PI3 KINASE INHIBITORS AND USES THEREOF

• US 20110230476A1
• Filed: 09/09/2010
• Published: 09/22/2011
• Est. Priority Date: 09/09/2009
• Status: Abandoned Application

• Current Assignee: Celgene Car LLC (Bristol-Myers Squibb Company)
• Original Assignee: Avila Therapeutics Inc. (Bristol-Myers Squibb Company)
• Inventors: QIAO, LIXIN, SINGH, JUSWINDER, ZHU, ZHENDONG, KLUGE, ARTHUR F., NIU, DEQIANG, MAZDIYASNI, HORMOZ, PETTER, RUSSELL C., KUNTZ, KEVIN
• Application Number:
  US12/878,965
• Publication Number:
  US 20110230476A1
• Time in Patent Office: Days
• US Class Current: 514/230.5
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

Abstract

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

Claims

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:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

22-45. -45. (canceled)

46. A compound of formula I:

47-54. -54. (canceled)

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

56. The compound according to claim 55, wherein Ring B² 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 B² is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 2 nitrogen atoms.

58. The compound according to claim 55, wherein Ring B² is 1H-indazolyl, optionally substituted phenyl, phenol, or optionally substituted pyridyl or pyrimidyl.

63. The compound according to claim 55, wherein Ring A² 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 A² is optionally substituted morpholinyl.

66. The compound according to claim 64, wherein Ring A² is selected from the following:

67. The compound according to claim 55, wherein Ring A² is a bridged, bicyclic morpholino group.

69. The compound according to claim 55, wherein Ring A² is selected from:

70. The compound according to claim 55, wherein T² is a bivalent, straight, saturated or unsaturated C_1-6 hydrocarbon chain.

72. The compound according to claim 70, wherein T² is —

CH₂—

, —

C≡

C—

, or —

CH₂C≡

C—

.

73. The compound according to claim 55, wherein T² is a covalent bond or —

C(O)—

.

78. The compound according to claim 55, wherein T² is a covalent bond, methylene, or a C_2-4 hydrocarbon chain wherein one methylene unit of T² is replaced by —

C(O)NH—

.

80. The compound according to claim 55, wherein Ring C¹ 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 C¹ is a piperazinyl or piperidinyl ring.

83. The compound according to claim 55, wherein Ring C¹ is a tetrahydropyridyl ring, a phenyl ring, or a cyclohexyl ring.

86. The compound according to claim 55, wherein T³ is a bivalent, straight, saturated C_1-6 hydrocarbon chain.

88. The compound according to claim 86, wherein T³ is —

CH₂—

or —

CH₂CH₂—

.

89. The compound according to claim 55, wherein T³ is —

C(O)—

or a covalent bond.

91. The compound according to claim 55, wherein Ring D² 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 D² is tetrahydropyridyl, piperidinyl or piperazinyl.

94. The compound according to claim 55, wherein Ring D² is phenyl.

95. The compound according to claim 55, wherein Ring D² is absent.

96. The compound according to claim 55, wherein

97. The compound according to claim 96, wherein

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 A² is optionally substituted morpholinyl;

b) Ring B² is an optionally substituted group selected from indazolyl, aminopyrimidinyl, or phenol;

c)

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 A² is optionally substituted morpholinyl;

b) Ring B² 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) T² is a covalent bond, methylene, or a C_2-4 hydrocarbon chain wherein one methylene unit of T² is replaced by —

C(O)NH—

;

d) Ring C¹ is phenyl, or an optionally substituted 6-membered saturated, partially unsaturated, or aromatic heterocyclic ring having 1-2 nitrogens;

e) T³ is a covalent bond or —

C(O)—

; and

f) Ring D² 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 A² is optionally substituted morpholinyl;

b) Ring B² is an optionally substituted group selected from indazolyl, phenol, or aminopyrimidine;

c) T² is a covalent bond, methylene, or a C₃ hydrocarbon chain wherein one methylene unit of T² is replaced by —

C(O)NH—

;

d) Ring C¹ is phenyl, piperazinyl, piperidinyl, or tetrahydropyridyl;

e) T³ is a covalent bond or —

C(O)—

; and

f) Ring D² 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:

344. The compound according to claim 55, wherein R¹ 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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, —

C(O)O—

, cyclopropylene, —

O—

, —

N(R)—

, or —

C(O)—

;

Y is hydrogen, C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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, NO₂, halogen, CN, a suitable leaving group, or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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 —

SO₂—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

N(R)SO₂—

, or —

SO₂N(R)—

; and

Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

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, NO₂, 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═

CHCH₂N(CH₃)—

, —

NRC(O)CH═

CHCH₂O—

, —

CH₂NRC(O)CH═

CH—

, —

NRSO₂CH═

CH—

, —

NRSO₂CH═

CHCH₂—

, —

NRC(O)(C═

N₂)—

, —

NRC(O)(C═

N₂)C(O)—

, —

NRC(O)CH═

CHCH₂N(CH₃)—

, —

NRSO₂CH═

CH—

, —

NRSO₂CH═

CHCH₂—

, —

NRC(O)CH═

CHCH₂O—

, —

NRC(O)C(═

CH₂)CH₂—

, —

CH₂NRC(O)—

, —

CH₂NRC(O)CH═

CH—

, —

CH₂CH₂NRC(O)—

, or —

CH₂NRC(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, NO₂, or CN.

349. The compound according to claim 348, wherein L is —

NHC(O)CH═

CH—

, —

NHC(O)CH═

CHCH₂N(CH₃)—

, —

NHC(O)CH═

CHCH₂O—

, —

CH₂NHC(O)CH═

CH—

, —

NHSO₂CH═

CH—

, —

NHSO₂CH═

CHCH₂—

, —

NHC(O)(C═

N₂)—

, —

NHC(O)(C═

N₂)C(O)—

, —

NHC(O)CH═

CHCH₂N(CH₃)—

, —

NHSO₂CH═

CH—

, —

NHSO₂CH═

CHCH₂—

, —

NHC(O)CH═

CHCH₂O—

, —

NHC(O)C(═

CH₂)CH₂—

, —

CH₂NHC(O)—

, —

CH₂NHC(O)CH═

CH—

, —

CH₂CH₂NHC(O)—

, or —

CH₂NHC(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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

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 R¹ 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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

,

Y is hydrogen, C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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, NO₂, halogen, CN, a suitable leaving group, or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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 —

SO₂—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

N(R)SO₂—

, or —

SO₂N(R)—

; and

Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

352. The compound according to claim 351, wherein Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

353. The compound according to claim 352, wherein L is —

C≡

C—

, —

C≡

CCH₂N(isopropyl)-, —

NHC(O)C≡

CCH₂CH₂—

, —

CH₂—

C≡

C—

CH₂—

, —

C≡

CCH₂O—

, —

CH₂C(O)C≡

C—

, —

C(O)C≡

C—

, or —

CH₂C(═

O)C≡

C—

.

354. The compound according to claim 55, wherein R¹ 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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

OC(O)—

, or —

C(O)O—

;

Y is hydrogen, C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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, NO₂, halogen, CN, a suitable leaving group, or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, 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 —

SO₂—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

N(R)SO₂—

, or —

SO₂N(R)—

; and

Z is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

355. The compound according to claim 354, wherein Y is hydrogen or C_1-6 aliphatic optionally substituted with oxo, halogen, NO₂, or CN.

356. The compound according to claim 55, wherein R¹ 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, NO₂, or CN;

(ii) C_2-6 alkenyl optionally substituted with oxo, halogen, NO₂, or CN;

or

(iii) C_2-6 alkynyl optionally substituted with oxo, halogen, NO₂, 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)

357. The compound according to claim 356, wherein L is a covalent bond, —

CH₂—

, —

NH—

, —

C(O)—

, —

CH₂NH—

, —

NHCH₂—

, —

NHC(O)—

, —

NHC(O)CH₂OC(O)—

, —

CH₂NHC(O)—

, —

NHSO₂—

, —

NHSO₂CH₂—

, —

NHC(O)CH₂OC(O)—

, or —

SO₂NH—

.

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

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

360. The compound of claim 55, wherein R¹ 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)SO₂—

, —

SO₂N(R)—

, —

S—

, —

S(O)—

, —

SO₂—

, —

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, NO₂, or CN.

361. The compound of claim 360, wherein R¹ is —

C(O)CH₂CH₂C(O)CH═

C(CH₃)₂, —

C(O)CH₂CH₂C(O)CH═

CH(cyclopropyl), —

C(O)CH₂CH₂C(O)CH═

CHCH₃, —

C(O)CH₂CH₂C(O)CH═

CHCH₂CH₃, —

C(O)CH₂CH₂C(O)C(═

CH₂)CH₃, —

C(O)CH₂NHC(O)CH═

CH₂, —

C(O)CH₂NHC(O)CH₂CH₂C(O)CH═

CHCH₃, —

C(O)CH₂NHC(O)CH₂CH₂C(O)C(═

CH₂)CH₃, —

S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═

C(CH₃)₂, —

S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═

CHCH₃, —

S(O)₂CH₂CH₂NHC(O)CH₂CH₂C(O)CH═

CH₂, —

C(O)(CH₂)₃NHC(O)CH₂CH₂C(O)CH═

CHCH₃, or —

C(O)(CH₂)₃NHC(O)CH₂CH₂C(O)CH═

CH₂.

362. The compound of claim 55, wherein R¹ is 6-12 atoms long.

363. The compound of claim 361, wherein R¹ is at least 8 atoms long.

364. The compound according to claim 55, wherein R¹ is selected from:

365. The compound according to claim 55, wherein R¹ is selected from:

366. The compound according to claim 55, wherein R¹ 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.

59-62. -62. (canceled)

65. (canceled)

68. The compound according to claim 65, wherein Ring A² is selected from:

71. (canceled)

74-77. -77. (canceled)

79. (canceled)

82. (canceled)

84-85. -85. (canceled)

87. (canceled)

90. (canceled)

93. (canceled)

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

104-133. -133. (canceled)

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

135-176. -176. (canceled)

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

178-226. -226. (canceled)

227. A compound of formula III:

228-234. -234. (canceled)

235. A compound of formula IV:

236-239. -239. (canceled)

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

241-251. -251. (canceled)

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

253-258. -258. (canceled)

259. A compound of formula VII:

260-267. -267. (canceled)

268. A compound of formula VIII:

269. (canceled)

270. A compound of formula IX:

271-273. -273. (canceled)

274. A compound of formula X:

275-277. -277. (canceled)

278. A compound of formula XI:

279-285. -285. (canceled)

286. A compound of formula XII:

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

288-343. -343. (canceled)

375-415. -415. (canceled)