Inhibitors of indoleamine 2,3-dioxygenase and methods of their use

Patent metadata

Field	Value
Publication number	US-11447449-B2
Application number	US-201916959487-A
Country	US
Kind code	B2
Filing date	Jan 3, 2019
Priority date	Jan 5, 2018
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

The present invention provides a compound of formula (II): an inhibitor of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases. Its prodrugs are disclosed.

First claim

What is claimed:

1. A compound of formula (I):

wherein:
R 1 is a straight or branched C 1 -C 8 alkyl substituted with

R 2 ,
Y is CH or N;
L 1 is independently a bond or a straight or branched C 1 -C 8 alkylene;
L 2 is independently a bond, a straight or branched C 1 -C 8 alkylene,
—OC(O)N(R c )CH(R b )—, —C(O)N(R c )L 3 -, C 3 -C 6 cycloalkyl,

R 2 is independently NH 2 ,

L 3 is independently a straight or branched C 1 -C 6 alkylene;
L 4 is independently a bond, a straight or branched C 1 -C 6 alkylene wherein two carbon atoms of said alkylene are optionally replaced by —C(O)N(R c )— or —N(R c )C(O)—;
R 3 , R 4 , R 5 and R 6 are independently H or C 1 -C 4 alkyl;
R 7 and R 8 are independently H or C 1 -C 6 alkyl;
R 9 is aryl optionally substituted with one to three substituents selected from: halo, OH, CN, C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, C 1 -C 6 haloalkyl, benzyl, and phenoxy;
R a is independently halo, OH, CN, C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R b and R c are independently H, or C 1 -C 6 alkyl;
R d is independently H, C 1 -C 6 alkyl, —CH 2 OC(O)(C 1 -C 6 alkyl), —CH 2 OC(O)O(C 1 -C 6 alkyl), or Bn; and
R e is independently C 1 -C 6 alkyl optionally substituted with a substituent selected from halo, OH, CN, C 1 -C 4 alkyl, —OC 1 -C 6 alkyl, and C 1 -C 4 haloalkyl;
or a salt, a stereoisomer, a tautomer, or a solvate thereof.

2. The compound according to claim 1 , wherein:
R 1 is a straight or branched C 1 -C 6 alkyls substituted with R 2 ,

L 1 is independently a bond or a straight or branched C 1 -C 6 alkylene;
L 2 is independently a bond, a straight or branched C 1 -C 6 alkylene,
—OC(O)N(R c )CH(R b )—, —C(O)N(R c )L 3 -, C 3 -C 6 cycloalkyl,

and
R 9 is phenyl optionally substituted with one to three substituents selected from: halo, OH, CN, C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.

3. The compound according to claim 1 , wherein:
R 2 is independently NH 2 ,

R a is independently C 1 -C 4 alkyl or —OC 1 -C 4 alkyl
R b is independently H or C 1 -C 4 alkyl; and
R c is independently H or C 1 -C 2 alkyl.

4. The compound according to claim 1 , wherein:
R 1 is

R 3 , R 4 and R 5 are H;
R 6 is CH 2 CH 3 ,
R 7 and R 8 are i-Bu; and
R 9 is 4-methoxy-phenyl.

5. The compound according to claim 1 , wherein:
R 1 is

6. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition of claim 1 , further comprising ipilimumab, nivolumab, or pembrolizumab or a combination thereof.

8. A method of treating cancer in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 ; wherein the cancer is skin cancer, bladder cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, colon cancer, blood cancer or lung cancer.

9. The compound according to claim 1 , wherein the compound is selected from
3S)-1-(((Benzyloxy)(hydroxy)phosphoryl)oxy)ethyl-3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-((3-(4-(Diisobutylamino)-3-(3 (p-tolyl)ureido)phenyl)pentanoyl)oxy)methyl 3-methoxy-4-(phosphonooxy) benzoate;
(S)-((3-(2,4-Dimethyl-6-(phosphonooxy)phenyl)-3-methylbutanoyl)oxy)methyl-3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-((4-(Phosphonooxy)butanoyl)oxy)methyl3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido) phenyl)pentanoate;
(3S)-2-Methyl-1-(2-(4-(phosphonooxy)phenyl)acetoxy)propyl3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-1-(2-(4-(Phosphonooxy)phenyl)acetoxy)ethyl-3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-(Hydroxy((pivaloyloxy)methoxy)phosphoryl)oxy)methyl-3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-(((Benzyloxy(hydroxy)phosphoryl)oxy)methyl-3-(4-diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-((Ethoxy(hydroxy)phosphoryl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-((Hydroxy(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-(2-(Methyl(((phosphonooxy)methoxy)carbonyl)amino)acetoxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-2-Methyl-1-(S)-3-methyl-2-((((phosphonooxy)methoxy)carbonyl)amino) butanoyl)oxy)propyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl(ureido)phenyl)pentanoate;
(3S,4S,5S)—(((S)-3-(4-(Diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoyl)oxy) methyl 3,4,5-trihydroxycyclohex-1-enecarboxylate;
(S)-(((4-(Phosphonooxy)butoxy)carbonyl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-((((5-(Phosphonooxy)butoxy)carbonyl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-((Hydroxy((isobutyryloxy)methoxy)phosphoryl)oxy)methyl 3-(4-diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-(Hydroxy((propionyloxy)methoxy)phosphoryl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-((Methyl(3-(phosphonooxy)propyl)carbamoyl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-(((S)-3-(4-(Diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoyl)oxy)methyl 2-((phosphonooxy)methyl)pyrrolidine-1-carboxylate;
(3S)-1-(Methyl(3-((phosphonooxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-(((S)-3-Methyl-2-(phosphonooxy)butanoyl)oxy)methyl 3(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-(((2-(Phosphonooxy)propoxy)carbonyl)oxy)methyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(S)-((Methyl(3-((phosphonooxy)methyl)pyridin-2-yl)carbamoyl)oxy)methyl 3-4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate;
(3S)-1-((Methyl(3-((2-(methylamino)acetoxy)methyl)pyridin-2-yl)carbamoyl)oxy)ethyl 3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)pentanoate dihydrochloride;
(S)-((Methyl(3-((2-(methylamino)acetoxy)methyl)pyridin-2-yl)

Assignees

• Bristol Myers Squibb Co

Inventors

• Balog James Aaron
• Seitz Steven P
• Williams David K
• Andappan Murugaiah Subbaiah Murugaiah

Classifications

• C07D295/155

  with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07F9/572

  Five-membered rings · CPC title

• C07F9/65515

  the oxygen atom being part of a five-membered ring · CPC title

• C07C275/42 Primary

  being further substituted by carboxyl groups · CPC title