IP Library › Patent Application 13414918

Patent Application

App. No. 13/414,918

PI3 KINASE INHIBITORS AND USES THEREOF

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Patent No.: US None
App. No.: 13/414,918

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Claims (199)

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R is a warhead group;

Ring A is an optionally substituted ring selected from a 4-8 membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-15 membered saturated or partially unsaturated bridged or spiro bicyclic heterocyclic ring having at least one nitrogen, at least one oxygen, and optionally 1-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring B is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

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

Ring C is absent or an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bridged or spiro bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

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

Ring D is absent or an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bridged bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring 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, or:

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur

2 . The compound according to claim 1 , wherein the compound is of formula I-d:

or a pharmaceutically acceptable salt thereof,

wherein R 2 is cyclopropyl or phenyl.

3 . The compound according to claim 2 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-2 nitrogen atoms, optionally substituted phenyl, or an optionally substituted 5-6 membered heteroaryl ring having 1-2 nitrogen atoms;

c) T 1 is a covalent bond;

d) Ring C is a 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 nitrogen atoms;

e) T 2 is —C(O)— or —CH 2 C(O)—; and

f) Ring D is optionally substituted phenyl.

4 . The compound according to claim 2 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is indazolyl, aminopyrimidinyl, or phenol;

c) T 1 is a covalent bond;

d) Ring C is piperazinyl, piperidinyl, or tetrahydropyridyl;

e) T 2 is —CH 2 C(O)—;

f) Ring D is phenyl.

5 . The compound according to claim 2 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is aminopyrimidinyl;

c) T 1 is a covalent bond;

d) Ring C is piperazinyl;

e) T 2 is —CH 2 C(O)—;

f) Ring D is phenyl.

6 . The compound according to claim 2 , wherein the compound is of formula I-d-i:

or a pharmaceutically acceptable salt thereof.

7 . The compound according to claim 6 , wherein the compound is of formula I-d-i-a:

or a pharmaceutically acceptable salt thereof.

8 . The compound according to claim 1 , wherein the compound is of formula I-e:

or a pharmaceutically acceptable salt thereof.

9 . The compound according to claim 8 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

c) Ring D is an optionally substituted group selected from phenyl or 6-membered heteroaryl ring having 1-3 nitrogens; and

d) R 1 is -L-Y, wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted with one or more —R groups, wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

10 . The compound according to claim 8 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is indazolyl, aminopyrimidinyl, or phenol;

c) Ring D is phenyl; and

d) R 1 is -L-Y, wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

11 . The compound according to claim 8 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is aminopyrimidinyl;

c) Ring D is phenyl; and

12 . The compound according to claim 8 , wherein the compound is of formula I-e-i:

or a pharmaceutically acceptable salt thereof.

13 . The compound according to claim 12 , wherein the compound is of formula I-e-i-a or I-e-I-b:

or a pharmaceutically acceptable salt thereof.

14 . The compound according to claim 1 , wherein the compound is of formula I-f:

or a pharmaceutically acceptable salt thereof,

wherein:

Ring D is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

15 . The compound according to claim 14 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

c) Ring C is a 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 nitrogen atoms;

d) Ring D is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

e) R 1 is -L-Y, wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted by one or more —R groups, wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

16 . The compound according to claim 14 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is indazolyl, aminopyrimidinyl, or phenol;

c) Ring C is piperazinyl, piperidinyl, or tetrahydropyridyl;

d) Ring D is optionally substituted benzothiazolyl, benzoxazolyl, or benzimidazolyl; and

e) R 1 is -L-Y, wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

17 . The compound according to claim 14 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A is optionally substituted morpholinyl;

b) Ring B is aminopyrimidinyl;

c) Ring C is piperazinyl;

d) Ring D is optionally substituted benzothiazolyl, benzoxazolyl, or benzimidazolyl; and

e) R 1 is -L-Y, wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

18 . The compound according to claim 14 , wherein Ring D is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

19 . The compound according to claim 14 , wherein Ring D is an optionally substituted ring selected from benzothiazole, benzoxazole, or benzimidazole.

20 . The compound according to claim 14 , wherein the compound is of formula I-f-i, I-f-ii, or I-f-iii:

or a pharmaceutically acceptable salt thereof,

wherein R 3 is —R, —C(O)R, or —SO 2 R.

21 . The compound according to claim 14 , wherein the compound is of formula I-f-i-a, I-f-ii-a, or I-f-iii-a:

or a pharmaceutically acceptable salt thereof,

wherein R 3 is —R, —C(O)R, or —SO 2 R.

22 . The compound according to claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

23 . The compound according to claim 1 , wherein the compound is selective for PI3Kα.

24 . The compound according to claim 1 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted with one or more —R groups, wherein L has at least one double bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;

Y is hydrogen, C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 R e groups; and

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:

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

Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

25 . The compound according to claim 24 , wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—; and

Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

26 . The compound according to claim 25 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

27 . The compound according to claim 25 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —OC(O)—.

28 . The compound according to claim 24 , wherein L is —NRC(O)CH═CH—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRC(O)CH═CHCH 2 O—, —CH 2 NRC(O)CH═CH—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)(C═N 2 )—, —NRC(O)(C═N 2 )C(O)—, —NRC(O)CH═CHCH 2 N(CH 3 )—, —NRSO 2 CH═CH—, —NRSO 2 CH═CHCH 2 —, —NRC(O)CH═CHCH 2 O—, —NRC(O)C(═CH 2 )CH 2 —, —CH 2 NRC(O)—, —CH 2 NRC(O)CH═CH—, —CH 2 CH 2 NRC(O)—, or —CH 2 NRC(O)cyclopropylene-; wherein R is H or optionally substituted C 1-6 aliphatic; and Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

29 . The compound according to claim 28 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, —NHC(O)C(═CH 2 )CH 2 —, —CH 2 NHC(O)—, —CH 2 NHC(O)CH═CH—, —CH 2 CH 2 NHC(O)—, or —CH 2 NHC(O)cyclopropylene-.

30 . The compound according to claim 24 , wherein L is a bivalent C 2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—.

31 . The compound according to claim 1 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted with one or more —R groups, wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—,

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:

Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

32 . The compound according to claim 31 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

33 . The compound according to claim 32 , wherein L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C—CCH 2 CH 2 —, —CH 2 —C≡CCH 2 —, —C≡CCH 2 O—, —CH 2 C(O)C≡C—, —C(O)C≡C—, or —CH 2 C(═O)C≡C—.

34 . The compound according to claim 1 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted with one or more —R groups, wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, or —C(O)O—;

each R e is independently selected from -Q-Z, oxo, NO 2 , halogen, CN, a suitable leaving group, or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN, wherein:

Z is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

35 . The compound according to claim 34 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

36 . The compound according to claim 1 , wherein R 1 is -L-Y, wherein:

L is a covalent bond, —C(O)—, —N(R)C(O)—, or a bivalent C 1-8 saturated or unsaturated, straight or branched, hydrocarbon chain; and

Y is selected from the following (i) through (xvii):

(i) C 1-6 alkyl substituted with oxo, halogen, NO 2 , or CN;

(ii) C 2-6 alkenyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iii) C 2-6 alkynyl optionally substituted with oxo, halogen, NO 2 , or CN; or

(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 R e groups; or

(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-4 R e groups; or

wherein each R, Q, Z; or

(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups; or

(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 R e groups;

(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups; or

(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 R e groups; or

wherein each R e is as defined above and described herein; or

(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 R e groups; or

(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 R e groups.

37 . The compound according to claim 36 , wherein L is a covalent bond, —CH 2 —, —NH—, —C(O)—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—.

38 . The compound according to claim 37 , wherein L is a covalent bond.

39 . The compound according claim 36 , wherein Y is selected from:

wherein each R e is independently selected from a suitable leaving group, CN, NO 2 or oxo.

40 . The compound of claim 1 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain optionally substituted with one or more —R groups, wherein two or three methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, —SO 2 N(R)—, —S—, —S(O)—, —SO 2 —, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—; and

Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

41 . The compound of claim 40 , wherein R 1 is —C(O)CH 2 CH 2 C(O)CH═C(CH 3 ) 2 , —C(O)CH 2 CH 2 C(O)CH═CH(cyclopropyl), —C(O)CH 2 CH 2 C(O)CH═CHCH 3 , —C(O)CH 2 CH 2 C(O)CH═CHCH 2 CH 3 , —C(O)CH 2 CH 2 C(O)C(═CH 2 )CH 3 , —C(O)CH 2 NHC(O)CH═CH 2 , —C(O)CH 2 NHC(O)CH 2 CH 2 C(O)CH═CHCH 3 , —C(O)CH 2 NHC(O)CH 2 CH 2 C(O)C(═CH 2 )CH 3 , —S(O) 2 CH 2 CH 2 NHC(O)CH 2 CH 2 C(O)CH═C(CH 3 ) 2 , —S(O) 2 CH 2 CH 2 NHC(O)CH 2 CH 2 C(O)CH═CHCH 3 , —S(O) 2 CH 2 CH 2 NHC(O)CH 2 CH 2 C(O)CH═CH 2 , —C(O)(CH 2 ) 3 NHC(O)CH 2 CH 2 C(O)CH═CHCH 3 , or —C(O)(CH 2 ) 3 NHC(O)CH 2 CH 2 C(O)CH═CH 2 .

42 . The compound of claim 1 , wherein R 1 is 6-12 atoms long.

43 . The compound of claim 42 , wherein R 1 is at least 8 atoms long.

44 . The compound according to claim 1 , wherein R 1 is selected from:

wherein each R is independently a suitable leaving group, NO 2 , CN, or oxo.

45 . The compound according to claim 1 , wherein R 1 is selected from:

46 . The compound according to claim 1 , wherein R 1 is selected from:

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

48 . The composition according to claim 47 , in combination with an additional therapeutic agent.

49 . The composition according to claim 48 , wherein the additional therapeutic agent is a chemotherapeutic agent.

50 . A method for inhibiting PI3K-alpha, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound according to claim 1 .

51 . A method for inhibiting PI3K-alpha, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound according to claim 1 .

52 . The method according to claim 51 , wherein the PI3K-alpha, or a mutant thereof, activity is inhibited irreversibly.

53 . The method according to claim 52 , wherein the PI3K-alpha, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys862 of PI3K-alpha.

54 . A method for treating a PI3Kα-mediated disorder, disease, or condition in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1 .

55 - 62 . (canceled)

63 . A conjugate comprising PI3K-alpha, or a mutant thereof, having a cysteine residue, Cys862, wherein the Cys862 is covalently, and irreversibly, bonded to an inhibitor, such that inhibition of the PI3 kinase is maintained, wherein said conjugate is of formula C-1:

Cys862-modifier-inhibitor moiety C-1

wherein:

the Cys862 is Cys862 of PI3K-alpha, or a mutant thereof;

the modifier is a bivalent group resulting from covalent bonding of a warhead group with the Cys862 of the PI3 kinase;

the warhead group is a functional group capable of covalently binding to Cys862; and the inhibitor is of formula I*:

wherein the wavy bond indicates the point of attachment to the cysteine via the modifier;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered heterocylic ring 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, or:

64 - 91 . (canceled)

92 . A compound of formula II:

wherein:

R 1′ is a bivalent warhead group;

T p is a bivalent tethering moiety; and

R p is a detectable moiety.

93 - 102 . (canceled)

103 . A method comprising the steps of:

(a) providing one or more tissues, cell types, or a lysate thereof, obtained from a patient administered at least one dose of a compound according to claim 1 ;

(b) contacting said tissue, cell type, or a lysate thereof, with a compound according to claim 1 tethered to a detectable moiety to form a probe compound, to covalently modify at least one protein kinase present in said tissue, cell type, or a lysate thereof; and

(c) measuring the amount of said protein kinase covalently modified by the probe compound to determine occupancy of said protein kinase by said compound of claim 1 as compared to occupancy of said protein kinase by said probe compound.

104 - 106 . (canceled)

Assignments (2)

CHANGE OF NAME Recorded Sep 28, 2012

From: AVILA THERAPEUTICS, INC.

To: CELGENE AVILOMICS RESEARCH, INC.

Reel/Frame 029058/0066 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 23, 2012

From: QIAO, LIXIN; NIU, DEQIANG; PETTER, RUSSELL C.; ZHU, ZHENDONG

To: AVILA THERAPEUTICS, INC.

Reel/Frame 028254/0274 →