Tricyclic indole mcl-1 inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-2016106731-A1
Application number	US-201514885181-A
Country	US
Kind code	A1
Filing date	Oct 16, 2015
Priority date	Oct 17, 2014
Publication date	Apr 21, 2016
Grant date	—

Abstract

The present invention provides for compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein. The present invention also provides for pharmaceutical compositions as well as methods for using compounds for treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 protein.

First claim

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
L 1 is selected from a covalent bond or an optionally substituted bivalent straight or branched C1-6 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O) 2 —, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, or —S(O) 2 N(R)—;
A is —O—, —S—, —S(O)—, —S(O) 2 —, —N(R′)—, or optionally substituted —CH 2 —;
R 1 is hydrogen, —R, —OR, —SR, —S(O)R, —S(O) 2 R, —S(O) 2 N(R) 2 , —N(R) 2 , —C(O)N(R) 2 , —C(O)R, —C(O)OR, —NRC(O)R, —NRC(O)OR, —NRC(O)N(R) 2 , —NRS(O) 2 R, —NRS(O) 2 N(R) 2 , —C(O)OH, —C(O)R x , —S(O) 2 OH, or —S(O) 2 R y , or is selected from

R 2 is selected from R, halo, —NH 2 , —CN, —NO 2 , —CF 3 —C(O)-L 3 -R z , —C(O)N(R)-L 3 -R z , —C(O)N(R)—C(R) 2 -L 3 -R z , —C(O)O-L 3 -R z or —C(O)S-L 3 -R z ;
L 3 is selected from a covalent bond or an optionally substituted bivalent straight or branched C 1-8 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced with -Cy-, —O—, —S—, —N(R)—, —N(R)C(O)—, —N(R)S(O) 2 —, —C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, or —S(O) 2 N(R)—;
-Cy- is an optionally substituted bivalent ring independently selected from phenylene, 3-8 membered saturated or partially unsaturated carbocyclylene, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R z is hydrogen, R, —OR, —SR, —S(O)R, —S(O) 2 R, —S(O) 2 N(R) 2 , —N(R) 2 , —C(O)N(R) 2 , —C(O)R, —C(O)OR, —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , —N(R)S(O) 2 R, —N(R)S(O) 2 N(R) 2 , —C(O)OH, —C(O)R x , —S(O) 2 OH, or —S(O) 2 R 3 , or is selected from:

R x is selected from —C(O)OR, —N(R)S(O) 2 CF 3 , —N(R)C(O)R, —N(R)C(O)OR, —N(R)C(O)N(R) 2 , or —N(R)S(O) 2 R;
R y is selected from —N(R)C(O)CF 3 , —N(R)C(O)R, or —N(R)C(O)N(R) 2 ;
each R is independently selected from hydrogen or an optionally substituted group selected from C 1-12 aliphatic or a ring selected from a 3-10 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 6-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;
L 2 is an optionally substituted bivalent straight or branched C 3-6 hydrocarbon chain wherein one or two methylene units of L 2 are optionally and independently replaced with —O—, —S—, or —N(R′)—, and wherein two substituents of L 2 are optionally taken together to form an optionally substituted bivalent ring selected from 3-8 membered saturated or partially unsaturated carbocyclylene or 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R′ is independently hydrogen or optionally substituted C 1-4 alkyl;
R 3 is an optionally substituted ring selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R 4 , R 5 , and R 6 is independently selected from R, halogen, —CN, —NO 2 , —CF 3 , —C(O)OR′, —OR′, —SR′, —C(O)N(R′) 2 —N(R′) 2 , —S(O) 2 N(R) 2 , —N(R′)S(O) 2 CF 3 , —C(O)R′, —N(R′)C(O)R′, —S(O)R′, —S(O) 2 R′, —N(R′)C(O)OR′, and —N(R′)S(O) 2 R′; and
optionally R 2 and -A-L 1 -, R 2 and -L 2 -R 3 , R 4 and R 5 , R 5 and R 6 and/or R 6 and -A-L 1 - are independently taken together with their intervening atoms to form an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated carbocyclic ring, phenyl, a 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2 . The compound of claim 1 , wherein A is —S—, —S(O)— or —S(O) 2 —.

3 . The compound of claim 1 , wherein L 1 is an optionally substituted bivalent straight or branched C 2-3 hydrocarbon chain.

4 . The compound of claim 1 of the formula Ia, Ib, Ic or Id:

or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2.

5 . The compound of claim 1 , wherein R 1 is hydrogen.

6 . The compound of claim 1 , wherein R 2 is selected from —C(O)O-L 3 -R z or —C(O)N(R)-L 3 -R z .

7 . The compound of claim 6 , wherein R 2 is —CO 2 H, —C(O)NHSO 2 CH 3 or —C(O)NHSO 2 C 6 H 5 .

8 . The compound of claim 1 , wherein L 2 is an optionally substituted bivalent straight or branched C 3-4 hydrocarbon chain wherein one methylene unit of L 2 is optionally replaced with —O—.

9 . The compound of claim 8 , wherein L 2 is —CH 2 CH 2 O— or —CH 2 CH 2 CH 2 O—.

10 . The compound of claim 1 , wherein R 3 is optionally substituted phenyl or an optionally substituted 6-10 membered bicyclic saturated, partially unsaturated or aryl ring.

11 . The compound of claim 10 , wherein R 3 is

12 . The compound of claim 1 , wherein R 4 is hydrogen.

13 . The compound of claim 1 , wherein R 5 is hydrogen.

14 . The compound of claim 1 , wherein R 6 is hydrogen or halogen.

15 . The compound of claim 14 , wherein R 6 is hydrogen.

16 . The compound of claim 14 , wherein R 6 is —Cl.

17 . The compound of claim 1 , selected from the group consisting of:
6-(2-(naphthalen-1-yloxy)ethyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid; N-(methylsulfonyl)-6-(2-(naphthalen-1-yloxy)ethyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxamide; 6-(2-(4-chloro-3,5-dimethylphenoxy)ethyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid; 1-(2-(naphthalen-1-yloxy)ethyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid; 6-(2-(naphthalen-1-yloxy)ethyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5-carboxylic acid; 6-(2-(naphthalen-1-yloxy)ethyl)-N-(phenylsulfonyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]

Assignees

• Univ Vanderbilt

Inventors

• Lee Taekyu
• Burke Jason P
• Olejniczak Edward T
• Belmar Johannes
• Bian Zhiguo
• Fesik Stephen W

Classifications

• A61K31/542

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D513/06

  Peri-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4745 Primary

  condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48) · CPC title

• C07D498/06

  Peri-condensed systems · CPC title