AZAINDOLES USEFUL AS INHIBITORS OF JAK AND OTHER PROTEIN KINASES

• US 20140249138A1
• Filed: 02/18/2014
• Published: 09/04/2014
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Salituro, Francesco, Farmer, Luc, Bethiel, Randy, Harrington, Edmund, Green, Jeremy, Court, John, Come, Jon, Lauffer, David, Aronov, Alex, Binch, Hayley, Boyall, Dean, Charrier, Jean-Damien, Everitt, Simon, Fraysse, Damien, Mortimore, Michael, Pierard, Francoise, Robinson, Daniel, Wang, Jian, Pinder, Joanne, Wang, Tiansheng, Pierce, Albert
• Granted Patent: US 8,987,454 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/695 Silicon compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• 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 19/04 : for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 : Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 27/06 : Antiglaucoma agents or miotics
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/18 : for HIV
• 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 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
• CPC Class Codes: C07F 7/0805 : comprising only Si, C or H atoms

Abstract

The present invention relates to inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

1. A compound of formula I-A, I-C, or I-D:

2. The compound of claim 1, wherein:

a) R¹ is T-R′

, wherein T is a bond or is an optionally substituted C₁-C₆alkylidene chain wherein up to two methylene units are optionally and independently replaced with —

O—

, —

S—

, —

NR′

—

, —

OCO—

, —

COO—

, —

SO₂—

or —

CO—

, and R′

is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered aryl or heteroaryl group;

or

b) R¹ is —

Si(R′

)₃, R′

is hydrogen, C₁-C₄-alkyl, or an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3. The compound of claim 1, wherein R¹ is hydrogen, C₁-C₄alkyl, —

COR′

, —

SO₂R′

, or —

Si(R′

)₃.

4. The compound of claim 1, wherein R¹ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, p-toluenesulfonyl (Ts), t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), or triethylsilyl (TES).

5. The compound of claim 1, wherein R², R³, and R⁴ are each independently hydrogen, R′

, halogen, CN, NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COCH2R′

, or —

NR′

CO(CH2)2R′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

(CH₂)₂N(R′

)₂, —

CONR′

(CH₂)₃N(R′

)₂, —

CONR′

(CH₂)₄N(R′

)₂, —

O(CH₂)₂OR′

, O(CH₂)₃OR′

, O(CH₂)₄OR′

, —

O(CH₂)₂N(R′

)₂, —

O(CH₂)₃N(R′

)₂, or —

O(CH₂)₄N(R′

)₂.

6. The compound of claim 1, wherein R², R³, and R⁴ are each independently —

Cl, —

Br, —

F, —

CN, —

COOH, —

COOMe, —

NH₂, —

N(CH₃)₂, —

N(Et)₂, —

N(iPr)₂, —

O(CH₂)₂OCH₃, —

CONH₂, —

COOCH₃, —

OH, —

CH₂OH, —

NHCOCH₃, —

SO₂NH₂, —

SO₂N(Me)₂, or an optionally substituted group selected from C₁-C₄alkyl, C₁-C₄alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

7. The compound of claim 1, wherein:

a) R², R³, and R⁴ are each hydrogen;

b) one of R², R³, or R⁴ is hydrogen;

c) two of R², R³, or R⁴ is hydrogen;

d) R² and R⁴ are both hydrogen, and R³ is halogen, CN, NO₂, or V—

R′

;

e) R² and R⁴ are both hydrogen, and R³ is an optionally substituted group selected from a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

f) R² and R⁴ are both hydrogen, and R³ is an optionally substituted 5- or 6-membered saturated, partially unsaturated, or fully unsaturated ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or

g) R² and R⁴ are both hydrogen, and R³ is an optionally substituted ring selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, triazolyl, pyrazinyl, thiadiazolyl, or oxadiazolyl.

8. The compound of claim 1, wherein R², R³, and R⁴ are each optionally substituted with z occurrences of R⁶, wherein z is 0-5 and R⁶ is ═

O, ═

NR″

, ═

S, halogen, —

CN, —

NO₂, or Z—

R″

, wherein Z is a bond or an optionally substituted C₁-C₆ alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —

NR″

—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR″

—

, —

NR″

CO—

, —

NR″

CO₂—

, —

SO₂NR″

—

, —

NR″

SO₂—

, —

CONR″

NR″

—

, —

NR″

CONR″

—

, —

OCONR″

—

, —

NR″

NR″

—

, —

NR″

SO₂NR″

—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR″

—

, and each occurrence of R″

is independently hydrogen or an optionally substituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or two occurrences of R″

are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9. The compound of claim 8, wherein z is 0, 1, 2, or 3, and each occurrence of R⁶ is independently hydrogen, R″

, —

CH₂R″

, halogen, CN, NO₂, —

N(R″

)₂, —

CH₂N(R″

)₂, —

OR″

, —

CH₂OR″

, —

SR″

, —

CH₂SR″

, —

COOR″

, —

NR″

COR″

, —

NR″

COOR″

, —

CON(R″

)₂, —

SO₂N(R″

)₂, —

CONR″

(CH₂)₂N(R″

)₂, —

CONR(CH₂)₃N(R″

)₂, —

CONR″

(CH₂)₄N(R″

)₂, —

O(CH₂)₂OR″

, —

O(CH₂)₃OR″

, —

O(CH₂)₄OR″

, —

O(CH₂)₂N(R″

)₂, —

O(CH₂)₃N(R″

)₂, —

O(CH₂)₄N(R″

)₂, —

NR″

CH(CH₂OH)R″

, —

NR″

CH(CH₂CH₂OH)R″

, —

NR″

(CH₂)R″

, —

NR″

(CH₂)₂R″

, —

NR″

(CH₂)₃R″

, —

NR″

(CH₂)₄R″

, —

NR″

(CH₂)N(R″

)₂, —

NR″

(CH₂)₂N(R″

)₂, —

NR″

(CH₂)₃N(R″

)₂, —

NR″

(CH₂)₄N(R″

)₂, —

NR″

(CH₂)OR″

, —

NR″

(CH₂)₂OR″

, —

NR″

(CH₂)₃OR″

, or —

NR″

(CH₂)₄OR″

.

10. The compound of claim 8, wherein z is 1, 2, or 3 and each occurrence of R⁶ is independently —

F, —

Cl, —

Br, —

CN, —

OH, —

NH₂, —

CH₂OH, C₁-C₆alkyl, —

O(C₁-C₆alkyl), —

CH₂O(C₁-C₆alkyl), —

CO(C₁-C₆alkyl), —

COO(C₁-C₆alkyl), —

NHSO₂(C₁-C₆alkyl), —

SO₂NH₂, —

CONH₂, —

CON(C₁-C₆alkyl), —

SO₂(C₁-C₆alkyl), —

SO₂phenyl, phenyl, benzyl, —

N(C₁-C₆alkyl)₂, or —

S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups is independently and optionally substituted, and wherein each of the foregoing C₁-C₆alkyl groups is linear, branched, or cyclic.

15. The compound of claim 1, wherein each occurrence of R⁵ is independently hydrogen, R′

, —

CH₂R′

, halogen, —

CN, —

NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COCH₂R′

, —

NR′

CO(CH₂)₂R′

, —

NR′

COOR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

(CH₂)₂N(R′

)₂, —

CONR(CH₂)₃N(R′

)₂, —

CONR′

(CH₂)₄N(R′

)₂, —

O(CH₂)₂OR′

, —

O(CH₂)₃OR′

, —

O(CH₂)₄OR′

, —

O(CH₂)₂N(R′

)₂, —

O(CH₂)₃N(R′

)₂, —

O(CH₂)₄N(R′

)₂, —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

(CH₂)R′

, —

NR′

(CH₂)₂R′

, —

NR′

(CH₂)₃R′

, —

NR′

(CH₂)₄R′

, —

NR′

(CH₂)N(R′

)₂, —

NR′

(CH₂)₂N(R′

)₂, —

NR′

(CH₂)₃N(R′

)₂, —

NR′

(CH₂)₄N(R′

)₂, —

NR′

(CH₂)OR′

, —

NR′

(CH₂)₂OR′

, —

NR′

(CH₂)₃OR′

, or —

NR′

(CH₂)₄OR′

.

16. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R⁵ is —

N(R′

)₂, —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

(CH₂)R′

, —

NR′

(CH₂)₂R′

, —

NR′

(CH₂)N(R′

)₂, or —

NR′

(CH₂)₂N(R′

)₂.

17. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R⁵ is —

OR′

.

18. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R⁵ is —

NR′

COR′

, —

NR′

COCH₂R′

, or —

NR′

CO(CH₂)₂R′

.

19. The compound of claim 1, wherein x is 1, 2, or 3, and at least one occurrence of R⁵ is an optionally substituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

20. The compound of claim 1, wherein x is 1 or 2, and each occurrence of R⁵ is independently halogen, R′

, CN, —

CH₂CN, —

(CH₂)₂CN, NO₂, —

CH₂NO₂, —

(CH₂)₂NO₂, CON(R′

)₂, —

CH₂CON(R′

)₂, —

(CH₂)₂CON(R′

)₂, COOR′

, —

CH₂COOR′

, —

(CH₂)₂COOR′

, —

SO₂N(R′

)₂, —

CH₂SO₂N(R′

)₂, —

(CH₂)₂SO₂N(R′

)₂, —

NR′

SO₂R′

, —

CH₂NR′

SO₂R′

, —

(CH₂)₂NR'"'"'SO₂R′

, NR′

CON(R′

)₂, —

CH₂NR′

CON(R′

)₂, —

(CH₂)₂NR′

CON(R′

)₂, —

NR′

SO₂N(R′

)₂, —

CH₂NR′

SO₂N(R′

)₂, —

(CH₂)₂NR′

SO₂N(R′

)₂, —

COCOR′

, —

CH₂COCOR′

, —

(CH₂)₂COCOR′

, —

N(R′

)₂, —

CH₂N(R′

)₂, —

(CH₂)₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

(CH₂)₂OR′

, —

NR′

COR′

, —

NR′

COCH₂R′

, —

NR′

CO(CH₂)₂R′

, —

CH₂NR′

COR′

, or —

(CH₂)₂NR′

COR′

.

21. The compound of claim 20, wherein R⁵ is CN, —

CH₂CN, —

(CH₂)₂CN, —

NO₂, —

CH₂NO₂, —

(CH₂)₂NO₂, OR′

, —

CH₂OR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

N(R′

)₂, or R′

.

22. The compound of claim 20, wherein each occurrence of R⁵ is independently hydrogen, halogen, CN, —

CH₂CN, —

(CH₂)₂CN, NO₂, —

CH₂NO₂, —

(CH₂)₂NO₂, —

CONH₂, —

CON(C₁-C₄alkyl), —

SO₂NH₂, —

SO₂N(C₁-C₄alkyl), NH₂, —

N(C₁-C₄alkyl), —

OH, —

O(C₁-C₄alkyl), —

CH₂OH, —

CH₂O(C₁-C₄alkyl), or an optionally substituted 5- or 6-membered unsaturated ring wherein 0-3 ring carbon atoms is optionally replaced by oxygen, sulfur, or nitrogen.

23. The compound of claim 1, wherein R⁵ is optionally substituted with y occurrences of R⁷, wherein y is 0-5 and R⁷ is ═

O, ═

NR″

, ═

S, halogen, —

CN, —

NO₂, or W—

R″

, wherein W is a bond or an optionally substituted C₁-C₆ alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —

NR″

—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR″

—

, —

NR″

CO—

, —

NR″

CO₂—

, —

SO₂NR″

—

, —

NR″

SO₂—

, —

CONR″

NR″

—

, —

NR″

CONR″

—

, —

OCONR″

—

, —

NR″

NR″

—

, —

NR″

SO₂NR″

—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR″

—

, and each occurrence of R″

is independently hydrogen or an optionally substituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or two occurrences of R″

, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

24. The compound of claim 23, wherein y is 0, 1, 2, or 3, and each occurrence of R⁷ is independently hydrogen, R″

, —

CH₂R″

, halogen, —

CN, —

NO₂, —

N(R″

)₂, —

CH₂N(R″

)₂, —

OR″

, —

CH₂OR″

, —

SR″

, —

CH₂SR″

, —

COOR″

, —

NR″

COR″

, —

NR″

COOR″

, —

CON(R″

)₂, —

SO₂N(R″

)₂, —

CONR″

(CH₂)₂N(R″

)₂, —

CONR(CH₂)₃N(R″

)₂, —

CONR″

(CH₂)₄N(R″

)₂, —

O(CH₂)₂OR″

, —

O(CH₂)₃OR″

, —

O(CH₂)₄OR″

, —

O(CH₂)₂N(R″

)₂, —

O(CH₂)₃N(R″

)₂, —

O(CH₂)₄N(R″

)₂, —

NR″

CH(CH₂OH)R″

, —

NR″

CH(CH₂CH₂OH)R″

, —

NR″

(CH₂)R″

, —

NR″

(CH₂)₂R″

, —

NR″

(CH₂)₃R″

, —

NR″

(CH₂)₄R″

, —

NR″

(CH₂)N(R″

)₂, —

NR″

(CH₂)₂N(R″

)₂, —

NR″

(CH₂)₃N(R″

)₂, —

NR″

(CH₂)₄N(R″

)₂, —

NR″

(CH₂)OR″

, —

NR″

(CH₂)₂OR″

, —

NR″

(CH₂)₃OR″

, or —

NR″

(CH₂)₄OR″

.

25. The compound of claim 23, wherein y is 1, 2, or 3 and each occurrence of R⁷ is independently —

F, —

Cl, —

Br, —

CN, —

OH, —

NH₂, —

CH₂OH, C₁-C₆alkyl, —

O(C₁-C₆alkyl), —

CH₂O(C₁-C₆alkyl), —

CO(C₁-C₆alkyl), —

COO(C₁-C₆alkyl), —

NHSO₂(C₁-C₆alkyl), —

SO₂NH₂, —

CONH₂, —

CON(C₁-C₆alkyl), —

SO₂(C₁-C₆alkyl), —

SO₂phenyl, phenyl, benzyl, —

N(C₁-C₆alkyl)₂, or —

S(C₁-C₆alkyl), wherein each of the foregoing phenyl, benzyl, and C₁-C₆alkyl groups is independently and optionally substituted, and wherein each of the foregoing C₁-C₆alkyl groups is linear, branched, or cyclic.

26. The compound of claim 1, wherein x is 1, 2, or 3;

at least one occurrence of R⁵ is —

N(R′

)₂, —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

(CH₂)R′

, —

NR′

(CH₂)₂R′

, —

NR′

(CH₂)N(R′

)₂, —

NR′

(CH₂)₂N(R′

)₂, —

OR′

, —

NR′

COR′

, —

NR′

COCH₂R′

, or —

NR′

CO(CH₂)₂R′

; and

R′

is a C₁-C₆aliphatic group or a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or two occurrences of R′

are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each occurrence of R′

is optionally substituted with y occurrences of R⁷, wherein v is 0-5 and R⁷ is ═

O, ═

NR″

, ═

S, halogen, —

CN, —

NO₂, or W—

R″

, wherein W is a bond or an optionally substituted C₁-C₆ alkylidene chain, wherein up to two methylene units of the chain are optionally and independently replaced by —

NR″

—

, —

S—

, —

O—

, —

CS—

, —

CO₂—

, —

OCO—

, —

CO—

, —

COCO—

, —

CONR″

—

, —

NR″

CO—

, —

NR″

CO₂—

, —

SO₂NR″

—

, —

NR″

SO₂—

, —

CONR″

NR″

—

, —

NR″

CONR″

—

, —

OCONR″

—

, —

NR″

NR″

—

, —

NR″

SO₂NR″

—

, —

SO—

, —

SO₂—

, —

PO—

, —

PO₂—

, or —

POR″

—

, and each occurrence of R″

is independently hydrogen or an optionally substituted C₁-C₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or two occurrences of R″

, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

27. The compound of claim 26, wherein R′

is hydrogen, C₁-C₆alkyl optionally substituted with 1-3 occurrences of R⁷, or is a 5-10-membered monocyclic or bicyclic saturated, partially unsaturated or fully unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring is optionally substituted with 1-3 occurrences of R⁷.

28. The compound of claim 26, wherein R′

is hydrogen, C₁-C₄alkyl optionally substituted with 1-3 occurrences of R⁷, or is a ring selected from;

29. The compound of claim 1, wherein R⁵ is —

N(R′

)₂ and the two occurrences of R′

are taken together with the nitrogen atom to which they are bound to form an optionally substituted 3-10-membered monocyclic or bicyclic heterocyclic ring. In certain embodiments, the ring is selected from;

32. The compound according to claim 1, wherein R² and R⁴ are each independently selected from —

H, —

Cl, —

Br, —

F, —

CN, —

COOH, —

COOR′

, —

NH₂, —

N(CH₃)₂, —

N(Et)₂, —

N(iPr)₂, —

NHR′

, —

OR′

, —

SR′

, —

O(CH₂)₂OCH₃, —

CONH₂, —

CONHR′

, —

CON(R′

)₂, —

OH, —

CH₂OH, CH₂NH₂, —

CH₂NHR′

, —

CH2N(R′

)₂, —

C(R′

)₂N(R′

)₂, —

NHCOCH₃, —

N(R′

)COR′

, —

SO₂NH₂, —

SO₂N(Me)₂, or an optionally substituted group selected from C₁-C₆ aliphatic, C₁-C₆ alkyloxy, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

33. The compound according to claim 32, wherein R² and R⁴ are each hydrogen.

36. The compound according to claim 1, wherein R³ is selected from H, Cl, Br, F, —

CN, —

COOH, —

COOMe, —

NH₂, —

N(R′

)₂, —

NO₂, —

OR′

, —

CON(R′

)₂, —

COOR′

, —

OH, —

SR′

, —

C(R′

)₂OR′

, —

N(R′

)COR′

, —

N(R′

)C(O)OR′

, —

SO₂NH₂, —

SO₂N(R′

)₂, or an optionally substituted group selected from C₁-C₄ aliphatic, C₁-C₄ alkyloxy or —

C═

C—

C₁-C₄ aliphatic.

37. The compound according to claim 36, wherein R³ is selected from —

H, —

Cl, —

Br, —

CN, —

COOH, —

COOMe, —

CONHR′

, —

CON(Me)₂, —

CH₂OH, —

NO₂, —

NH₂ or an optionally substituted C₁-C₄ aliphatic.

38. The compound according to claim 37, wherein R³ is selected from —

Cl, —

Br, —

CN or an optionally substituted C₁-C₄ aliphatic.

39. The compound according to claim 37, wherein R³ is —

Cl.

40. The compound according to claim 1, wherein R¹, R² and R⁴ are hydrogen and R³ is selected from —

Cl, —

Br, —

CN or an optionally substituted C₁-C₄ aliphatic.

41. The compound according to claim 37, wherein R³ is H, OR′

, NR′

C(O)R′

, NR′

C(O)OR′

, CON(R′

)₂ or COOMe.

42. The compound according to claim 37, wherein R³ is OR′

, NR′

C(O)R′

or NR′

C(O)OR′

.

43. The compound according to claim 1, wherein R¹, R² and R⁴ are hydrogen and R³ is selected from H, OR′

, NR′

C(O)R′

, NR′

C(O)OR′

, CON(R′

)₂ or COOMe.

44. The compound according to claim 1, wherein x is 1, 2, or 3;

wherein each occurrence of R⁵ is independently selected from R′

, —

CH₂R′

, halogen, CN, NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COR⁸R′

,

—

NR′

COOR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

R⁸N(R′

)₂, —

OR⁸OR′

, —

OR⁸N(R′

)₂, —

NR′

CH(R⁹)R′

, —

NR′

CH(R⁹)C(O)OR′

, —

N(R′

)R⁸R′

, —

N(R′

)R⁸R′

, —

N(R′

)R⁸N(R′

)₂, —

N(R′

)R⁸OR′

, —

NR′

CH(R⁹)R′

, —

NR′

CH₂C(O)N(R′

)₂, or —

NR′

CH(R⁹)C(O)N(R′

)₂, wherein R⁸ is an optionally substituted C₁-C₄ alkyl and R⁹ is an optionally substituted C₁-C₆ aliphatic.

45. The compound according to claim 44, wherein each occurrence of R⁵ is independently selected from R′

, —

CH₂R′

, halogen, —

CN, —

NO₂, —

N(R′

)₂, —

CH₂N(R′

)₂, —

OR′

, —

CH₂OR′

, —

SR′

, —

CH₂SR′

, —

COOR′

, —

NR′

COR′

, —

NR′

COCH₂R′

, —

NR′

CO(CH₂)₂R′

, —

NR′

COOR′

, —

CON(R′

)₂, —

SO₂N(R′

)₂, —

CONR′

(CH₂)₂N(R′

)₂, —

CONR(CH₂)₃N(R′

)₂, —

CONR′

(CH₂)₄N(R′

)₂, —

O(CH₂)₂OR′

, O(CH₂)₃OR′

, O(CH₂)₄OR′

, —

O(CH₂)₂N(R′

)₂, —

O(CH₂)₃N(R′

)₂, —

O(CH₂)₄N(R′

)₂, —

NR′

CH(CH₂OR⁹)R′

, —

NR′

CH(CH₂CH₂OR⁹)R′

, —

NR′

CH(CH₃)R′

, NR′

CH(CF₃)R′

, —

NR′

CH(CH₃)C(O)OR′

, —

NR′

CH(CF₃)C(O)OR′

, —

NR′

(CH₂)R′

, —

NR′

(CH₂)₂R′

, —

NR′

(CH₂)₃R′

, —

NR′

(CH₂)₄R′

, —

NR′

(CH₂)N(R′

)₂, —

NR′

(CH₂)₂N(R′

)₂, —

NR′

(CH₂)₃N(R′

)₂, —

NR′

(CH₂)₄N(R′

)₂, —

NR′

(CH₂)OR′

, —

NR′

(CH₂)₂OR′

, —

NR′

(CH₂)₃OR′

, —

NR′

(CH₂)₄OR′

, —

NR′

CH(CH₂CH₃)R′

, —

NR′

CH₂C(O)N(R′

)₂, —

NR′

CH(CH₃)C(O)N(R′

)₂, NR′

CH(CF₃)C(O)N(R′

)₂, —

NR′

CH(CH₂CH₃)C(O)N(R′

)₂, —

NR′

CH(CH(CH₃)₂)C(O)N(R′

)₂, —

NR′

CH(C(CH₃)₃)C(O)N(R′

)₂, —

NR′

CH(CH₂CH(CH₃)₂)C(O)N(R′

)₂, —

NR′

CH(CH₂OR⁹)C(O)N(R′

)₂ or —

NR′

CH(CH₂CH₂N(Me)₂)C(O)N(R′

)₂.

46. The compound according to claim 44, wherein at least one occurrence of R⁵ is independently selected from —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂OMe)R′

, —

NR′

CH(CH₂OEt)R′

, —

NR′

CH(CH₂OCF₃)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

CH(CH₂CH₂OMe)R′

, —

NR′

CH(CH₂CH₂OEt)R′

, —

NR′

CH(CH₂CH₂OCF₃)R′

, —

NR′

CH(CH₃)C(O)OR′

, —

NR′

CH(CF₃)C(O)OR′

, —

NR′

CH(CH₃)C(O)N(R′

)₂, —

NR′

CH(CF₃)C(O)N(R′

)₂, —

NR′

CH(CH₂CH₃)C(O)N(R′

)₂, —

NR′

CH(CH₂OH)C(O)N(R′

)₂, —

NR′

CH(CH₂OMe)C(O)N(R′

)₂, —

NR′

CH(CH₂OEt)C(O)N(R′

)₂ or —

NR′

CH(CH₂OCF₃)C(O)N(R′

)₂, wherein R′

is an optionally substituted C₁-C₄ aliphatic.

47. The compound according to claim 44, wherein said at least one occurrence of R⁵ is selected from NHCH₂C(O)NHR′

, —

NHCH(CH₃)C(O)NHR′

, —

NHCH(CH₂CH₃)C(O)NHR′

, —

NHCH(CH(CH₃)₂)C(O)NHR′

, —

NHCH(C(CH₃)₃)C(O)NHR′

, —

NHCH(CH₂CH(CH₃)₂)C(O)NHR′

, —

NHCH(CH₂OH)C(O)NHR′

, —

NHCH(CH₂OMe)C(O)NHR′

or —

NHCH(CH₂CH₂N(Me)₂)C(O)NHR′

, wherein R′

is an optionally substituted C₁-C₄ aliphatic.

48. The compound according to claim 44, wherein at least one occurrence of R⁵ is independently selected from —

NHR′

, —

NH(CH₂)R′

, —

NH(CH₂)₂R′

, —

NHCH(CH₃)R′

, —

NHCH₂C(O)NHR′

, —

NHCH(CH₃)C(O)NHR′

, —

NHCH(CH₂CH₃)C(O)NHR′

, —

NHCH(CH(CH₃)₂)C(O)NHR′

, —

NHCH(C(CH₃)₃)C(O)NHR′

, —

NHCH(CH₂CH(CH₃)₂)C(O)NHR′

, —

NHCH(CH₂OH)C(O)NHR′

, —

NHCH(CH₂OMe)C(O)NHR′

or —

NHCH(CH₂CH₂N(Me)₂)C(O)NHR′

, wherein R′

is an optionally substituted phenyl.

49. The compound according to claim 44, wherein said at least one occurrence of R⁵ is —

NHCH(CH₃)R′

, wherein R′

is optionally substituted phenyl.

50. The compound according to claim 44, wherein at least one occurrence of R⁵ is H, halogen, CH₃, CF₃, COOH, COOMe or OR′

, wherein R′

is C₁-C₄ aliphatic.

51. The compound according to claim 44, wherein x is 2 or 3 and at least one occurrence of R⁵ is F.

52. The compound according to claim 44, wherein R¹, R² and R⁴ are hydrogen and R⁵ is selected from —

NHR′

, —

NH(CH₂)R′

, —

NH(CH₂)₂R′

, —

NHCH(CH₃)R′

, —

NHCH₂C(O)NHR′

, —

NHCH(CH₃)C(O)NHR′

, —

NHCH(CH₂CH₃)C(O)NHR′

, —

NHCH(CH(CH₃)₂)C(O)NHR′

, —

NHCH(C(CH₃)₃)C(O)NHR′

, —

NHCH(CH₂CH(CH₃)₂)C(O)NHR′

, —

NHCH(CH₂OH)C(O)NHR′

, —

NHCH(CH₂OMe)C(O)NHR′

or —

NHCH(CH₂CH₂N(Me)₂)C(O)NHR′

, wherein R′

is an optionally substituted phenyl.

53. The compound according to claim 44, wherein R¹, R² and R⁴ are hydrogen and R⁵ is selected from —

NR′

CH(CH₂OH)R′

, —

NR′

CH(CH₂OMe)R′

, —

NR′

CH(CH₂OEt)R′

, —

NR′

CH(CH₂OCF₃)R′

, —

NR′

CH(CH₂CH₂OH)R′

, —

NR′

CH(CH₂CH₂OMe)R′

, —

NR′

CH(CH₂CH₂OEt)R′

, —

NR′

CH(CH₂CH₂OCF₃)R′

, —

NR′

CH(CH₃)C(O)OR′

, —

NR′

CH(CF₃)C(O)OR′

, —

NR′

CH(CH₃)C(O)N(R′

)₂, —

NR′

CH(CF₃)C(O)N(R′

)₂, —

NR′

CH(CH₂CH₃)C(O)N(R′

)₂, —

NR′

CH(CH₂OH)C(O)N(R′

)₂, —

NR′

CH(CH₂OMe)C(O)N(R′

)₂, —

NR′

CH(CH₂OEt)C(O)N(R′

)₂ or —

NR′

CH(CH₂OCF₃)C(O)N(R′

)₂, wherein R′

is an optionally substituted C₁-C₄ aliphatic.

54. The compound according to claim 1, wherein R′

is selected from hydrogen, a C₁-C₆aliphatic group optionally substituted with y occurrences of R⁷, or R′

is a ring selected from;

55. The compound according to claim 1, wherein x is 2, 3 or 4 and at least two R⁵ on adjacent ring members are R′

, and wherein said two R⁵ are taken together with the atoms to which they are bound to form an optionally substituted 3-12 membered saturated, partially saturated or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

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

59. The composition of claim 58, further comprising an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s Disease, a treatment for Parkinson'"'"'s Disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an agent for treating schizophrenia, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an agent for treating a blood disorder, or an agent for treating an immunodeficiency disorder.

61. A method of treating or alleviating a disease or disorder selected from immune responses such as allergic or type I hypersensitivity reactions or asthma;

autoimmune diseases such as transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis;

neurodegenerative disorders;

or solid and hematologic malignancies, comprising administering to a patient in need thereof a compound according to claim 1.

62. The method of claim 61, comprising the further step of administering to said patient an additional therapeutic agent.

63. The method of claim 61, wherein the disease is an autoimmune disease and is transplant rejection, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis, or multiple sclerosis.

64. The method of claim 61, wherein the disease is hypertension, angina pectoris, cerebrovascular contraction, asthma, peripheral circulation disorder, premature birth, cancer, erectile dysfunction, arteriosclerosis, spasm (cerebral vasospasm and coronary vasospasm), retinopathy (e.g., glaucoma), inflammatory disorders, autoimmune disorders, AIDS, osteoporosis, myocardial hypertrophy, ischemia/reperfusion-induced injury, or endothelial dysfunction.

65. A method of treating, preventing or lessening the severity of a disease or disorder selected from heart disease, diabetes, Alzheimer'"'"'s disease, immunodeficiency disorders, inflammatory diseases, hypertension, allergic diseases, autoimmune diseases, destructive bone disorders, osteoporosis, proliferative disorders, infectious diseases, immunologically-mediated diseases, viral diseases, hyperplasia, reperfusion/ischemia in stroke, heart attacks, organ hypoxia, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer, hepatic ischemia, myocardial infarction, congestive heart failure, pathologic immune conditions involving T cell activation, and neurodegenerative disorders comprising administering to a patient in need thereof a compound according to claim 1.

66. The method according to claim 65, wherein said cancer is selected from melanoma, lymphoma, neuroblastoma, leukemia, or a cancer selected from colon, breast, lung, kidney, ovary, endometrial, pancreatic, renal, central nervous system, cervical, prostate, or cancer of the gastric tract, CML, AML, APL, acute lymphocytic leukemia (ALL), mastocytosis or gastrointestinal stromal tumor (GIST).

11-14. -14. (canceled)

30. (canceled)

31. (canceled)

34. (canceled)

35. The compound according to claim 34, wherein R¹ is hydrogen.

56. (canceled)

57. A compound selected from:

60. (canceled)