Patent Application

App. No. 15/481,908

Abstract

Claims (70)

1 . A compound having Structural Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X is N;

Y is —N(R 5 )— or —CH(R 5 )—;

Z is —O—, —S—, —C(R) 2 — or N(R 7 );

W is C(R 1 )(R 1 ) or N(R 7 ); provided that Z and W are not both N(R 7 ) at the same time;

V is N or C(R);

each R is independently selected from hydrogen, methyl or CF 3 ;

each R 1 is independently selected from hydrogen, alkoxy, or alkyl optionally substituted with OH or SH;

or two R 1 are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkyl, or a 4-7 membered saturated heterocyclyl ring wherein said cycloalkyl or heterocyclyl is optionally substituted with methyl, halo or CF 3 ;

R 2 is selected from phenyl, a 3-7 membered cycloalkyl, C 2 -C 4 alkyl, or CF 3 , wherein the phenyl or cycloalkyl is optionally substituted with a single substituent selected from methyl, CF 3 or fluoro;

each R 3 is independently selected from —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C 1 -C 4 fluoroalkyl, —C(O)—O—(C 1 -C 4 alkyl), -phenyl, -heteroaryl, C 3 -C 7 cycloalkyl, —CH 2 —N(C 1 -C 4 alkyl) 2 , C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), —C 1 -C 4 alkyl optionally substituted with halo or —OH, or two R 3 s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl;

R 5 is selected from: C 1 -C 4 alkyl, —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 0 -C 2 alkylene)-Q, —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 0 -C 2 alkylene)-Q, —C(O)—O—(C 0 -C 2 alkylene)-Q, —C(O)—(C 1 -C 2 alkylene)-O—(C 0 -C 2 alkylene)-Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—N(R 6 )—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—N(R 6 )—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)-C(O)N(R 6 )—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)-C(O)—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )C(O)O—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)N(R 6 )—(C 2 -C 6 alkynyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 2 -C 6 alkenyl), C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 0 -C 2 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-C(O)C(O)N(R)(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-S(O) 0-2 —(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)C(O)N(R 6 ) (C 1 -C 6 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6 alkyl), or —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 Q, wherein:

any alkylene moiety present in R 5 is optionally substituted with OH or F;

any terminal methyl moiety present in R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, —OH or CO 2 H;

each R 6 is independently selected from hydrogen and methyl;

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl optionally substituted by —OH, C 1 -C 4 alkoxy, —(C 1 -C 4 alkylene)-OC(O)O—(C 1 -C 4 alkyl), —C(O)O—(C 1 -C 4 alkyl), —CN, fluoro, chloro, and bromo;

each R 7 is independently -G-L-M;

G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;

L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR 8 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;

M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

D is a covalent bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;

E is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN;

each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

m is 0, 1, 2 or 3.

2 . The compound of claim 1 , wherein:

X is N;

Y is —N(R 5 )— or —CH(R 5 )—;

Z is —O—, —S—, —C(R) 2 — or N(R 7 );

W is C(R 1 )(R 1 ) or N(R 7 ); provided that (1) when Z is —C(R) 2 —, then W is not C(R 1 )(R 1 ); and (2) Z and W are not both N(R 7 ) at the same time;

V is N or C(R);

each R is independently selected from hydrogen, methyl or CF 3 ;

each R 1 is independently selected from hydrogen, alkoxy, or alkyl optionally substituted with OH or SH;

or two R 1 are taken together with the carbon atom to which they are bound to form a 3-7 membered cycloalkyl, or a 4-7 membered saturated heterocyclyl ring wherein said cycloalkyl or heterocyclyl is optionally substituted with methyl, halo or CF 3 ;

R 2 is selected from phenyl, a 3-7 membered cycloalkyl, or C 2 -C 4 alkyl, wherein the phenyl or cycloalkyl is optionally substituted with a single substituent selected from methyl, CF 3 or fluoro;

each R 3 is independently selected from —C 1 -C 4 alkyl optionally substituted with halo, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), —C 1 -C 4 fluoroalkyl, —C(O)—O—(C 1 -C 4 alkyl), -phenyl, -heteroaryl, C 3 -C 7 cycloalkyl, —CH 2 —N(C 1 -C 4 alkyl) 2 , C(O)—N—(C 1 -C 4 alkyl) 2 , —C(O)—NH—(C 1 -C 4 alkyl), or two R 3 s are taken together to form a 3-8 saturated ring or a fused phenyl wherein said saturated ring or fused phenyl is optionally substituted with 1 to 2 methyl;

R 5 is selected from: —C(O)—(C 1 -C 4 alkyl), —C(O)—(C 0 -C 2 alkylene)-Q, —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 0 -C 2 alkylene)-Q, —C(O)—O—(C 1 -C 2 alkylene)-Q, —C(O)—(C 1 -C 2 alkylene)-O—(C 0 -C 2 alkylene)-Q, —C(O)—C(O)-Q, —S(O) 2 -Q, —C(O)—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—N(R 6 )—(C 1 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —C(O)—N(R 6 )—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)N(R 6 )—(C 2 -C 6 alkynyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 2 -C 6 alkenyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )—(C 0 -C 2 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-C(O)C(O)N(R)(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—C(O)—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —(C 0 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —C(O)—(C 1 -C 2 alkylene)-S(O) 0-2 —(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), —C(O)—(C 1 -C 4 alkylene)-C(O)C(O)N(R 6 )(C 1 -C 6 alkyl), —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 —(C 1 -C 6 alkyl), or —C(O)—(C 1 -C 4 alkylene)-N(R 6 )S(O) 2 Q, wherein:

any alkylene moiety present in R 5 is optionally substituted with OH or F;

any terminal methyl moiety present in R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , or C(O)CF 3 ;

each R 6 is independently selected from hydrogen and methyl;

Q is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl; and Q is optionally substituted with up to 3 substituents independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, —CN, fluoro, chloro, and bromo;

each R 7 is independently -G-L-M;

G is a bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched hydrocarbon chain wherein optionally one, two or three methylene units of the hydrocarbon chain are independently replaced by —NR 8 —, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;

L is a covalent bond or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by cyclopropylene, —NR 8 —, —N(R 8 )C(O)—, —C(O)N(R 8 )—, —N(R 8 )SO 2 —, SO 2 N(R 8 )—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, —C(═S)—, —C(═NR 8 )—, —N═N—, or —C(═N 2 )—;

M is E, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -D-E, oxo, NO 2 , halogen, CN, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;

D is a covalent bond or a bivalent C 1 -C 6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of D are optionally and independently replaced by —NR 8 —, —S—, —O—, —C(O)—, —SO—, or —SO 2 —;

E is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with oxo, halogen, or CN;

each R 8 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or an optionally substituted group selected from phenyl, a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

m is 0, 1, 2 or 3.

3 . The compound of claim 1 , wherein each R 1 is the same and is selected from methyl and hydrogen.

4 . The compound of claim 1 , wherein Z is —O—.

5 . The compound of claim 1 , wherein Z is —C(CH 3 ) 2 — and each R 1 is hydrogen.

6 . The compound of claim 1 , wherein Z is —CH 2 —.

7 . The compound of claim 1 , wherein Z is —N(R 7 )—.

8 . The compound of claim 1 , wherein Y is —N(R 5 )—.

9 . The compound of claim 1 , wherein R 2 is selected from phenyl optionally substituted with a single fluoro or a single methyl, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl optionally substituted with a single methyl, isopropyl, ethyl and methyl.

10 . The compound of claim 9 , wherein R 2 is selected from cyclohexyl, cyclobutyl, cyclopropyl, ethyl and isopropyl.

11 . The compound of claim 10 , wherein R 2 is cyclohexyl; Z is —O—; and each R 1 is hydrogen.

12 . The compound of claim 10 , wherein R 2 is selected from cyclobutyl, cyclopropyl, ethyl and isopropyl; Z is —O—; and each R 1 is methyl.

13 . The compound of claim 1 , wherein R 5 is selected from —C(O)—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 0-2 -Q, —C(O)—(CH 2 ) 1-2 —O—(CH 2 ) 0-2 -Q, —C(O)—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—N(R 6 )—(C 1 -C 4 alkylene)-C(O)—O—(C 1 -C 4 alkyl), —C(O)—(CH 2 ) 0-2 —N(R 6 )—(C 2 -C 6 alkenyl), —C(O)—(CH 2 ) 1-2 —O—(C 1 -C 4 alkyl), —C(O)—O—(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(CH 2 ) 0-4 —C(O)—O—(C 1 -C 4 alkyl), and —C(O)—(CH 2 ) 1-2 —S—(C 1 -C 4 alkyl).

14 . The compound of claim 1 , wherein R 5 is —C(O)—(C 0 -C 2 alkylene)-C(O)N(R 6 )—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)-C(O)—(C 1 -C 6 alkyl), —C(O)—(C 0 -C 2 alkylene)-N(R 6 )C(O)O—(C 1 -C 6 alkyl).

15 . The compound of claim 1 , wherein each R 7 is independently selected from:

16 . The compound of claim 1 , wherein R 7 is independently selected from

—C(O)—CH 3 , —SO 2 CH 3 and —CH 2 CH 2 OH.

17 . A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

18 . The composition of claim 17 , further comprising a second therapeutic agent.

19 . A method of treating a cancer characterized by the presence of an IDH1 mutation, wherein the IDH1 mutation result in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α-ketoglutarate to R(−)-2-hydroxyglutarate in a patient, comprising the step of administering to the patient in need thereof a composition of claim 30 .

20 . The method of claim 19 , wherein the IDH1 mutation is an IDH1 R132H mutation.

21 . The method of claim 20 , wherein the cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes (MDS), myeloproliferative neoplasm (MPN), or colon cancer.

22 . The method of claim 19 , further comprising administering to the patient in need thereof a second therapeutic agent.

Assignments (8)