Inhibitors of C-MET and uses thereof

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

Y is —C(O)— or a bond;

R 1 is a C 1-6 aliphatic, wherein up to three methylene units are replaced by —NH—, —NR 11 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)O—, —C(O)NH—, —C(O)NR 11 —, —NC(═N—CN)N, —NHCO—, —NR 11 CO—, —NHC(O)O—, —NR 11 C(O)O—, —SO 2 NH—, —SO 2 NR 11 —, —NHSO 2 —, —NR 11 SO 2 —, SO 2 —, —NHC(O)NH—, —NR 11 C(O)NH—, —NHC(O)NR 11 —, —NR 11 C(O)NR 11 , —OC(O)NH—, —OC(O)NR 11 —, —NHSO 2 NH—, —NR 11 SO 2 NH—, —NHSO 2 NR 11 —, —NR 11 SO 2 NR 11 —, —SO—, or —SO 2 —; a C 3-10 monocyclic or bicyclic cycloaliphatic; a C 6-10 monocyclic or bicyclic aryl; a 5-10 membered monocyclic or bicyclic heteroaryl; or a 5-10 membered monocyclic or bicyclic heterocyclyl; wherein R 1 is optionally substituted with 1-6 occurrences of J R1 ;

each R 11 is independently selected from C 1-6 aliphatic, C 3-10 monocyclic or bicyclic cycloaliphatic, C 6-10 monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl, or 5-10 membered monocyclic or bicyclic heterocyclyl; or two R 11 groups, on the same substituent or different substituents, together with the atom(s) to which each R 11 group is bound, form a 3-8 membered heterocyclyl;

each J R1 is independently selected from halogen, OH, OR, NO 2 , NH 2 , NHR, NR 2 , SH, SR, CN, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; or two J R1 , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O;

each R is independently selected from a C 1-4 aliphatic or C 3-4 cycloaliphatic optionally substituted with 1-4 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN;

R 2 is H, a C 1-6 aliphatic, C 3-6 cycloaliphatic, halogen, OH, OR, NO 2 , NH 2 , NHR, NR 2 , SH, SR, CN, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; wherein said C 1-6 aliphatic or C 3-6 cycloaliphatic is optionally substituted with 1-4 occurrences of J R2 ;

each J R2 is independently selected from halogen, OH, OR, NO 2 , NH 2 , NHR, NR 2 , SH, SR, CN, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or R; or two J R2 , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O;

T is —SO 2 NR 4 —, —CONR 4 — or —C(O)O—;

R 4 is H or a C 1-6 aliphatic or C 3-7 cycloaliphatic optionally substituted with 1-6 occurrences of J R4 ;

each J R4 is independently selected from halogen, OH, OR′, NO 2 , NH 2 , NHR′, NR′ 2 , SH, SR′, CN, 5-6 membered aryl or heteroaryl, or R′; or two J R4 , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O;

each R′ is independently selected from a C 1-6 aliphatic or C 3-7 cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN;

b is 0 or 1;

L is a C 1-6 aliphatic wherein up to three methylene units are replaced by —NH—, —NR 5 —, —O—, —S—, —CO 2 —, —OC(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 5 —, —NC(═N—CN)N, —NHCO—, —NR 5 CO—, —NHC(O)O—, —NR 5 C(O)O—, —SO 2 NH—, —SO 2 NR 5 —, —NHSO 2 —, —NR 5 SO 2 —, —NHC(O)NH—, —NR 5 C(O)NH—, —NHC(O)NR 5 —, —NR 5 C(O)NR 5 , —OC(O)NH—, —OC(O)NR 5 —, —NHSO 2 NH—, —NR 5 SO 2 NH—, —NHSO 2 NR 5 —, —NR 5 SO 2 NR 5 —, —SO—, or —SO 2 —, wherein L is optionally substituted with 1-4 occurrences of R 6 ;

each R 5 is independently selected from C 1-6 aliphatic, C 3-10 monocyclic or bicyclic cycloaliphatic, C 6-10 monocyclic or bicyclic aryl, 5-10 membered monocyclic or bicyclic heteroaryl, or 5-10 membered monocyclic or bicyclic heterocyclyl; or two R 5 groups, on the same substituent or different substituents, together with the atom(s) to which each R 5 group is bound, form a 3-8 membered heterocyclyl;

each R 6 is independently selected from halogen, OH, OR′, NO 2 , NH 2 , NHR′, NR′ 2 , SH, SR′, CN, or R′; or two R 6 , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O;

n is 0 or 1;

R 3 is H or an optionally substituted group selected from a C 1-6 aliphatic, a C 3-10 monocyclic or bicyclic cycloaliphatic, a C 6-10 monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein R 3 is optionally substituted with 1-6 occurrences of J R3 ; or R 3 and R 4 , together with the nitrogen to which R 4 is attached, form a 5-10 membered monocyclic or bicyclic heterocyclyl or heteroaryl, wherein n is 0 and said heterocyclyl or heteroaryl is optionally substituted with 1-6 occurrences of J R3 ;

each J R3 is independently selected from —(U) m —X;

U is a C 1 aliphatic, wherein up to two methylene units are optionally and independently replaced by G U and wherein U is optionally substituted with 1-4 J u ;

G U is —NH—, —NR 7 —, —O—, —S—, —CO 2 —, —O C(O)—, —C(O)CO—, —C(O)—, —C(O)NH—, —C(O)NR 7 —, —NC(═N—CN)N—, —NHCO—, —NR 7 CO—, —NHC(O)O—, —NR 7 C(O )O—, —SO 2 NH—, —SO 2 NR 7 —, —NHSO 2 —, —NR 7 SO 2 —, —NHC(O)NH—, —NR 7 C(O)NH—, —NHC(O)NR 7 —, —NR 7 C(O)NR 7 , —OC(O)NH—, —OC(O)NR 7 —, —NHSO 2 NH—, —NR 7 SO 2 NH—, —NHSO 2 NR 7 —, —NR 7 SO 2 NR 7 —, —SO—, or —SO 2 —;

R 7 is C 1-6 aliphatic or C 3-7 cycloaliphatic optionally substituted with 1-6 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN;

m is 0 or 1;

each J U is independently selected from halogen, OH, OR′, NO 2 , NH 2 , NHR′, NR′ 2 , SH, SR′, CN, or R′; or two J U , together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O;

X is H, halogen, OH, OR, NO 2 , NH 2 , NHR, NR 2 , SH, SR, CN, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR, or a group selected from a C 1-6 aliphatic, a C 3-10 monocyclic or bicyclic cycloaliphatic, a C 6-10 monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein said group is optionally substituted with 1-4 J X , or two X, together with the carbon(s) to which they are attached, form a cyclopropyl ring or C═O; wherein X is not H when m is 0;

each J X is independently selected from halogen, OH, OR, NO 2 , NH 2 , NHR, NR 2 , SH, SR, CN, C(O)NH 2 , C(O)NHR, C(O)NR 2 , C(O)OH, C(O)OR, NHC(O)H, NHC(O)R, NRC(O)H, NRC(O)R, NHC(O)OH, NHC(O)OR, NRC(O)OH, NRC(O)OR; and

R 9 is selected from H; halogen; OH; NO 2 ; NH 2 ; SH; CN; or a group selected from a C 1-6 aliphatic or a C 3-7 cycloaliphatic, wherein said group is optionally substituted with 1-6 occurrences of halogen, OH, NO 2 , NH 2 , SH or CN.

2. The compound or salt thereof according to claim 1 , wherein Y is C(O) and the compound is of formula II:

3. The compound or salt thereof according to claim 2 , wherein R′ is a C 1-3 aliphatic.

4. The compound or salt thereof according to claim 1 , wherein R 2 is CH 3 .

5. The compound or salt thereof according to claim 1 , wherein said compound is of formula IIIa, IIIb or IIIc:

6. The compound or salt thereof according to claim 1 , wherein R 3 and R 4 , together with the nitrogen to which R 4 is attached, form a monocyclic or bicyclic heterocyclyl or bicyclic heteroaryl selected from the following:

wherein Z is CH 2 , NH, O or S, and wherein the hydrogens of said CH 2 of Z is optionally substituted by 1-2 occurrences of J R3 and the hydrogen of said NH of Z is optionally substituted by JR 3 .

7. The compound or salt thereof according to claim 1 , wherein L is —CH 2 —.

8. The compound or salt thereof according to claim 1 , wherein n is 0.

9. The compound or salt thereof according to claim 1 , wherein R 3 is a C 1-4 aliphatic, a C 3-6 monocyclic cycloaliphatic, phenyl, a 5-6 membered monocyclic heteroaryl, or a 5-10 membered monocyclic or bicyclic heterocyclyl, wherein R 3 is optionally substituted with 1-4 occurrences of J R3 .

10. The compound or salt thereof according to claim 9 , wherein R 3 is a C 1-4 aliphatic, a C 3-6 monocyclic cycloaliphatic, phenyl, a 5-6 membered monocyclic heteroaryl, or a 5-6 membered monocyclic heterocyclyl, wherein R 3 is optionally substituted with 1-4 occurrences of J R3 .

11. The compound or salt thereof according to claim 10 , wherein each occurrence of J R3 is selected from halogen; OH; OR; CN; NH 2 ; NHR; NR 2 ; C(O)NH 2 ; C(O)NHR; C(O)NR 2 ; NHCOR; C(O)OR; C(O)OH; oxo; (CH 2 ) 0-3 phenyl optionally substituted with halogen, OH, OR, NO 2 , NH 2 , SH or CN; or C 1-4 aliphatic optionally substituted with halogen, OH, OR, NO 2 , NH 2 , SH or CN.

12. The compound or salt thereof according to claim 1 , wherein R 8 is selected from H, halogen, cyclopropyl, or a C 1-3 aliphatic optionally substituted with 1-3 occurrences of halogen or OH.

13. The compound or salt thereof according to claim 1 , wherein R 9 is selected from H, OH, halogen, cyclopropyl, or a C 1-3 aliphatic optionally substituted with 1-3 occurrences of halogen or OH.

14. A compound selected from

15. A compound selected from

16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17. A method of inhibiting phosphatidylinositol 3-kinase (PI3K) activity in a biological sample, comprising contacting said biological sample with a compound or salt thereof according to claim 1 .

18. A method of treating or lessening the severity of a disease or condition selected from rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, lacrimal parotid gland syndrome, chronic obstructive pulmonary disease, pancreatitis, myocardial infarction, diabetes, multiple sclerosis or cancer comprising administering a compound according to claim 1 or a composition comprising said compound to a patient in need thereof.