US 20150353527A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0353527 A1 Zisman (43) Pub. Date: Dec. 10, 2015 (54) NON-SELECTIVE KINASE INHIBITORS Publication Classification (71) Applicant: arence ZIAMAN, Slingerlands, NY (51) Int. Cl. (US) C07D 40/12 (2006.01) (72) Inventor: Lawrence S Zisman, Slingerlands, NY C07D 24/20 (2006.01) (US) C07D 403/2 (2006.01) (73) Assignee: PULMOKINE, INC. Slingerlands, NY (52) U.S. Cl. (US) CPC ............ C07D401/12 (2013.01); C07D 403/12 (21) Appl. No.: 14f76O139 (2013.01); C07D 241/20 (2013.01) y x- - - 9 (22) PCT Filed: Jan. 9, 2014 (57) ABSTRACT (86). PCT No.: PCT/US1.4/10778 T.S. ). L. 9, 2015 Disclosed herein are compounds, compositions, and methods e 19 for preventing and treating proliferative diseases associated Related U.S. Application Data with aberrant receptor tyrosine kinase (RTK) activity. The (60) Provisional application No. 61/751.217, filed on Jan. therapeutic indications described herein more specifically 10, 2013, provisional application No. 61/889,887, relate to the non-selective inhibition of RTKs associated with filed on Oct. 11, 2013. vascular and pulmonary disorders. Patent Application Publication Dec. 10, 2015 Sheet 1 of 26 US 2015/0353527 A1 FIG. 1A $: 8:3 $38: Coacentration (nM) FG, B C s C am u was e D 9 9 A. Concentration (nM) Patent Application Publication Dec. 10, 2015 Sheet 2 of 26 US 2015/0353527 A1 F.G. 1 C Concentration (in M) F.G. 1D c C R sa spagh d g e d A. :::::: Concentration (in M) Patent Application Publication Dec. 10, 2015 Sheet 3 of 26 US 2015/0353527 A1 FG. 2A 120% 5 IC50 (uM) || | 100% PK10453: 0.590 3094 || Imatinib: 0.434 a 60% g xxPK10453 N 40% f xximatinib O 20% SS O O% 5.00 O.50 O.05 F.G. 2B 120% IC50 (uM) 100% PK10453: 0.33O matinib: 0.620 80% 60% 40% 20% 5.00 O.50 O.05 Patent Application Publication Dec. 10, 2015 Sheet 4 of 26 US 2015/0353527 A1 IC50 (M) PK10453: O. 132 S. 100% natinib:Mia 1.81 t g 80% C 60% S. 40% & PKO453 a ximatinib S. 20% - - - SS -- O% &x-H 5.OOO 0.500 O.OSO 0.005 Dose (M) F.G. 2) IC50 (uM) 120.0% PK10453 0.429 9 imatinib 3.25 it 100.0% - - - - - - - - - - - - - - - 2 80.0% alf 60.0% ». PK10453 40.0% SS 20.0% 0.0% 4 H Patent Application Publication Dec. 10, 2015 Sheet 5 of 26 US 2015/0353527 A1 FIG. 2E PDGF 10 ng/ml + + + + + + + + Drug (uM) 67 34 17 84 A2 21 1 OS PK10453 pAKT(S473) PDGFAA matinib PK10453 pAKTCT308) PDGFAA PK10453 pAKT(S473) PDGF BB PK10453 pAKT(T308) PDGF BB Patent Application Publication Dec. 10, 2015 Sheet 6 of 26 US 2015/0353527 A1 FG, 3 16OO FIG. 4A ·Æ}.**~*~~~~~~~~);~:O,^~~~~); Olung plV 2OO 40 60 Time (min) Patent Application Publication Dec. 10, 2015 Sheet 7 of 26 US 2015/0353527 A1 F.G. 4B 3OOO 28OO . 2600 2400 2200 2000 1800 lung piNH Plasma piNH 1600 1400 1200 1000 800 600 400 200 r O .. : O 20 40 60 80 Time (min) F.G. 5A 100 - Patent Application Publication Dec. 10, 2015 Sheet 8 of 26 US 2015/0353527 A1 BEST AWAABE MAGE F.G. SB ? : FG, SC 9/27 FIG.SD .2 Patent Application Publication Dec. 10, 2015 Sheet 9 of 26 US 2015/0353527 A1 BES AWAABEMAGE FIG. 6A 60 4. O Treatment Day 10/27 FIG. 6B Patent Application Publication Dec. 10, 2015 Sheet 10 of 26 US 2015/0353527 A1 BES AVAILABLE IMAGE 320 O O 8 Patent Application Publication Dec. 10, 2015 Sheet 11 of 26 US 2015/0353527 A1 FG F.G. 7C O2 O D4 D8 Patent Application Publication Dec. 10, 2015 Sheet 12 of 26 US 2015/0353527 A1 BEST AWAABE MAGE g FIG. 8B F.G. 8C F.G. 8D Patent Application Publication Dec. 10, 2015 Sheet 13 of 26 US 2015/0353527 A1 BES AWAABLE IMAGE F.G. 10A FG, 10B 14/27 FG. A F.G. B FG, 1C Patent Application Publication Dec. 10, 2015 Sheet 14 of 26 US 2015/0353527 A1 BES AVALABEWAGE F.G. 1D FIG. 11E F.G. 1 F F.G. 1G F.G. 11H F.G. 1 15/27 F.G. 12A F.G. 12B Patent Application Publication Dec. 10, 2015 Sheet 15 of 26 US 2015/0353527 A1 BEST AWAABE MAGE FIG. 12C F.G. 12E FG, 12F F.G. 13B Patent Application Publication Dec. 10, 2015 Sheet 16 of 26 US 2015/0353527 A1 BEST AWAABE MAGE F.G. 13C F.G. 13D F.G. 14A 2,000: pAKThr3O8) 1,500 : ta. AK 1,000 500 A. 4.5 5 5.5 6 6.5 7 7.5 17/27 F.G. 4B pAKT(Thr308) 3,000 ota AK Patent Application Publication Dec. 10, 2015 Sheet 17 of 26 US 2015/0353527 A1 F.G. 14D 500 pAKT (Ser473 400 a AK 300 200 100 Patent Application Publication Dec. 10, 2015 Sheet 18 of 26 US 2015/0353527 A1 F.G. 4F V D4 D8 FIG. SA o STAT3 pSTAT3 3,000 2000: 1,000 Patent Application Publication Dec. 10, 2015 Sheet 19 of 26 US 2015/0353527 A1 FIG. 15B 4,000 3,000 2000 1,000 8 0.4 8 :8 O. 3 -- -- Patent Application Publication Dec. 10, 2015 Sheet 20 of 26 US 2015/0353527 A1 12,000 FIG. 16A ppERK1 800 800 400 200 1. i FIG. 16C Patent Application Publication Dec. 10, 2015 Sheet 21 of 26 US 2015/0353527 A1 16 OOC F.G. 6) ERK1 14DDC 12DDC OOOC 6 0,900 0.800 0,700 w O,600 0,500 0.400 O3OO ---- 0.200 0.00 0,000 : V Patent Application Publication Dec. 10, 2015 Sheet 22 of 26 US 2015/0353527 A1 F.G. 7A PDGFAA 3.3 . O3: X3:33 s: : Kis FG. 17B PDGFBB * ". .- M M M M M M M M M M M M M M M M M M M M M M M M M M M M ::iii: PDGFAA iratin: K{2:33. K. Patent Application Publication Dec. 10, 2015 Sheet 23 of 26 US 2015/0353527 A1 FIG. 17D PDGFBB . .in . K.3 33 3.3 : SF OLM :: ; ; ; 8x88; ; ;8:38: 1 ATN 8 3. 888 fiv. 388 88 ..... F.G. 18A : ; ; ; ; ;- .. ::: ; Drug Concentration (micromolar) *:::{3487 33 ri::::::gr:-i: ...atio:-- 3:gf::::... $33: 33 iciatic: ; 3 :::::t&s w8x 8K 2.337 33 ririt: gir:-ir:::::::::cr+ 33rgfrii. 8.338 88 ric: 3:3: ... :::::::::s -- 3:a::::: 383 ri: pre-i:33:iors. 33rig fr; . .338 38 ric:3:33:3: ... ::::::t&s Patent Application Publication Dec. 10, 2015 Sheet 24 of 26 US 2015/0353527 A1 F W P K ... O A. S. 3 C R P K . F.G. 18B + 1 O N G / M L PD G F B B s .3 k A .5 . O. O. Drug Concentration (micromolar) 9 se (A) PK1045330 minute pre-incubation + 1Ong/mL PDGF BB use (B) PK1045330 minute pre-incubation + 10ng/mL PDGF BB arras PK1057130 minute pre-incubation + 1Ong/mL PDGF BB Patent Application Publication Dec. 10, 2015 Sheet 25 of 26 US 2015/0353527 A1 FG, 18C ; : : Drug Concentration (micromolar) i-K:3488 38 :::::::is re-ic: ;83tion - K3333333 finista 8-incubati 33;g fir: 383- 38 inciatio: g;; 3:3: 3::::::::: F.G. 18) O o Y. O o, N scoO C O SN Structure 2 - N Structure 2a esN? OStructure 3 N ?SS1. Joro Structure 41.N 2 N Patent Application Publication Dec. 10, 2015 Sheet 26 of 26 US 2015/0353527 A1 250 forgopogrom 3 : 3 & 3 & 8 & 33 33 3: 3 3: 3 F.G. 20 Treatment Day & & 83-** x:x:::::::::::3 Treatment Day US 2015/0353527 A1 Dec. 10, 2015 NON-SELECTIVE KNASE INHIBITORS 0007. In concert with the development and administration of first generation RTK inhibitors, e.g., imatinib, RTKs have CROSS-REFERENCE TO RELATED evolved inhibitor resistance by acquiring certain mutations. APPLICATIONS See, e.g., Shah et al., Science, 305, 395-402 (2004). For 0001. This application is a 35 U.S.C. 371 National Stage example, in diseased patients refractory to certain kinase entry of PCT/US2014/010778, filed Jan. 9, 2014, which inhibitors, e.g., imatinib, it has been shown that the hydro claims priority to U.S. Provisional Application No. 61/751, phobic pocket 'gatekeeper residue' frequently possesses 217 filed Jan. 10, 2013, and U.S. Provisional Application No. mutations. See Pao et al., PLos Med. 2(3):e73 (2005). Such 61/889,887, filed Oct. 11, 2013, the entire contents of which mutations have been identified with respect to ABL, i.e., at the are hereby incorporated by reference in their entirety. T315 residue, and at analogous positions in KIT, PDGFRO. EGFR, and other kinases. Id. Hence, new RTK inhibitors with STATEMENT OF GOVERNMENTSPONSORED Superior efficacy developed in model systems that phenotypi RESEARCH cally resemble human disease pathologyare required for pre venting and treating diseases possessing aberrant RTKactiv 0002 This invention was made with United States govern 1ty. ment support under Grant Number 1R43HL 102946-01 and 2R44HL 102946-02 awarded by the National Institute of SUMMARY OF THE INVENTION Health. The United States government has certain rights in the invention. 0008. In one aspect, the present disclosure provides a method of non-selective kinase receptor inhibition for treat FIELD OF THE INVENTION ing pulmonary disorders in a Subject, including: administer ing to the Subject a therapeutically effective amount of a 0003.