Tricyclic indole Mcl-1 inhibitors and uses thereof

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 C 1-6 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 —C(O)N(R)-L 3 -R z and —C(O)O-L-R z ;

L 3 is selected from a covalent bond and 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 , and —N(R)S(O) 2 R;

R y is selected from —N(R)C(O)CF 3 , —N(R)C(O)R, and —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, and sulfur, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen and 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 and 3-8 membered saturated or partially unsaturated heterocyclylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and 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 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, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 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 —CO 2 H, —C(O)NHSO 2 CH 3 or —C(O)NHSO 2 C 6 H 5 .

7. 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-.

8. The compound of claim 7 , wherein L 2 is —CH 2 CH 2 O— or —CH 2 CH 2 CH 2 O—.

9. 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.

10. The compound of claim 9 , wherein R 3 is

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

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

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

14. The compound of claim 13 , wherein R 6 is hydrogen.

15. The compound of claim 13 , wherein R 6 is —Cl.

16. 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]indole-5-carboxamide;

6-(3-(naphthalen-1-yloxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

N-(methylsulfonyl)-6-(3-(naphthalen-1-yloxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxamide;

6-(3-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

6-(3-((4-chloronaphthalen-1-yl)oxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

6-(3-((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

6-(3-(4-chloro-3-methylphenoxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

6-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid;

1-(3-(naphthalen-1-yloxy)propyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid;

N-(methylsulfonyl)-1-(3-(naphthalen-1-yloxy)propyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxamide;

1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid;

1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(phenylsulfonyl)-5,6-dihydro-4H-pyrrolo[3,2,1-]quinoline-2-carboxamide;

7-(3-(naphthalen-1-yloxy)propyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid;

N-(methylsulfonyl)-7-(3-(naphthalen-1-yloxy)propyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxamide;

7-(3-(naphthalen-1-yloxy)propyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid 1-oxide;

7-(3-(naphthalen-1-yloxy)propyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid 1,1-dioxide;

6-(3-(naphthalen-1-yloxy)propyl)-2,3-dihydro-[1,4]thiazino[2,3,4-hi]indole-5-carboxylic acid 1,1-dioxide;

7-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxylic acid;

7-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-N-(phenylsulfonyl)-3,4-dihydro-2H-[1,4]thiazepino[2,3,4-hi]indole-6-carboxamide;

6-(3-(naphthalen-1-yloxy)propyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5-carboxylic acid;

6-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5-carboxylic acid;

9-chloro-6-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-5-carboxylic acid; and

7-chloro-1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein the compound has a Ki value less than about 1 μM for inhibition of Mcl-1.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable carrier.

19. The pharmaceutical composition of claim 18 , further comprising one or more other therapeutically active agents selected from the group consisting of anti-cancer agents consisting of alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, aurora kinase inhibitors, Bcl-2 family protein inhibitors, Bcr-Abl kinase inhibitors, biologic response modifies, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, inhibitors of apoptosis protein (IAPs), immunologicals, intercalating antibiotics, kinase inhibitors, mammalian target of rapamycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors, microRNA's, small inhibitory ribonucleic acids (siRNAs), non-steroidal anti-inflammatory drugs (NSAID's), poly ADP (adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinum chemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids, deltoids, plant alkaloids, and topoisomerase inhibitors.