Phenyl and pyridinyl substituted piperidines and piperazines as inhibitors of IDH1 mutants and their use in treating cancer

1. A compound having Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein:

X is CR 4 ;

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 4 is selected from hydrogen, —CN, halo, C 1 -C 4 alkoxy, —CH 2 NH(C 1 -C 4 alkyl), C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl), C 1 -C 4 fluoroalkyl, C(O)—N—(C 1 -C 4 alkyl) 2 , C(O)—NH—(C 2 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), or a 5-membered heteroaryl;

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;

provided that:

when X is —C(CN)—, Y is —N(R 5 )—, m is 0, R 2 is phenyl or C 2 -C 4 alkyl, and Z is —O— or —S—, then each R 1 is not simultaneously methyl; and

when X is —C(CN)—, Y is —N(R 5 )—, m is 0, R 2 is phenyl or C 2 -C 4 alkyl, and Z is —CH 2 —, then each R 1 is not simultaneously hydrogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is —C(CN)—.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Z is —O—.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same and is selected from methyl and hydrogen.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is —N(R 5 )—.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclohexyl, cyclobutyl, cyclopropyl, ethyl and isopropyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclohexyl; Z is —O—; and each R 1 is hydrogen.

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclobutyl, cyclopropyl, ethyl and isopropyl; Z is —O—; and each R 1 is methyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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—(C1-C4 alkyl), and —C(O)—(CH 2 ) 1-2 —S—(C 1 -C 4 alkyl).

11. The compound of claim 1 , having Structural Formula II or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is the same and is selected from hydrogen and methyl;

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, and isopropyl;

R 3a is selected from hydrogen and methyl;

R 3b is selected from hydrogen, methyl, ethyl, isobutyl, isopropyl, phenyl, —C(O)—O—CH 2 CH 3 , —C(O)—O—CH 3 , and —CH 2 —O—CH 3 ;

R 3c is selected from hydrogen and methyl; and

R 3d is selected from hydrogen, phenyl and methyl, wherein one of R 3a , R 3b , R 3c , and R 3d is not hydrogen.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is methyl; and

R 2 is selected from ethyl, isopropyl, cyclopropyl and cyclobutyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein:

R 3a , R 3c and R 3d are simultaneously hydrogen; and

R 3b is selected from (R)-methyl, (R)-ethyl, (R)-isopropyl, and C(O)—O—CH 2 CH 3 .

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein

R 3a , R 3c and R 3d are simultaneously hydrogen; and

R 3b is (R)-methyl.

15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is hydrogen; and

R 2 is cyclohexyl.

16. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from —C(O)—(CH2) 0-2 —OCH 3 , —C(O)—CH 2 —OCH 2 CH 3 , —C(O)-furanyl, —C(O)—NH—CH 2 —CH═CH 2 , —C(O)—(CH 2 ) 1-2 —C(O)—OCH 3 , —C(O)—(CH 2 ) 2 —SCH 3 , —C(O)-cyclopropyl, —C(O)—CH 2 -cyclopropyl, —C(O)—CH 2 CH 3 , —C(O)—(CH 2 ) 2 CH 3 , —C(O)—CH 2 Cl, —C(O)—NH—CH 3 , —C(O)—CH 2 -thienyl, —C(O)—NH—(CH 2 ) 2 —C(O)—OCH 3 , —C(O)—CH 2 -pyridinyl, —C(O)—(CH 2 ) 2 —O-phenyl, —C(O)—CH 2 -pyrazolyl, and —C(O)-oxazolyl.

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

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

19. A method of treating a cancer with an IDH1 R132X mutation, the method comprising the step of administering to the patient in need thereof a pharmaceutical composition of claim 17 , wherein the cancer is selected from glioma, acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), sarcoma, melanoma, lung cancer, cholangiocarcinoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), colon cancer, prostate cancer and angio-immunoblastic non-Hodgkin's lymphoma (NHL).

20. The method of claim 19 , wherein the IDH1 R132X mutation is an IDH1 R132H mutation.

21. The method of claim 20 , wherein the cancer is selected from glioblastoma, paraganglioma, non-small cell lung cancer, and chondrosarcoma.

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