C. [0025] FIG. 7 shows the XRPD of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)- 1H-pyrrole-2-carboxylic acid [ 1 -(3-chlorophenyl)-2-hydroxyethyl]amide malonate Form A acquired in transmission mode.
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