IP Library › Granted Patent US 12,692,248
Granted Patent B2
US 12,692,248 · App. 18/556,243 · Granted Jul 28, 2026

Solid state forms of (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof

Inventors: Stephen W. Kaldor (San Diego, CA); Toufike Kanouni (Palm Beach Gardens, FL); Andrew Phimister (Kensington, CA); Jayachandra P. Reddy (West Palm Beach, FL)
Assignee: PIERRE FABRE MEDICAMENT
C07D401/12A61K31/5377
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Quick Facts
Patent No.
US 12,692,248
App. No.
18/556,243
Filed
Oct 19, 2023
Granted
Jul 28, 2026
Kind
B2
Art Unit
1623
USPC
514/235.5
Abstract

The present disclosure relates to solid state forms of (S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof. Such solid state forms are useful in preparation of pharmaceutical compositions and dosage forms for the treatment of disease.

Claims (24)

1 . A solid form of(S)—N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide hydrochloride, depicted below as Compound 2,

wherein the solid form is crystalline.

2 . The solid form of claim 1 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of 19.7°±0.3.

3 . The solid form of claim 2 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of 11.1°±0.3 and 21.2°±0.3.

4 . The solid form of claim 2 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of 15.8°±0.3 and 22.0°=0.3.

5 . The solid form of claim 2 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of 13.9°±0.3, 18.5° 0.3, 21.7°±0.3, and 22.5°±0.3.

6 . The solid form of claim 2 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of 9.7°±0.3, 23.3°±0.3, and 23.8°±0.3.

7 . The solid form of claim 1 , wherein the solid form exhibits at least one X-ray powder diffraction reflection selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°=0.3.

8 . The solid form of claim 7 , wherein the solid form exhibits at least two X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3.

9 . The solid form of claim 8 , wherein the solid form exhibits at least three X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°=0.3.

10 . The solid form of claim 9 , wherein the solid form exhibits at least four X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3.

11 . The solid form of claim 10 , wherein the solid form exhibits at least five X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°±0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3.

12 . The solid form of claim 11 , wherein the solid form exhibits at least six X-ray powder diffraction reflections selected from 9.7°±0.3, 11.1°±0.3, 13.9°±0.3, 15.8°±0.3, 18.5°±0.3, 19.7°±0.3, 21.2°=0.3, 21.7°±0.3, 22.0°±0.3, 22.5°±0.3, 23.3°±0.3, and 23.8°±0.3.

13 . The solid form of claim 1 , wherein the solid form exhibits an X-ray powder diffraction reflection at a 2-theta value of the crystalline solid state form of Compound 2 exhibits at least one X-ray powder diffraction reflection selected from 20.3°±0.2, 23.4°±0.2, and 24.0°±0.2.

14 . The solid form of claim 1 , wherein the solid form exhibits the X-ray powder diffraction pattern as shown in FIG. 3 .

15 . The solid form of claim 1 , wherein the solid form exhibits a differential scanning calorimetry thermogram comprising an endothermic peak at 229.9° C.±5.0.

16 . The solid form of claim 1 , wherein the solid form exhibits the differential scanning calorimetry thermogram as shown in FIG. 4 .

17 . The solid form of claim 1 , wherein the solid form exhibits less than 1.0%±0.5 weight loss up to 160° C.±10.0 as determined by thermogravimetric analysis.

18 . The solid form of claim 1 , wherein the solid form exhibits the thermogravimetric analysis thermogram as shown in FIG. 4 .

19 . A pharmaceutical composition comprising the solid form of claim 1 and a pharmaceutically acceptable excipient.

20 . The pharmaceutical composition of claim 19 , further comprising a disintegrating agent.

21 . The pharmaceutical composition of claim 20 , wherein the disintegrating agent is croscarmellose sodium.

22 . A method of inhibiting receptor tyrosine kinase effector RAF comprising administering to the subject with a condition in need thereof, the solid form of claim 1 .

23 . The method of claim 22 , wherein the condition is cancer or neoplastic disease.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE CORRECT THE RECEIVING PARTY DATA COMPANY NAME IS: PIERRE FABRE MEDICAMENT PREVIOUSLY RECORDED AT REEL: 66638 FRAME: 147. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Sep 11, 2024
From: KINNATE BIOPHARMA INC.
To: PIERRE FABRE MÉDICAMENT
Reel/Frame 068939/0656 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 4, 2024
From: KINNATE BIOPHARMA INC.
To: PIERRE FABRE MÉDICAMENT, SAS
Reel/Frame 066638/0147 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 20, 2023
From: KALDOR, STEPHEN W.; KANOUNI, TOUFIKE; PHIMISTER, ANDREW; REDDY, JAYACHANDRA P.
To: KINNATE BIOPHARMA INC.
Reel/Frame 065299/0626 →
Continuity (2)
Provisional Application 63178752 · Apr 23, 2021
Related Publication 20240208931A1 · Jun 27, 2024
References Cited (88)
US 5846514A · Foster et al. · 1998 [cited by applicant]
US 6334997B1 · Foster et al. · 2002 [cited by applicant]
US 10927111B2 · Kaldaor et al. · 2021 [cited by applicant]
US 11098031B1 · Kaldor et al. · 2021 [cited by applicant]
US 11377431B2 · Kaldor et al. · 2022 [cited by applicant]
US 11407737B2 · Kaldor et al. · 2022 [cited by applicant]
US 11667634B2 · Kaldor et al. · 2023 [cited by applicant]
US 11746095B2 · Kaldor et al. · 2023 [cited by applicant]
US 20040157827A1 · Pevarello et al. · 2004 [cited by applicant]
US 20050256174A1 · Wood et al. · 2005 [cited by applicant]
US 20070054916A1 · Patel et al. · 2007 [cited by applicant]
US 20070244120A1 · Dumas et al. · 2007 [cited by applicant]
US 20080114006A1 · Flynn et al. · 2008 [cited by applicant]
US 20090036419A1 · Chen et al. · 2009 [cited by applicant]
US 20090054436A1 · Borzilleri et al. · 2009 [cited by applicant]
US 20110183997A1 · Chianelli et al. · 2011 [cited by applicant]
US 20120040951A1 · Chuaqui et al. · 2012 [cited by applicant]
US 20140275003A1 · Barsanti et al. · 2014 [cited by applicant]
US 20150119392A1 · Flynn et al. · 2015 [cited by applicant]
US 20160075727A1 · Burger et al. · 2016 [cited by applicant]
US 20170260207A1 · Aversa et al. · 2017 [cited by applicant]
US 20190175606A1 · Aversa et al. · 2019 [cited by applicant]
US 20200347052A1 · Kaldor et al. · 2020 [cited by applicant]
US 20210300904A1 · Kaldor et al. · 2021 [cited by applicant]
US 20220340543A1 · Kaldor et al. · 2022 [cited by applicant]
US 20230081390A1 · Kaldaor et al. · 2023 [cited by applicant]
US 20230255977A1 · Franovic et al. · 2023 [cited by applicant]
EP 2112150B1 · 2013 [cited by applicant]
WO WO03068229A1 · 2003 [cited by applicant]
WO WO2006071940A2 · 2006 [cited by applicant]
WO WO2008034008A2 · 2008 [cited by applicant]
WO WO2013184119A1 · 2013 [cited by applicant]
WO WO2014151616A1 · 2014 [cited by applicant]
WO WO2016038581A1 · 2016 [cited by applicant]
WO WO2016038582A1 · 2016 [cited by applicant]
WO WO2020024009A1 · 2020 [cited by applicant]
WO WO2020168172A1 · 2020 [cited by applicant]
WO WO2020198058A1 · 2020 [cited by applicant]
WO WO2020227020A1 · 2020 [cited by applicant]
WO WO2021081375A1 · 2021 [cited by applicant]
WO WO2022060996A1 · 2022 [cited by applicant]
WO WO2022081469A1 · 2022 [cited by applicant]
WO WO2022226221A1 · 2022 [cited by applicant]
WO WO2022226261A1 · 2022 [cited by applicant]
Anastassiadis et al. Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol. 29(11):1039-45 (2011). [cited by applicant]
Berge et al. Pharmaceutical Salts. Journal of Pharmaceutical Sciences 66(1):1-19 (Jan. 1977). [cited by applicant]
CAS Chemical Structure Search #3191415 Updated (Apr. 2020). [cited by applicant]
CAS Chemical Structure Search dated Apr. 24, 2019. [cited by applicant]
CAS Search dated Apr. 26, 2023. [cited by applicant]
Chapman et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine 364(26):2507-2516 (2011). [cited by applicant]
Chemical Structure Search report data Feb. 27, 2019. [cited by applicant]
Davies et al. Mutations of the BRAF Gene in Human Cancer. Nature 417:949-954 (2002). [cited by applicant]
Evans. Synthesis of Radiolabelled Compounds. Journal of Radioanalytical Chemistry 64(1-2):9-32 (1981). [cited by applicant]
Hauschild et al. Dabrafenib in BRAF-mutated Metastatic Melanoma: A Multicentre, Open-Label, Phase 3 Randomised Controlled Trial. Lancet 380(9839):358-65 (2012). [cited by applicant]
Henry et al. Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity… [cited by applicant]
Kabalka et al., The synthesis of radiolabeled compounds via organometallic intermediates. Tetrahedron 45(21):6601-6621 (1989). [cited by applicant]
Kania et al. The Discovery of Exarafenib (KIN-2787), a Solution to the Challenges of Pan-RAF kinase Inhibition. PowerPoint presentation at Winter Conference on Medicinal & Bioorganic Chemistry (Jan. 2023). [cited by applicant]
Kinnate Biopharma. RAF Clinico-Genomic Landscape Study PowerPoint. (Nov. 2021). [cited by applicant]
Lv et al. Design, synthesis and biological evaluation of novel 4-alkynylquinoline derivatives as PI3K/mTOR dual inhibitors. Eur J Med Chem 99:36-50 (2015). [cited by applicant]
Manabe. Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human BRAF-alteration driven non-small cell lung cancer (NSCLC). Presentation from IASLC 2022 Targeted Therapies of L… [cited by applicant]
Mckean et al. Design and rationale of a first in human (FIH) phase 1/1b study evaluating KIN-2787, a potent and highly selective pan-RAF inhibitor, in adult patients with BRAF- and NRAS-mutation positive solid tumors. A… [cited by applicant]
Miller et al. Antitumor activity of KIN-2787, a next-generation pan-RAF inhibitor, in preclinical models of human RAF/RAS mutant melanoma. American Association for Cancer Research Poster #2674 (2022). [cited by applicant]
Nishiguchi et al. Design and Discovery of N-(2-Methyl-5′-morpholino-6′-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3′-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Tar… [cited by applicant]
Owsley et al. Prevalence of class I-III BRAF mutations among 114,662 cancer patients in a large genomic database. Exp Biol Med (Maywood) 246(1):31-39 (2021). [cited by applicant]
PCT/US2020/024009 International Invitation to Pay Additional Fees dated Jun. 2, 2020. [cited by applicant]
PCT/US2020/024009 International Search Report and Written Opinion dated Jul. 28, 2020. [cited by applicant]
PCT/US2020/030786 International Invitation to Pay Additional Fees dated Jul. 14, 2020. [cited by applicant]
PCT/US2020/030786 International Search Report and Written Opinion dated Sep. 14, 2020. [cited by applicant]
PCT/US2020/057132 International Invitation to Pay Additional Fees dated Dec. 8, 2020. [cited by applicant]
PCT/US2020/057132 International Search Report and Written Opinion dated Feb. 9, 2021. [cited by applicant]
PCT/US2021/050690 International Search Report and Written Opinion dated Dec. 27, 2021. [cited by applicant]
PCT/US2021/054403 International Search Report and Written Opinion dated Dec. 28, 2021. [cited by applicant]
PCT/US2022/025815 International Search Report and Written Opinion dated Jul. 28, 2022. [cited by applicant]
PCT/US2022/025875 International Search Report and Written Opinion dated Jul. 25, 2022. [cited by applicant]
Ramurthy, Savithri, et al., Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targ… [cited by applicant]
Reg/Caplus and Marpat. Science IP Report dated Sep. 17, 2020. [cited by applicant]
Rosse. Pyridyl Isonicotinamide Inhibitors of RAF Kinase. ACS Med. Chem. Lett. 7:1022-1023 (2016). [cited by applicant]
Science IP Report dated Jul. 13, 2020 (873 pgs). [cited by applicant]
Severson et al. Occurrence of BRAF class II and III alterations is common across solid tumors and is associated with inferior clinical outcomes in NSCLC and melanoma. American Association for Cancer Research Poster #412… [cited by applicant]
Severson et al. Real-World Clinical Genomic Analysis of Patients with BRAF Mutated Cancers Identifies BRAF Class II and III as a Population of Unmet Medical Need. ESMO Targeted Anticancer Therapies Congress 2022. Poster… [cited by applicant]
Spira et al. A Phase 1 Clinical Trial Evaluating Monotherapy With Exarafenib (KIN-2787), a Highly Selective Pan-RAF Inhibitor, in BRAF-Altered Solid Tumors and NRAS-Mutant Melanoma. PowerPoint Presentation American Asso… [cited by applicant]
Subbiah et al. Pan-Cancer Efficacy of Vemurafenib in BRAF V600-Mutant Non-Melanoma Cancers. Cancer Discov 10(5):657-663 (2020). [cited by applicant]
U.S. Appl. No. 17/167,599 Office Action dated Oct. 31, 2022. [cited by applicant]
U.S. Appl. No. 17/738,327 Office Action dated Apr. 18, 2023. [cited by applicant]
U.S. Appl. No. 18/296,726 Office Action dated Jul. 18, 2023. [cited by applicant]
Wang et al. Exarafenib (KIN-2787) is a potent, selective pan-RAF inhibitor with activity in preclinical models of BRAF Class II/III mutant and NRAS mutant melanoma. American Association for Cancer Research Annual Meetin… [cited by applicant]
Yaeger et al. Targeting Alterations in the RAF-MEK Pathway. Cancer Discov 9(3):329-341 (2019). [cited by applicant]
Japanese Office Action for Japanese Application No. 2023-565206, dated Oct. 14, 2025, with partial English translation. [cited by applicant]