IP Library › Patent Application 16378095
Patent Application
App. No. 16/378,095

DIARYL MACROCYCLE POLYMORPH

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Patent No.
US None
App. No.
16/378,095
Abstract

This disclosure relates to polymorphs of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one that are useful in the treatment of disease, such as cancer, in mammals. This disclosure also relates to compositions including such polymorphs, and to methods of using such compositions in the treatment of diseases, such as cancer, in mammals, especially in humans.

Claims (90)

1 - 17 . (canceled)

18 . A compound of the formula II

wherein R 1 and R 2 are each independently H or PG, and R 3 and R 4 are each independently C 1 -C 4 alkyl.

19 . The compound of claim 18 , wherein R 1 and R 2 are PG.

20 . The compound of claim 18 , wherein R 2 is H.

21 . The compound of claim 18 , wherein R 1 is H.

22 . The compound of claim 20 , wherein R 1 is PG.

23 . The compound of claim 21 , wherein R 2 is PG.

24 . The compound of claim 18 , wherein R 3 and R 4 are methyl.

25 . The compound of claim 18 , wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts.

26 . (canceled) .

27 . The compound of claim 18 having the formula

28 . A process for preparing a compound of the formula I

comprising

(a) contacting a compound of the formula A

with a compound of the formula B-14

in the presence of a base to provide a compound of the formula C

or

(b) contacting a compound of the formula C with an inorganic base to provide a compound of the formula D

or

(c) contacting a compound of the formula D with an acid to provide a compound of the formula E

or

(d) contacting a compound of the formula E with a base in the presence of a phosphinate reagent to provide the compound of the formula I.

29 . A process for preparing a compound of the formula B

wherein

PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide,

Bn, trityl, benzylidene, and Ts; and

R 3 and R 4 are each independently C 1 -C 4 alkyl;

comprising

(a) contacting a compound of the formula B-1

wherein R 4 is C 1 -C 4 alkyl; with a compound of the formula B-2R

wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; in the presence of an azodicarboxylate reagent and a phosphine reagent to provide a compound of the formula B-3

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl;

or

(b) contacting a compound of the formula B-3

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with (R)-2-methyl-2-propanesulfinamide to provide a compound of the formula B-5

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl;

or

(c) contacting a compound of the formula B-5

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with a reducing agent to provide a compound of the formula B-6

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl;

or

(d) contacting a compound of the formula B-6

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl;

with an iodine reagent to provide a compound of the formula B.

30 . A process for preparing a compound of the formula B

wherein

PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide,

Bn, trityl, benzylidene, and Ts; and

R 3 and R 4 are each independently C 1 -C 4 alkyl;

comprising

(a) reacting a compound of the formula B-7

wherein R 4 is C 1 -C 4 alkyl; under conditions suitable for preparing a compound of the formula B-8

wherein R 4 is C 1 -C 4 alkyl; and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; or

(b) contacting a compound of the formula B-8

wherein R 4 is C 1 -C 4 alkyl; and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; with a compound of the formula B-2R

wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; in the presence of an azodicarboxylate reagent and a phosphine reagent to provide a compound of the formula B-9

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; and R 3 and R 4 are each independently C 1 -C 4 alkyl; or

(c) contacting a compound of the formula B-9

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with an inorganic base to provide a compound of the formula B.

31 . A process for preparing a compound of the formula B

wherein

PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide,

Bn, trityl, benzylidene, and Ts; and

R 3 and R 4 are each independently C 1 -C 4 alkyl;

comprising

(a) reacting a compound of the formula B-10

with a compound of the formula B-2S

wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; in the presence of a base to provide a compound of the formula B-11

wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; or

(b) contacting a compound of the formula B-11

wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; with a nucleophile to provide a compound of the formula B-12

wherein R 3 and R 4 are each independently C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts;

or

(c) contacting a compound of the formula B-12

wherein R 3 and R 4 are each independently C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; with a reducing agent to provide a compound of the formula B.

32 . A process for preparing a compound of the formula B

wherein

PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide,

Bn, trityl, benzylidene, and Ts; and

R 3 and R 4 are each independently C 1 -C 4 alkyl;

comprising

(a) reacting a compound of the formula B-12

wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; R 3 and R 4 are each independently C 1 -C 4 alkyl; under conditions suitable for preparing a compound of the formula B-13

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; R 3 is C 1 -C 4 alkyl; and R 5 is C 1 -C 3 alkyl; or

(b) contacting a compound of the formula B-13

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; R 3 is C 1 -C 4 alkyl; and R 5 is C 1 -C 3 alkyl; with a reducing agent to provide a compound of the formula B-9

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; and R 3 and R 4 are each independently C 1 -C 4 alkyl; or

(c) contacting a compound of the formula B-9

wherein each PG is independently selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts, provided that each PG is different; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with an inorganic base to provide a compound of the formula B.

Assignments (1)
CHANGE OF NAME Recorded Aug 19, 2019
From: TP THERAPEUTICS, INC.
To: TURNING POINT THERAPEUTICS, INC.
Reel/Frame 050084/0756 →