USOO9676746B2 (12) United States Patent (10) Patent No.: US 9,676,746 B2 DeCrescenzo et al. (45) Date of Patent: Jun. 13, 2017 (54) CRYSTALLINE FORMS OF CHCLNO, USPC .......................................................... 514/343 See application file for complete search history. (71) Applicants: BIOMED VALLEY DISCOVERIES, INC., Kansas City, MO (US); (56) References Cited VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US) U.S. PATENT DOCUMENTS 7,354,939 B2 4/2008 Martinez-Botella et al. (72) Inventors: Gary DeCrescenzo, Parkville, MO 2003/0040536 A1 2/2003 Hale et al. (US); Dean Welsch, Parkville, MO 2004.0029857 A1 2/2004 Hale et al. (US); Petinka I. Vlahova, West 2015,005.1209 A1 2/2015 Bock et al. Lafayette, IN (US); Stephan X. M. Boerrigter, West Lafayette, IN (US); OTHER PUBLICATIONS Alexander Aronov, Newton, MA (US); Ali Keshavarz-Shokri, San Diego, CA Chemietek "Certificate of Analysis: Ulixertinib (Hydrochloride)” (US); Alexander N. Scangas, Copyright 2014. Retrieved from the Internet retrieved on Sep. 9, Wilmington, MA (US); Kathy 2016 <URL: http://www.chemietek.com/ProductFiles/Coal Ulixertinib.%20(HC1%20salt),%20Lot%2001.%20Certificate Stavropoulos, Quincy, MA (US); %20of%20Analysis.pdf>. Benjamin Littler, Carlsbad, CA (US); International Search Report for PCT/US2016/015829 mailed Apr. 7, Irina Nikolaevna Kadiyala, Newton, 2016. MA (US); Rossitza Gueorguieva Kohno M and Pouyssegur J. (2006) Targeting the ERK signaling Alargova, Brighton, MA (US) pathway in cancer therapy. Ann Med 38: 200-211. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) (73) Assignees: BioMed Valley Discoveries, Inc., Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. J Pharm Pharmaceut Sci 9(3):317-326. Kansas City, MO (US); Vertex Written Opinion of the International Searching Authority for PCT/ Pharmaceuticals Incorporated, US2016/015829 mailed Apr. 7, 2016. Boston, MA (US) Primary Examiner — Yevegeny Valenrod (*) Notice: Subject to any disclaimer, the term of this (74) Attorney, Agent, or Firm — Bryan Cave LLP patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. (57) ABSTRACT (21) Appl. No.: 15/011,377 The present invention provides crystalline forms of a com pound of formula (I): (22) Filed: Jan. 29, 2016 (65) Prior Publication Data US 2016/0221987 A1 Aug. 4, 2016 Related U.S. Application Data (60) Provisional application No. 62/110,449, filed on Jan. 30, 2015. C. (51) Int. Cl. CO7D 40/04 (2006.01) A6 IK 45/06 (2006.01) A6 IK 3/4439 (2006.01) Also provided are pharmaceutical compositions that include (52) U.S. Cl. the provided crystalline forms and methods of using the CPC ........ C07D 401/04 (2013.01); A6IK3I/4439 provided crystalline forms and pharmaceutical compositions (2013.01); A61K 45/06 (2013.01) for the treatment of cancer. (58) Field of Classification Search CPC ... CO7D 401/04; A61K 31/4439; A61K 45/06 82 Claims, 14 Drawing Sheets U.S. Patent Jun. 13, 2017 Sheet 1 of 14 US 9,676,746 B2 8 s ..-assis-- - ^ 3r : X S r sy 3 s (syriano) sistiau U.S. Patent Jun. 13, 2017 Sheet 2 of 14 US 9,676,746 B2 & s s S. s S.S s U.S. Patent Jun. 13, 2017 Sheet 3 of 14 US 9,676,746 B2 b i s b b b b & a : b s SSSssssssss S. Ex k w8. & U.S. Patent Jun. 13, 2017 Sheet 4 of 14 US 9,676,746 B2 was 3.xxxxxxxxx xxxx was SSSSSSSSSSSSSSS Sassassasssssssssssssssssssssssss -Saxxx xxxx xxxxx xxxxxxxxxx-xxxxxx --xxxxx xxxx-xx-xxx-xxxxxxxxxxx-xxxxxxxx xxx; RSSSS *Sasas: SSSSS &Swississssssssssssssssssssssss: Sassasssssss:::::::::::::::::: xxxssssssssssssssssssssssssssssssss-Xxxxxx...SSS sw8xx s was: i S www.www.swisssssssssssssssssssssssssssssssssssssssssssssssssssssss SSSSSSSSSSSSSSSSS: s U.S. Patent Jun. 13, 2017 Sheet 6 of 14 US 9,676,746 B2 &x Ss eyes sww R&eeeeeeee w & | W S. S. S S & S. is is 888 & 8 U.S. Patent Jun. 13, 2017 Sheet 9 of 14 US 9,676,746 B2 -Y^mss U.S. Patent Jun. 13, 2017 Sheet 10 of 14 US 9,676,746 B2 s8. R Sssssssssssssssssssaxxx xxxxaaaaaaaaaaaaaaaaaassssssssssss assssssssssssssssssssssss: s:SSSSSSSSSSSSSSSSSS333Sssssssssssss Y--------------Saxxx-x-xx-xx-xxx-xx-x-x-xx-xx-x- s sixx xxx; U.S. Patent Jun. 13, 2017 Sheet 12 of 14 US 9,676,746 B2 M * Ow & xxxxx^^^ &r -Y & ^ r s Y x S. R & S. U.S. Patent Jun. 13, 2017 Sheet 13 of 14 US 9,676,746 B2 --******… ~~~~…,„~~~~~~*~~~~~~~~~~….... sh: k, x retressertarresearrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrre S. s U.S. Patent Jun. 13, 2017 Sheet 14 of 14 US 9,676,746 B2 ^ aaaaaaaaaaaaaaaa. ------ sistssixxxesssssssssssssssssssssssssssssssssssssssssss 3. US 9,676,746 B2 1. 2 CRYSTALLINE FORMS OF CHCL-NO, boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide can be prepared which exhibit improved properties, e.g. Surpris CROSS-REFERENCE TO RELATED ingly improved stability and improved solubility character APPLICATIONS istics. Thus, the present invention provides crystalline 4-(5- This patent application claims the benefit of U.S. Provi Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car sional Patent Application No. 62/110,449, filed Jan. 30. boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. 2015, which is incorporated by reference herein in its entirety. The present invention also provides crystalline free base 10 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- FIELD OF THE INVENTION carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide. The present invention also provides a crystalline free base The present invention relates to crystalline forms of of a compound of formula: 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide, 15 which is useful as an inhibitor of ERK protein kinase. BACKGROUND OF THE INVENTION Mitogen-activated protein kinase (MAPK) pathways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation C 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, 25 represent attractive blockade targets in the development of cancer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Pat. No. 7,354,939 B2 discloses, inter alia, having an X-ray powder diffraction (XRPD) pattern com compounds effective as inhibitors of ERK protein kinase. prising a characteristic peak at about 19.5° 20. One of these compounds, 4-(5-Chloro-2-isopropylamin 30 The present invention also provides a crystalline free base opyridin-4-yl)-1H-pyrrole-2-carboxylic acid 1-(3-chloro of a compound of formula: phenyl)-2-hydroxyethylamide, is a compound according to formula (I): 35 40 C C. 45 having an XRPD pattern comprising characteristic peaks at about 9.1 and 19.5° 20. The present invention also provides a crystalline free base Pharmaceutical compositions are often formulated with a of a compound of formula: crystalline solid of the active pharmaceutical ingredient 50 (API). The specific crystalline form of the API can have significant effects on properties such as stability and solu bility/bioavailability. Instability and solubility characteris tics can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount 55 of a drug over a given time frame (Peterson et al., 2006). There exists an unmet need for crystalline forms of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2- C carboxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide which exhibit improved properties for formulation of phar 60 maceutical compositions. The present application is directed to meeting this and other needs. SUMMARY OF THE INVENTION having an XRPD pattern comprising characteristic peaks at 65 about 9.1, 15.4, 19.5 and 21.4° 20. It has been discovered that crystalline forms of 4-(5- The present invention also provides a crystalline free base Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car of a compound of formula: US 9,676,746 B2 C having one or more XRPD 20-reflections () selected from having an XRPD pattern comprising characteristic peaks at the group consisting of about 9.1, 12.5, 15.2, 15.4, 19.2, about 6.7 and 11.0° 20. 19.5, 20.3, 20.5, 21.4, 21.7, 21.9, 23.1, 23.3, 23.6, and 24.3. The present invention also provides a crystalline hydro The present invention also provides a crystalline free base chloride salt of a compound of formula: of a compound of formula: 25 C C 30 having an XRPD pattern comprising characteristic peaks at having an XRPD pattern substantially as shown in FIG. 1. about 6.7, 11.0, 17.6 and 19.9° 20. The present invention also provides pharmaceutical com The present invention also provides a crystalline hydro positions comprising any of the crystalline compounds of chloride salt of a compound of formula: the present invention. 35 The present invention also provides a method of treating a cancer in a Subject in need thereof comprising adminis tering to the subject an effective amount of any of the crystalline compounds of the present invention. The present invention also provides a method of treating 40 a cancer in a Subject in need thereof comprising adminis tering to the subject an effective amount of any of the pharmaceutical compositions of the present invention. The present invention also provides crystalline 4-(5- Chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-car 45 boxylic acid 1-(3-chlorophenyl)-2-hydroxyethylamide mono HC1. The present invention also provides a crystalline hydro having one or more XRPD 20-reflections () selected from chloride salt of a compound of formula: the group consisting of about 6.1, 6.7, 11.0, 12.1, 13.7, 15.2. 50 16.5, 17.6, 17.9, 18.4, 18.7, 19.6, 19.9, and 20.4.