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WO 2019/075108 Al 18 April 2019 (18.04.2019) W 1P O PCT

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WO 2019/075108 Al 18 April 2019 (18.04.2019) W 1P O PCT (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 2019/075108 Al 18 April 2019 (18.04.2019) W 1P O PCT (51) International Patent Classification: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, C07D 471/04 (2006.01) A61K 31/437 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, A61P 35/00 (2006.01) HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (21) International Application Number: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, PCT/US20 18/055279 OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (22) International Filing Date: SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, 10 October 2018 (10. 10.2018) TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (30) Priority Data: UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 62/570,573 10 October 2017 (10. 10.2017) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 62/643,950 16 March 2018 (16.03.2018) us EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, 62/656,668 12 April 2018 (12.04.2018) us MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 62/669,288 09 May 2018 (09.05.2018) us TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 62/676,417 25 May 2018 (25.05.2018) us KM, ML, MR, NE, SN, TD, TG). 62/712,707 31 July 2018 (3 1.07.2018) us Published: (72) Inventors; and — with international search report (Art. 21(3)) (71) Applicants: METCALF, Andrew T. [US/US]; c/o Ar¬ — before the expiration of the time limit for amending the ray BioPharma Inc., 3200 Walnut Street, Boulder, Col¬ claims and to be republished in the event of receipt of orado 80301 (US). FRY, David [US/US]; c/o Array Bio¬ amendments (Rule 48.2(h)) Pharma Inc., 3200 Walnut Street, Boulder, Colorado 80301 — with sequence listing part of description (Rule 5.2(a)) (US). MCFADDIN, Elizabeth A. [US/US]; c/o Array Bio¬ Pharma Inc., 3200 Walnut Street, Boulder, Colorado 80301 (US). KOLAKOWSKI, Gabrielle R. [US/US]; c/o Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301 (US). HAAS, Julia [US/US]; c/o Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301 (US). TANG, Tony P. [US/US]; c/o Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 8030 1(US). JIANG, Yu- tong [US/US]; c/o Array BioPharma Inc., 3200 Walnut Street, Boulder, Colorado 80301 (US). (74) Agent: FOLLETT, Angela D. et al; Fish & Richardson P.C., P.O. Box 1022, Minneapolis, Minnesota 55440-1022 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, ≡≡ (54) Title: CRYSTALLINE FORMS — (57) Abstract: Provided herein are compound of Formula I-IV and pharmaceutically acceptable salts thereof which ex- hibit rearranged during transfection (RET) kinase inhibition. In particular, provided herein are novel crystalline forms of 4-(6-(4-((6-methoxypyridin-3 -yl)methyl)piperazin-l -yl)pyridin-3 -yl)-6-( 1-methyl- lH-pyrazol-4-yl)pyrazolo [1,5-a]pyridine-3 -car- bonitrile (Formula I), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3. 1. 1]heptan-3 yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula II), 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl ® )-3,6-diazabicyclo[3. 1. 1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula III), 6-(2-hydroxy-2-methyl- propoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine- (Formula IV), and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the compounds, processes for making the com- pounds, and the use of the compounds in therapy. More particularly, the application relates to novel crystalline forms of Formula I- IV and pharmaceutically acceptable salts thereof useful in the treatment and prevention of diseases which can be treated with a RET ¾ kinase inhibitor, including RET-associated diseases and disorders. CRYSTALLINE FORMS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Serial Nos. 62/570,573, filed on October 10, 2017; 62/643,950, filed on March 16, 2018; 62/656,668, filed on April 12, 2018; 62/669,288, filed on May 9, 2018; 62/676,417, filed on May 25, 2018; and 62/712,707, filed on July 31, 2018; the contents of each of which are hereby incorporated by reference in their entireties. BACKGROUND [0002] RET is a single-pass transmembrane receptor belonging to the tyrosine kinase superfamily that is required for normal development, maturation, and maintenance of several tissues and cell types (Mulligan, L . M., Nature Reviews Cancer (2014) 14:173-186). The extracellular portion of the RET kinase contains four calcium-dependent cadherin-like repeats involved in ligand binding and a juxtamembrane cysteine-rich region necessary for the correct folding of the RET extracellular domain, while the cytoplasmic portion of the receptor includes two tyrosine kinase subdomains. [0003] RET signaling is mediated by the binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which also includes neurturin (NTRN), artemin (ARTN), and persephin (PSPN) (Arighi et al, Cytokine Growth Factor Rev. (2005) 16:441-67). Unlike other receptor tyrosine kinases, RET does not directly bind to GFLs and requires an additional co-receptor: that is, one of four GDNF family receptor-a (GFRa) family members, which are tethered to the cell surface by a glycosylphosphatidylinositol linkage. GFLs and GFRa family members form binary complexes that in turn bind to RET and recruit it into cholesterol-rich membrane subdomains, which are known as lipid rafts, where RET signaling occurs. [0004] Upon binding of the ligand-co-receptor complex, RET dimerization and autophosphorylation on intracellular tyrosine residues recruits adaptor and signaling proteins to stimulate multiple downstream pathways. Adaptor protein binding to these docking sites leads to activation of Ras-MAPK and PI3K-Akt/mTOR signaling pathways or to recruitment of the CBL family of ubiquitin ligases that functions in RET downregulation of the RET-mediated functions. [0005] Aberrant RET expression and/or activity have been demonstrated in different cancers and in gastrointestinal disorders such as irritable bowel syndrome (IBS). SUMMARY [0006] Compounds of Formula I-IV, 4-(6-(4-((6-methoxypyridin-3-yl)methyl)piperazin-l- yl)pyridin-3-yl)-6-(l-methyl-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula I); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3, 6- diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula II); 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-(6-methoxynicotinoyl)-3,6-diazabicyclo[3.1.1]heptan-3- yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula III); and 6-(2-hydroxy-2- methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-l-yl)pyridin-3- yl)pyrazolo[l,5-a]pyridine-3-carbonitrile (Formula IV) are inhibitors of RET kinase, and are useful for treating diseases such as proliferative diseases, including cancers. [0007] Accordingly, provided herein is a compound of Formula I-IV: I II and pharmaceutically acceptable salts, amorphous, and polymorph forms thereof. [0008] Also provided herein is a crystalline form of a compound of Formula I, wherein the crystalline form is Form A, and is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2Θvalues of 4.4±0.2, 14.6±0.2, and 18.3±0.2. [0009] Also provided herein is a crystalline form of a compound of Formula II, wherein the crystalline form is Form 1, and is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2Θvalues of 16.5±0.2, 18.9±0.2, and 26.0±0.2. [0010] Also provided herein is a crystalline form of a compound of Formula III, wherein the crystalline form is Form A, and is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2Θvalues of 17.3±0.2, 19.2±0.2, and 23.9±0.2. [0011] Also provided herein is a crystalline form of a compound of Formula IV, wherein the crystalline form is Form A, and is characterized by having an X-ray powder diffraction (XRPD) pattern comprising peaks at °2Θvalues of 8.3±0.2, 16.3±0.2, and 21.9±0.2. [0012] Also provided herein is a solid oral pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I-IV, including pharmaceutically acceptable salts, amorphous, and polymorph forms thereof. [0013] Also provided herein is a liquid pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I-IV, including pharmaceutically acceptable salts, amorphous, and polymorph forms thereof.
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