IP Library › Patent Application 12878965

Patent Application

App. No. 12/878,965

PI3 KINASE INHIBITORS AND USES THEREOF

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Patent No.: US None
App. No.: 12/878,965

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Abstract

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

Claims (510)

1 . A conjugate comprising one or more PI3 kinases having a cysteine residue, CysX, wherein the CysX is covalently, and irreversibly, bonded to an inhibitor, such that inhibition of the PI3 kinase is maintained, wherein CysX is selected from Cys862 of PI3K-alpha, Cys2243 of MTOR, Cys838 of PI3K-alpha, Cys869 of PI3K-gamma, Cys815 of PI3K-delta, Cys841 of PI3K-beta, Class 1A, Cys1119 of PI3K-beta, Class 2, Cys3683 of DNA-PK, Cys2770 of ATM-Kinase, Cys2753 of ATM-Kinase, Cys1840 of PI4KA, Cys1844 of PI4KA, or Cys1797 of PI4KA.

2 . The conjugate according to claim 1 , comprising one or more PI3 kinases having a cysteine residue selected from:

(a) Cys862 of PI3K-alpha; or

(b) any one or more of Cys869 of PI3K gamma, Cys838 of PI3K alpha, Cys815 of PI3K delta, Cys841 of PI3K beta, Class 1 or Cys1119 of PI3K beta, Class 2.

3 . The conjugate of claim 1 , wherein said conjugate is of formula C:

CysX-modifier-inhibitor moiety C

wherein:

the CysX is selected from Cys862 of PI3K-alpha, Cys2243 of MTOR, Cys838 of PI3K-alpha, Cys869 of PI3K-gamma, Cys815 of PI3K-delta, Cys841 of PI3K-beta, Class 1A, Cys1119 of PI3K-beta, Class 2, Cys3683 of DNA-PK, Cys2770 of ATM-Kinase, Cys2753 of ATM-Kinase, Cys1840 of PI4KA, Cys1844 of PI4KA, or Cys1797 of PI4KA;

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

the warhead group is a functional group capable of covalently binding to CysX; and

the inhibitor moiety is a moiety that binds in the active site of the PI3 kinase.

4 . The conjugate of claim 1 , wherein said conjugate is of formula C-1:

Cys862-modifier-inhibitor moiety C-1

wherein:

the Cys862 is Cys862 of a PI3 kinase;

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 moiety is a moiety that binds in the active site of the PI3 kinase.

5 . The conjugate of claim 1 , wherein said conjugate is of formula C-2:

CysX-modifier-inhibitor moiety C-2

wherein:

the CysX is any one or more of Cys869 of PI3K gamma, Cys838 of PI3K alpha, Cys815 of PI3K delta, Cys841 of PI3K beta, Class 1 or Cys1119 of PI3K beta, Class 2;

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

the warhead group is a functional group capable of covalently binding to CysX; and

the inhibitor moiety is a moiety that binds in the active site of the PI3 kinase.

6 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula I-i:

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

Ring A 1 is an optionally substituted group selected from 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;

Ring B 1 is selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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 bivalent straight or branched, saturated or unsaturated C 1-6 hydrocarbon chain wherein one or more methylene units of T are optionally 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)—;

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:

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;

q and r are each independently 0-4; and

each R 2 and R 3 is independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .

7 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula II-i:

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

X 2 is CH or N;

Y 2 and Z 2 are independently CR 4 , C, NR 5 , N, O, or S, as valency permits;

represents a single or double bond, as valency permits;

R 1 is a warhead group;

Ring A 2 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;

R 4 is —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

R 5 is —R, —SO 2 R, —SOR, —C(O)R, —CO 2 R, or —C(O)N(R) 2 ;

Ring B 2 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 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 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 1 is absent or an optionally substituted ring 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;

T 3 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 3 are optionally 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 2 is absent or an optionally substituted ring 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.

8 . The conjugate of claim 2 , wherein the inhibitor moiety is of either of formula II-i-a or II-i-b:

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

R 4 is —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

9 . The conjugate of claim 2 , wherein the inhibitor moiety is of either of formula II-i-c or II-i-d:

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

Ring A 2 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 5-10 membered saturated or partially unsaturated bridged 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;

R 4 is R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

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 are optionally 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 C 2 is hydrogen or an optionally substituted ring selected from 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 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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.

10 . The conjugate of claim 2 , wherein the inhibitor moiety is of either of formula II-i-e or II-i-f:

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

R 5 is R, —SO 2 R, —SOR, —C(O)R, —CO 2 R, or —C(O)N(R) 2 ;

11 . The conjugate of claim 2 , wherein the inhibitor moiety is of either of formula II-i-g or II-i-h:

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

R 4 is —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

12 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula III-i:

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

X is O or S;

R 6 is an optionally substituted group selected from phenyl, napthyl, a 6-membered heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 7 is an optionally substituted C 1-6 aliphatic group;

R 8 is hydrogen or —NHR′;

R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic group; and

Ring A 3 is an optionally substituted group selected from phenyl, naphthyl, a 6-membered heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic heteroaryl ring having 1-3 nitrogens.

13 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula IV-i:

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

X is O or S;

R 9 is an optionally substituted group selected from phenyl, napthyl, a 6-membered heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 10 is an optionally substituted C 1-6 aliphatic group;

R 11 is hydrogen or —NHR′; and

R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

14 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula V-i-a or V-i-b:

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

R 12 is an hydrogen or an optionally substituted group selected from C 1-6 aliphatic, —(CH 2 ) m -(3-7 membered saturated or partially unsaturated carbocyclic ring), —(CH 2 ) m -(7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring), —(CH 2 ) m -(4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -(7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), —(CH 2 ) m -phenyl, —(CH 2 ) m -(8-10 membered bicyclic aryl ring), —(CH 2 ) m -(5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or —(CH 2 ) m -(8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur);

each R 13 and R 14 is independently —R″, halogen, —NO 2 , —CN, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —CO 2 R″, —C(O)C(O)R″, —C(O)CH 2 C(O)R″, —S(O)R″, —S(O) 2 R″, —C(O)N(R″) 2 , —SO 2 N(R″) 2 , —OC(O)R″, —N(R″)C(O)R″, —N(R″)N(R″) 2 , —N(R″)C(═NR″)N(R″) 2 , —C(═NR″)N(R″) 2 , —C═NOR″, —N(R″)C(O)N(R″) 2 , —N(R″)SO 2 N(R″) 2 , —N(R″)SO 2 R″, or —OC(O)N(R″) 2 ;

each R″ is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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; or

two R″ groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

m is an integer from 0 to 6, inclusive;

each n is independently 0, 1, or 2;

Ring A 5 is an optionally substituted ring 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

Ring B 5 is absent or an optionally substituted ring 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.

15 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula VI-i-a or VI-i-b:

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

R 15 is hydrogen or C 1-6 alkyl;

R 16 is hydrogen or an optionally substituted group selected from C 1-6 alkyl, C 1-6 alkoxy, or (C 1-6 alkylene)-R 18 ; or

R 15 and R 16 are taken together with the intervening carbon to form an optionally substituted ring selected from a 3-7 membered carbocyclic ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 17 is hydrogen or C 1-6 alkyl;

R 18 is a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

Ring A 6 is absent or an optionally substituted group selected from a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

16 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula VII-i:

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

Ring A 7 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;

R 18 is R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

Ring B 7 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 7 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 are optionally 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 7 is an optionally substituted ring selected from 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 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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

Ring D 7 is absent or an optionally substituted ring selected from 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 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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.

17 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula VIII-i:

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

Ring A 8 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;

R 19 and R 20 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

Ring B 8 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 8 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 are optionally 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 8 is an optionally substituted ring selected from 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 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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

Ring D 8 is absent or an optionally substituted ring selected from 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 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, 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.

18 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula IX-i:

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

T 9 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 are optionally 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 A 9 is absent or an optionally substituted ring 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 7-10 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;

R 24 and R 25 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

z is 0, 1, or 2.

19 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula X-i:

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

each R 21 and R 22 is independently —R″, halogen, —NO 2 , —CN, —OR″, —SR″, —N(R″) 2 , —C(O)R″, —CO 2 R″, —C(O)C(O)R″, —C(O)CH 2 C(O)R″, —S(O)R″, —S(O) 2 R″, —C(O)N(R″) 2 , —SO 2 N(R″) 2 , —OC(O)R″, —N(R″)C(O)R″, —N(R″)N(R″) 2 , —N(R″)C(═NR″)N(R″) 2 , —C(═NR″)N(R″) 2 , —C═NOR″, —N(R″)C(O)N(R″) 2 , —N(R″)SO 2 N(R″) 2 , —N(R″)SO 2 R″, or —OC(O)N(R″) 2 ;

each k is independently 0, 1, or 2;

Ring A 10 is an optionally substituted ring 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;

Ring B 10 is an optionally substituted ring 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;

T 10 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 are optionally 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 C 10 is absent or an optionally substituted ring 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.

20 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula XI-i:

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

X 11 is CH or N;

Ring A 11 is an optionally substituted ring 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;

each R 23 is independently —R a , halogen, —NO 2 , —CN, —OR b , —SR b , —N(R b ) 2 , —C(O)R a , —CO 2 R a , —C(O)C(O)R a , —C(O)CH 2 C(O)R a , —S(O)R a , —S(O) 2 R a , —C(O)N(R a ) 2 , —SO 2 N(R a ) 2 , —OC(O)R a , —N(R a )C(O)R a , —N(R a )N(R a ) 2 , —N(R a )C(═NR a )N(R a ) 2 , —C(═NR a )N(R a ) 2 , —C═NOR a , —N(R a )C(O)N(R a ) 2 , —N(R a )SO 2 N(R a ) 2 , —N(R a )SO 2 R a , or —OC(O)N(R a ) 2 ;

each R a is independently hydrogen, C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 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; or

two R a groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R b is independently hydrogen, C, aliphatic, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R b groups on the same nitrogen are taken together with the nitrogen to which they are attached to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

w is 0, 1, or 2;

Ring B 11 is an optionally substituted ring 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;

T 11 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 are optionally 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 C 11 is absent or an optionally substituted ring 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.

21 . The conjugate of claim 2 , wherein the inhibitor moiety is of formula XII-i:

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

R 1 is a warhead group;

X 12 is CR 26 or N;

Y 12 is CR 27 or N;

Z 12 is CR 28 or N;

wherein at least one of X 12 , Y 12 , and Z 12 is N;

Ring A 12 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;

R 26 , R 27 , and R 28 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

Ring B 12 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 12 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 12 are optionally 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 12 is absent or an optionally substituted ring 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 13 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 13 are optionally 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 12 is absent or an optionally substituted ring 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.

22 - 45 . (canceled)

46 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring B 1 is selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-8 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 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;

R 1 is a warhead group;

q and r are each independently 0-4; and

each R 2 and R 3 is independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 .

47 - 54 . (canceled)

55 . A compound of formula II-a or II-b:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 4 is —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

56 . The compound according to claim 55 , wherein Ring B 2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

57 . The compound according to claim 56 , wherein Ring B 2 is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 2 nitrogen atoms.

58 . The compound according to claim 55 , wherein Ring B 2 is 1H-indazolyl, optionally substituted phenyl, phenol, or optionally substituted pyridyl or pyrimidyl.

59 - 62 . (canceled)

63 . The compound according to claim 55 , wherein Ring A 2 is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur.

64 . The compound according to claim 63 , wherein Ring A 2 is optionally substituted morpholinyl.

65 . (canceled)

66 . The compound according to claim 64 , wherein Ring A 2 is selected from the following:

67 . The compound according to claim 55 , wherein Ring A 2 is a bridged, bicyclic morpholino group.

68 . The compound according to claim 65 , wherein Ring A 2 is selected from:

69 . The compound according to claim 55 , wherein Ring A 2 is selected from:

70 . The compound according to claim 55 , wherein T 2 is a bivalent, straight, saturated or unsaturated C 1-6 hydrocarbon chain.

71 . (canceled)

72 . The compound according to claim 70 , wherein T 2 is —CH 2 —, —C≡C—, or —CH 2 C≡C—.

73 . The compound according to claim 55 , wherein T 2 is a covalent bond or —C(O)—.

74 - 77 . (canceled)

78 . The compound according to claim 55 , wherein T 2 is a covalent bond, methylene, or a C 2-4 hydrocarbon chain wherein one methylene unit of T 2 is replaced by —C(O)NH—.

79 . (canceled)

80 . The compound according to claim 55 , wherein Ring C 1 is an optionally substituted 6-membered saturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur.

81 . The compound according to claim 80 , wherein Ring C 1 is a piperazinyl or piperidinyl ring.

82 . (canceled)

83 . The compound according to claim 55 , wherein Ring C 1 is a tetrahydropyridyl ring, a phenyl ring, or a cyclohexyl ring.

84 - 85 . (canceled)

86 . The compound according to claim 55 , wherein T 3 is a bivalent, straight, saturated C 1-6 hydrocarbon chain.

87 . (canceled)

88 . The compound according to claim 86 , wherein T 3 is —CH 2 — or —CH 2 CH 2 —.

89 . The compound according to claim 55 , wherein T 3 is —C(O)— or a covalent bond.

90 . (canceled)

91 . The compound according to claim 55 , wherein Ring D 2 is optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having one or two heteroatoms independently selected from nitrogen, oxygen, or sulfur.

92 . The compound according to claim 91 , wherein Ring D 2 is tetrahydropyridyl, piperidinyl or piperazinyl.

93 . (canceled)

94 . The compound according to claim 55 , wherein Ring D 2 is phenyl.

95 . The compound according to claim 55 , wherein Ring D 2 is absent.

96 . The compound according to claim 55 , wherein

is selected from

97 . The compound according to claim 96 , wherein

comprises a spacer group having about 9 to about 11 atoms.

98 . The compound according to claim 55 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A 2 is optionally substituted morpholinyl;

b) Ring B 2 is an optionally substituted group selected from indazolyl, aminopyrimidinyl, or phenol;

and

comprises a spacer group having about 9 to about 11 atoms.

99 . The compound according to claim 55 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A 2 is optionally substituted morpholinyl;

b) Ring B 2 is an 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 2 is a covalent bond, methylene, or a C 2-4 hydrocarbon chain wherein one methylene unit of T 2 is replaced by —C(O)NH—;

d) Ring C 1 is phenyl, or an optionally substituted 6-membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-2 nitrogens;

e) T 3 is a covalent bond or —C(O)—; and

f) Ring D 2 is absent or phenyl.

100 . The compound according to claim 55 , wherein the compound has one or more, more than one, or all of the features selected from:

a) Ring A 2 is optionally substituted morpholinyl;

b) Ring B 2 is an optionally substituted group selected from indazolyl, phenol, or aminopyrimidine;

c) T 2 is a covalent bond, methylene, or a C 3 hydrocarbon chain wherein one methylene unit of T 2 is replaced by —C(O)NH—;

d) Ring C 1 is phenyl, piperazinyl, piperidinyl, or tetrahydropyridyl;

e) T 3 is a covalent bond or —C(O)—; and

f) Ring D 2 is absent or phenyl.

101 . The compound according to claim 55 , wherein the compound is selected from the group consisting of:

102 . The compound according to claim 101 selected from the group consisting of:

103 . A compound of formula II-c or II-d:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

Ring A 2 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 5-10 membered saturated or partially unsaturated bridged 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;

R 4 is R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

104 - 133 . (canceled)

134 . A compound of formula II-e or II-f:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 5 is R, —SO 2 R, —SOR, —C(O)R, —CO 2 R, or —C(O)N(R) 2 ;

135 - 176 . (canceled)

177 . A compound of formula II-g or II-h:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 4 is —R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

178 - 226 . (canceled)

227 . A compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

X is O or S;

R 7 is an optionally substituted C 1-6 aliphatic group;

R 8 is hydrogen or —NHR′;

R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic group; and

Ring A 3 is an optionally substituted group selected from phenyl, naphthyl, a 6-membered heteroaryl ring having 1-2 nitrogens, or an 8-10 membered bicyclic heteroaryl ring having 1-3 nitrogens.

228 - 234 . (canceled)

235 . A compound of formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

X is O or S;

R 10 is an optionally substituted C 1-6 aliphatic group;

R 11 is hydrogen or —NHR′; and

R′ is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

236 - 239 . (canceled)

240 . A compound of formula V-a or V-b:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

m is an integer from 0 to 6, inclusive;

each n is independently 0, 1, or 2;

241 - 251 . (canceled)

252 . A compound of formula VI-a or VI-b:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 15 is hydrogen or C 1-6 alkyl;

R 16 is hydrogen or an optionally substituted group selected from C 1-6 alkyl, C 1-6 alkoxy, or (C 1-6 alkylene)-R 18 ; or

R 17 is hydrogen or C 1-6 alkyl;

253 - 258 . (canceled)

259 . A compound of formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 18 is R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

260 - 267 . (canceled)

268 . A compound of formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 19 and R 20 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

269 . (canceled)

270 . A compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

R 24 and R 25 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

z is 0, 1, or 2.

271 - 273 . (canceled)

274 . A compound of formula X:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

each k is independently 0, 1, or 2;

275 - 277 . (canceled)

278 . A compound of formula XI:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

X 11 is CH or N;

w is 0, 1, or 2;

279 - 285 . (canceled)

286 . A compound of formula XII:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a warhead group;

X 12 is CR 26 or N;

Y 12 is CR 27 or N;

Z 12 is CR 28 or N;

wherein at least one of X 12 , Y 12 , and Z 12 is N;

R 26 , R 27 , and R 28 are independently R, halogen, —OR, —CN, —NO 2 , —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)N(R) 2 , —NRSO 2 R, or —N(R) 2 ;

287 . The compound according to claim 286 , wherein the compound is of formula XII-a:

288 - 343 . (canceled)

344 . The compound according to claim 55 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain 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.

345 . The compound according to claim 344 , 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.

346 . The compound according to claim 345 , 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)—.

347 . The compound according to claim 345 , 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)—.

348 . The compound according to claim 344 , 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.

349 . The compound according to claim 348 , 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-.

350 . The compound according to claim 344 , 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)—.

351 . The compound according to claim 55 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain 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:

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.

352 . The compound according to claim 351 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

353 . The compound according to claim 352 , wherein L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 —C≡C—CH 2 —, —C≡CCH 2 O—, —CH 2 C(O)C≡C—, —C(O)C≡C—, or —CH 2 C(═O)C≡C—.

354 . The compound according to claim 55 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain 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.

355 . The compound according to claim 354 , wherein Y is hydrogen or C 1-6 aliphatic optionally substituted with oxo, halogen, NO 2 , or CN.

356 . The compound according to claim 55 , 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

(vi)

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;

(x)

(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

(xii)

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

(xiv)

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

(xvi)

(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.

357 . The compound according to claim 356 , 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—.

358 . The compound according to claim 357 , wherein L is a covalent bond.

359 . The compound according claim 356 , wherein Y is selected from:

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

360 . The compound of claim 55 , wherein R 1 is -L-Y, wherein:

L is a bivalent C 2-8 straight or branched, hydrocarbon chain 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.

361 . The compound of claim 360 , 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 .

362 . The compound of claim 55 , wherein R 1 is 6-12 atoms long.

363 . The compound of claim 361 , wherein R 1 is at least 8 atoms long.

364 . The compound according to claim 55 , wherein R 1 is selected from:

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

365 . The compound according to claim 55 , wherein R 1 is selected from:

366 . The compound according to claim 55 , wherein R 1 is selected from:

367 . A composition comprising a compound according to claim 55 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

368 . The composition according to claim 367 , in combination with an additional therapeutic agent.

369 . The composition according to claim 368 , wherein the additional therapeutic agent is a chemotherapeutic agent.

370 . A method for inhibiting one or more PI3 kinases, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound according to claim 55 .

371 . A method for inhibiting one or more PI3 kinases, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound according to claim 55 .

372 . The method according to claim 371 , wherein the one or more PI3 kinases, or a mutant thereof, activity is inhibited irreversibly.

373 . The method according to claim 372 , wherein the one or more PI3 kinases, or a mutant thereof, activity is inhibited irreversibly by covalently modifying Cys862 of PI3K-alpha, Cys2243 of MTOR, Cys838 of PI3K-alpha, Cys869 of PI3K-gamma, Cys815 of PI3K-delta, Cys841 of PI3K-beta, Class 1A, Cys1119 of PI3K-beta, Class 2, Cys3683 of DNA-PK, Cys2770 of ATM-Kinase, Cys2753 of ATM-Kinase, Cys1840 of PI4KA, Cys1844 of PI4KA, or Cys 1797 of PI4KA.

374 . A method for treating a PI3Kα-mediated, a PI3Kγ-mediated, a PI3Kδ-mediated, a PI3Kβ-mediated, a PI3KC2β-mediated, an mTOR-mediated, a DNA-PK-mediated, an ATM-mediated and/or a PI4KIIIα-mediated disorder, disease, or condition in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 55 .

375 - 415 . (canceled)

Assignments (4)

MERGER AND CHANGE OF NAME Recorded Feb 16, 2017

From: CELGENE AVILOMICS RESEARCH, INC.; CELGENE CAR LLC

To: CELGENE CAR LLC

Reel/Frame 041738/0041 →

CHANGE OF NAME Recorded Sep 28, 2012

From: AVILA THERAPEUTICS, INC.

To: CELGENE AVILOMICS RESEARCH, INC.

Reel/Frame 029058/0066 →

CORRECTIVE ASSIGNMENT TO CORRECT THE APPLICATION NUMBER NEEDS TO BE UPDATED TO 12/878965 PREVIOUSLY RECORDED ON REEL 025962 FRAME 0973. ASSIGNOR(S) HEREBY CONFIRMS THE ORIGINALLY RECORDED AS APPLICATION NUMBER 12/878695. Recorded May 24, 2011

From: NIU, DEQIANG; PETTER, RUSSELL C.; SINGH, JUSWINDER; KLUGE, ARTHUR F.; MAZDIYASNI, HORMOZ; ZHU, ZHENDONG; QIAO, LIXIN; KUNTZ, KEVIN

To: AVILA THERAPEUTICS, INC.

Reel/Frame 026329/0157 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 11, 2011

From: NIU, DEQIANG; PETTER, RUSSELL C.; SINGH, JUSWINDER; KLUGE, ARTHUR F.; MAZDIYASNI, HORMOZ; ZHU, ZHENDONG; QIAO, LIXIN; KUNTZ, KEVIN

To: AVILA THERAPEUTICS, INC.

Reel/Frame 025962/0973 →