Granted Patent B2

US 10,434,101 · App. 15/869,635 · Granted Oct 8, 2019

Inventors: Kwangho Lee (Daejeon, KR); Deqiang Niu (Lexington, MA); Russell C. Petter (Stow, MA); Matthew Frank Baevsky (Northborough, MA); Juswinder Singh (Southborough, MA)

Assignee: Celgene CAR LLC

A61K31/506A61K31/5377A61K31/541A61K31/551C07D239/34C07D239/42C07D239/47C07D239/48C07D403/14

Abstract

Claims (60)

1. A method of preparing a compound of formula I:

or a salt thereof,

comprising treating a compound of formula S3:

or a salt thereof,

with an aniline of formula:

or a salt thereof,

in the presence of an acid;

wherein

n is 0, 1, or 2;

m is 0, 1, or 2, wherein m and n are not simultaneously 0;

W is —NH—;

R 1 is —OR;

each R is independently C 1-4 alkyl or C 1-4 fluoroalkyl;

R 2 is —CF 3 , Cl, or Br;

G is —O—, —NR 3 —, —S(O) 2 —, or —CH(OR 4 )—;

R 3 is —C(O)—R, —C(O)OR, —C(O)NHR, —SO 2 —R, —SO 2 NH 2 , —C(O)—C 1-4 alkylene-OH or—SO 2 —C 1-4 alkylene-OH;

R 4 is hydrogen, C 1-4 alkyl, or C 1-4 fluoroalkyl; and

R 5 is hydrogen or —C(O)OR.

2. The method of claim 1 , further comprising

a. treating the compound of formula I, or a salt thereof, with trifluoroacetic acid; and

b. treating an intermediate from step a with N,N-diisopropylethylamine and an agent selected from sulfamide, N-methyl-N-hydroxysuccinyl carbamate, methyl chloroformate, methanesulfonyl chloride, trifluoroacetic anhydride, tert-butyl isocyanate, and glycolic acid to thereby provide a compound of formula I, or a salt thereof.

3. The method of claim 1 , wherein the compound of formula S3, or salt thereof, is prepared by treating a compound of formula S2:

or a salt thereof,

with acryloyl chloride.

4. The method of claim 3 , wherein the compound of formula S2, or a salt thereof, is prepared by treating a compound of formula S1:

or a salt thereof,

with an acid suitable to remove a tert-butyloxycarbonyl (“Boc”) protecting group.

5. The method of claim 4 , wherein the compound of formula S1, or salt thereof, is prepared by treating a Boc-protected aniline of formula:

or a salt thereof,

with a pyrimidine of formula:

or a salt thereof,

in the presence of a base.

6. The method of claim 1 , wherein the acid is selected from trifluoroacetic acid and hydrochloric acid.

7. The method of claim 3 , wherein the compound of formula S3, or salt thereof, is prepared by treating a compound of formula S2, or salt thereof, with acryloyl chloride in the presence of a halogenated solvent.

8. The method of claim 7 , wherein the halogenated solvent is dichloromethane.

9. The method of claim 4 , wherein the acid suitable to remove a Boc group is trifluoroacetic acid.

10. The method of claim 5 , wherein the base is a tertiary amine.

11. The method of claim 10 , wherein the tertiary amine is N,N-diisopropylethylamine.

12. The method of claim 1 , wherein the compound of S3 is selected from:

or a salt thereof.

13. The method of claim 12 , wherein the compound of S3 is:

14. The method of claim 1 , wherein the aniline is selected from:

2-methoxy-4-morpholinoaniline;

2-methoxy-4-(4-acetylpiperazinyl)aniline;

2-methoxy-4-(4-(2-hydroxyacetyl)piperazinyl)aniline;

1-(4-(4-amino-3-methoxyphenyl)-1,4-diazepan-1-yl)ethanone;

tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate;

tert-butyl 4-(4-amino-3-ethoxyphenyl)piperazine-1-carboxylate;

2-difluoromethoxy- 4 -morpholinoaniline;

tert-butyl 4-(4-amino-3-difluoromethoxyphenyl)piperazine-1-carboxylate;

2-methoxy-4-(1,4-oxazepan-4-yl)aniline;

tert-butyl 4-(4-amino-3-methoxyphenyl)-1,4-diazepane-1-carboxylate;

tert-butyl 4-(4-amino-3-trifluoromethoxyphenyl)piperazine-1-carboxylate;

2-methoxy-4-S,S-dioxothiomorpholino-aniline; and

(S)-1-tert-butyl 2-methyl 4-(4-amino-3-methoxyphenyl)piperazine-1,2-dicarboxylate,

or a salt thereof.

15. The method of claim 14 , wherein the aniline is 2-methoxy-4-(4-acteylpiperazinyl)aniline.

16. The method of claim 1 , wherein the compound of formula I is selected from:

or a salt thereof.

17. The method of claim 16 , wherein the compound of formula I is:

Assignments (3)

Continuity (8)