Compounds Useful as Antagonists of CCR2

• US 20090197884A1
• Filed: 10/26/2006
• Published: 08/06/2009
• Est. Priority Date: 11/01/2005
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Soucy, Francois, Ye, Qing, Ghosh, Shomir, Raman, Prakash, Sprott, Kevin, Elder, Amy M., Griffiths, Sian
• Granted Patent: US 8,067,457 B2
• Time in Patent Office: Days
• US Class Current: 514/235.5
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 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: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides compounds of general formula I: or a pharmaceutically acceptable salt thereof, wherein X, n, Y, and R1 are defined generally and in subsets herein. Compounds of the invention are inhibitors of CCR2 and accordingly are useful for the treatment of a variety of inflammatory, allergic, and autoimmune diseases, disorders, or conditions.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein;

n is 1 or 2;

Y is —

Y₁-Y₂—

, or —

Y₃-Y₄—

wherein;

Y₁ is —

SO₂N(R′

)—

, —

C(O)N(R′

)—

;

—

C(O)N(R′

)C(O)—

, —

N(R′

)SO₂—

, or —

N(R′

)SO₂N(R′

)—

,

Y₂ is absent or is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₂ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

, or wherein Y₂, or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y₃ is —

N(R′

)C(O)—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)C(O)O—

; and

Y₄ is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₄ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

,

each R′

is independently hydrogen or optionally substituted C_1-6aliphatic;

R¹ is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is substituted at one or more carbon atoms with m independent occurrences of R²;

m is 0-6;

each occurrence of R² is independently halogen, ═

O, ═

S, —

CN, —

R^2b, —

N(R^2a)₂, —

OR^2a, —

SR^2b, —

S(O)₂R^2b, —

C(O)R^2a, —

C(O)OR^2a, —

C(O)N(R^2a)₂, —

S(O)₂N(R^2a)₂, —

OC(O)N(R^2a)₂, —

N(R′

)C(O)R^2a, —

N(R′

)SO₂R^2b, —

N(R′

)C(O)OR^2a, —

N(R′

)C(O)N(R^2a)₂, or —

N(R′

)SO₂N(R^2a)₂, or two occurrences of R^2a or R^2b are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^2a, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^2a is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^2b is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring B is substituted with r independent occurrences of —

R³;

r is 0-6;

each occurrence of R³ is independently —

R^3a, -T₁-R^3d, or —

V₁-T₁-R^3d, wherein;

each occurrence of —

R^3a independently halogen, —

CN, —

NO₂, —

R^3c, —

N(R^3b)₂, —

OR^3b, —

SR^3c, —

S(O)₂R^3c, —

C(O)R^3b, —

C(O)OR^3b, —

C(O)N(R^3b)₂, —

S(O)₂N(R^3b)₂, —

OC(O)N(R^3b)₂, —

N(R′

)C(O)R^3b, —

N(R′

)SO₂R^3c, —

N(R′

)C(O)OR^3b, —

N(R′

)C(O)N(R^3b)₂, or —

N(R′

)SO₂N(R^3b)₂, or two occurences of R^3b or R^3c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^3b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 611-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3d is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)O—

;

each occurrence of T₁ is independently C_1-6 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

X is —

O—

, —

S—

, —

SO₂—

, or —

N(W—

R⁴)—

;

W is absent or is a group selected from —

W₁-L₂-W₂—

, wherein W₁ and W₂ are each independently absent or are an optionally substituted C_1-3alkylene chain, and L₂ is absent or is a group selected from —

N(R)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R)—

, —

S(O)₂N(R)—

, —

OC(O)N(R)—

, —

N(R)C(O)—

, —

N(R)SO₂—

, —

N(R)C(O)O—

, —

N(R)C(O)N(R)—

, —

N(R)SO₂N(R)—

, —

OC(O)—

, or —

C(O)N(R)—

O—

, wherein R is hydrogen or C₁-C₄alkyl, provided that if W₁ is absent then L₂ is selected from —

C(O)—

, —

C(O)O—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R)—

, or —

S(O)₂N(R)—

R⁴ is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

provided that the compound is other than;

a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-;

d) 4-Morpholinebutanamide, N[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo;

e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride;

f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

g) Benzeneacetamide, 3,4-difluoro-α

-1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl), (α

S)—

;

i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl)-, (α

R)-;

j) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-;

k) [1,4′

-Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′

-propyl-;

l) [1,4′

-Bipiperidine]-3-carboxamide, N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-1′

-(phenylmethyl)-;

m) [1,4′

-Bipiperidine]-3-carboxamide, 1′

-[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)-;

n) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and

o) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-.

2. The compound of claim 1, wherein n is 1 and the compound has the structure of formula I-A:

3. The compound of claim 2, wherein r is 0, 1, or 2.

4. The compound of claim 3, wherein r is 1 and the compound has the structure of formula I-B:

5. The compound of claim 3, wherein r is 2 and the compound has the structure of I-B-i:

wherein the two occurrences of R³, taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring.

6. The compound of claim 4 or 5, wherein R¹ is an optionally substituted aryl group.

7. The compound of claim 5, wherein R¹ is an optionally substituted phenyl group.

8. The compound of claim 4 or 5, wherein R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S.

9. The compound of claim 8, wherein R¹ is an optionally substituted group selected from:

10. The compound of claim 8, wherein R¹ is an optionally substituted group selected from:

11. The compound of claims 4 or 5, wherein:

R¹ is an optionally substituted aryl group or R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, and

R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, ═

S, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)₂R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

12. The compound of claim 11, wherein each occurrence of R^1a is independently ═

O, halogen, —

R^1c, —

N(R^1b)₂, —

OR^1b, or —

SR^1c.

13. The compound of claim 11, wherein each occurrence of R^1a is independently C_1-4fluoroalkyl, —

O(C_1-4fluoroalkyl), or —

S(C_1-4fluoroalkyl).

14. The compound of claim 4 or 5, wherein Y is —

Y₁-Y₂ and Y₁ is —

SO₂N(R′

)—

, —

C(O)NR′

—

, or —

N(R′

)S(O)₂—

.

15. The compound of claim 4 or 5, wherein Y is —

Y₃-Y₄—

, - and Y₃ is —

N(R′

)C(O)—

.

16. The compound of claim 4 or 5, wherein Y is selected from:

17. The compound of claim 4 or 5, wherein X is O.

18. The compound of claim 4 or 5, wherein X is —

N(W—

R⁴).

19. The compound of claim 4 or 5, wherein X is O, m is 1, and R² is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

20. The compound of claim 4 or 5, wherein X is —

N(W—

R⁴) and R⁴ is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

21. The compound of claim 4 or 5, wherein X is —

N(W—

R⁴), W is absent and R⁴ is optionally substituted phenyl.

22. The compound of claim 4 or 5, wherein:

X is —

N(W—

R⁴) and R⁴ is an optionally substituted group selected from a monocyclic 3-8-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or X is —

N(W—

R⁴), W is absent and R⁴ is optionally substituted phenyl, wherein;

R⁴ is optionally substituted with 1-3 occurrences of R^4a and each occurrence of R^4a is independently —

R^4b, -T₁-R^4e, or —

V₁-T₁-R^4e, wherein each occurrence of —

R^4b is independently halogen, —

CN, —

NO₂, —

R^4d, —

N(R^4c)₂, —

OR^4c, —

SR^4d, —

S(O)₂R^4d, —

C(O)R^4c, —

C(O)OR^4c, —

C(O)N(R^4c)₂, —

S(O)₂N(R^4c)₂, —

OC(O)N(R^4c)₂—

N(R′

)C(O)R^4c, —

N(R′

)SO₂R^4d, —

N(R′

)C(O)OR^4c, —

N(R′

)C(O)N(R^4c)₂, or —

N(R′

)SO₂N(R^4c)₂, or two occurences of —

R^4b, —

R^4c or —

R^4d are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^4c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4c is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4d is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4e is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

;

each occurrence of T₁ is independently C_1-4 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

23. The compound of claim 21, wherein the phenyl group is substituted with 1 or 2 occurrences of R^4a, wherein each occurrence of R^4a is independently halogen, —

CN, —

C(O)N(R^4c)₂, —

O(R^4c), —

S(R^4d), —

N(R^4c)₂, —

C(O)O-T₁-R^4e, —

R^4d, or wherein two occurrences of R^4b, taken together with their intervening atoms, form a 5-6-membered spiro or fused carbocyclic or heterocyclyl ring.

24. The compound of claim 4 or 5, wherein R³ is —

OR^3b, —

SR^3c, —

V₁-T₁-R^3d, or T₁-R^3d, wherein V₁ is O or S, and T₁ is —

CH₂—

or —

CH₂—

CH₂—

.

25. The compound of claim 24, wherein R^3b, R^3c, and R^3d are each independently an optionally substituted group selected from C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

26. The compound of claim 25, wherein R^3b, R^3c, and R^3d are each independently optionally substituted C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, or an optionally substituted group selected from:

27. The compound of claim 24, wherein R^3b, R^3c, and R^3d are each independently an optionally substituted ring selected from bicyclic 8-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur or 8-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

28. The compound of claim 27, wherein R^3b, R^3c, and R^3d are each independently optionally substituted with 1-3 occurrences of R^3e, wherein R^3e is R^f, halogen, —

N(R^g)₂, —

OR^g, —

SR^f, —

S(O)₂R^f, —

COR^f, —

COOR^g, —

CON(R^g)₂, —

CON(R^g)₂, —

C(O)₂N C(O)N(R^g)₂, —

NR′

C(O)R^f, —

NR′

S(O)₂R^f, wherein R^f is an optionally substituted C_1-6 aliphatic group and R^g is hydrogen or an optionally substituted C_1-6 aliphatic group.

29. The compound of claim 28, wherein R^3b, R^3c, and R^3d are each independently optionally substituted with 1-3 occurrences of R^3e, wherein R^3e is C_1-4aliphatic, C_1-4haloaliphatic, or halogen.

30. The compound of claim 5, wherein r is 2 and two occurrences of R³, taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring selected from:

31. The compound of claim 4, wherein the compound has the structure of formula I-C:

32. The compound of claim 31, wherein X is O and the compound has the structure of formula I-D:

wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, ═

S, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)₂CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0 or 1, and when m is 1 R² is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

d) R³ is —

OR^3b, —

SR^3c, —

V₁-T₁-R^3d, or T₁-R^3d, wherein V₁ is O or S, and T₁ is —

CH₂—

or —

CH₂—

CH₂—

, wherein R^3b, R^3c, and R^3d are each independently an optionally substituted group selected from C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

33. The compound of claim 32, wherein:

a) R¹ is an optionally substituted group selected from;

and each occurrence of R^1a is independently ═

O, halogen, —

R^1c, —

N(R^1b)₂, —

OR^1b, or —

R^1c; and

b) R^3b, R^3c, and R^3d are each independently optionally substituted C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, or an optionally substituted group selected from;

wherein R^3b, R^3c, and R^3d are each independently optionally substituted with 1-3 occurrences of R^3e, wherein R^3e is C_1-4aliphatic, C_1-4haloaliphatic, or halogen.

34. The compound of claim 31, wherein X is N(W—

R⁴), and the compound has the structure of formula I-E;

wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)₂CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0;

d) R³ is —

OR^3b, —

SR^3c, —

V₁-T₁-R^3d, or T₁-R^3d, wherein V₁ is O or S, and T₁ is —

CH₂—

or —

CH₂—

CH₂—

, wherein R^3b, R^3c, and R^3d are each independently an optionally substituted group selected from C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

e) W is absent, and

f) R⁴ is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

35. The compound of claim 31, wherein X is N(W—

R⁴), and the compound has the structure of formula I-E;

wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)₂R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)₂CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0;

d) R³ is —

OR^3b, —

SR^3c, —

V₁-T₁-R^3d, or T₁-R^3d, wherein V₁ is O or S, and T₁ is —

CH₂—

or CH₂—

CH₂—

, wherein R^3b, R^3c, and R^3d are each independently an optionally substituted group selected from C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, 5-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

e) W is absent, and

f) R⁴ is optionally substituted phenyl.

36. The compound of claim 34 or 35, wherein R⁴ is optionally substituted with 1-3 occurrences of R^4a each occurrence of R^4a is independently —

R^4b, -T₁-R^4c, or —

V₁-T₁-R^4e, wherein;

each occurrence of —

R^4b is independently halogen, —

CN, —

NO₂, —

R^4d, —

N(R^4c)₂, —

R^4c, —

SR^4d, —

S(O)₂R^4d, —

C(O)R^4c, —

C(O)OR^4c, —

C(O)N(R^4c)₂, —

S(O)₂N(R^4c)₂, —

OC(O)N(R^4c)₂, —

N(R′

)C(O)R^4c, —

N(R′

)SO₂R^4d, —

N(R′

)C(O)OR^4c, —

N(R′

)C(O)N(R^4c)₂, or —

N(R′

)SO₂N(R^4c)₂, or two occurences of —

R^4b, —

R^4c or —

R^4d are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^4c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4c is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4d is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4e is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

; and

each occurrence of T₁ is independently C_1-6 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring.

37. The compound of claim 34 or 35, wherein:

a) R¹ is an optionally substituted group selected from;

and each occurrence of R^1a is independently ═

O, halogen, —

R^1c, —

N(R^1b)₂, —

OR^1b, or —

SR^1c; and

b) R^3b, R^3c, and R^3d are each independently optionally substituted C_1-4alkenyl, C_1-4alkynyl, C_1-4alkyl, or an optionally substituted group selected from;

wherein R^3b, R^3c, and R^3d are each independently optionally substituted with 1-3 occurrences of R^3e, wherein R^3e is C_1-4aliphatic, C_1-4haloaliphatic, or halogen.

38. The compound of claim 5, having the structure of formula I-F:

or a pharmaceutically acceptable salt thereof,

wherein the two occurrences of R³, taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring.

39. The compound of claim 38, wherein X is O and the compound has the structure of formula I-G:

or a pharmaceutically acceptable salt thereof, wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, ═

S, —

CN, —

NO₂, —

R^1c, —

N(R′

)₂, —

OR^1b, —

SR^1c, —

S(O)₂)R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)₂CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0 or 1, and when m is 1 R² is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

d) wherein the two occurrences of R³, taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring.

40. The compound of claim 39, wherein:

a) R¹ is an optionally substituted group selected from;

and each occurrence of R^1a is independently ═

O, halogen, —

R^1c, —

N(R^1b)₂, OR^1b, or SR^1c; and

b) the spiro ring formed from the two occurrences of R³ is an optionally substituted ring selected from;

41. The compound of claim 38, wherein X is N(W—

R⁴), and the compound has the structure of formula I-H;

or a pharmaceutically acceptable salt thereof, wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R^1b)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0;

d) wherein the two occurrences of R³, taken together, form an optionally substituted 3-6-membered spiro carbocyclic or heterocyclic ring;

e) W is absent, and

f) R⁴ is an optionally substituted group selected from a monocyclic 3-7-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a bicyclic 7-10-membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

42. The compound of claim 38, wherein X is N(W—

R⁴), and the compound has the structure of formula I-H;

or a pharmaceutically acceptable salt thereof, wherein;

a) R¹ is an optionally substituted 5-8-membered monocyclic or 7-10-membered bicyclic heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from N, O, or S, wherein R¹ is optionally substituted with 1-3 occurrences of R^1a, wherein each occurrence of R^1a is independently halogen, ═

O, —

CN, —

NO₂, —

R^1c, —

N(R^1b)₂, —

OR^1b, —

SR^1c, —

S(O)R^1c, —

C(O)R^1b, —

C(O)OR^1b, —

C(O)N(R^1b)₂, —

S(O)₂N(R^1b)₂, —

OC(O)N(R^1b)₂, —

N(R′

)C(O)R^1b, —

N(R′

)SO₂R^1c, —

N(R′

)C(O)OR^1b, —

N(R′

)C(O)N(R′

)₂, or —

N(R′

)SO₂N(R^1b)₂, or two occurences of R^1b or R^1c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur or two occurrences of R^1b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur, wherein;

each occurrence of R^1b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and

each occurrence of R^1c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b) Y is —

NH(CO)CH₂—

, —

NHS(O)₂CH₂, —

NHC(O)—

, —

NH(CO)CH₂NH—

, or —

NHS(O)₂—

;

c) m is 0;

d) the spiro ring formed from the two occurrences of R³ is an optionally substituted ring selected from;

e) W is absent, and

f) R⁴ is optionally substituted phenyl.

43. The compound of claim 41 or 42, wherein R⁴ is optionally substituted with 1-3 occurrences of R^4a and each occurrence of R^4a is independently —

R^4b, -T₁-R^4e, or —

V₁-T₁-R^4e, wherein;

each occurrence of —

R^4b is independently halogen, —

CN, —

NO₂, —

R^4d, —

N(R^4c)₂, —

OR^4c, —

SR^4d, —

S(O)₂R^4d, —

C(O)R^4c, —

C(O)OR^4c, —

C(O)N(R^4c)₂, —

S(O)₂N(R^4c)₂, —

OC(O)N(R^4c)₂, —

N(R′

)C(O)R^4c, —

N(R′

)SO₂R^4d, —

N(R′

)C(O)OR^4c, —

N(R′

)C(O)N(R^4c)₂, or —

N(R′

)SO₂N(R^4c)₂, or two occurrences of R^4b, R^4c or R^4d are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^4c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4c is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4d is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^4e is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

; and

each occurrence of T₁ is independently C_1-6 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring.

44. The compound of claim 41 or 42, wherein:

a) R¹ is an optionally substituted group selected from;

and each occurrence of R^1a is independently ═

O, halogen, —

R^1c, —

N(R^1b)₂, —

OR^1b, or SR^1c; and

b) the spiro ring formed from the two occurrences of R³ is an optionally substituted ring selected from;

45. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

n is 1 or 2;

Y is —

Y₁-Y₂—

, or —

Y₃-Y₄—

wherein;

Y₁ is —

SO₂N(R′

)—

, —

C(O)N(R′

)—

, —

C(O)N(R′

)C(O)—

, —

N(R′

)SO₂—

, or —

N(R′

)SO₂N(R′

)—

,

Y₂ is absent or is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₂ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

, or wherein Y₂, or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 54 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y₃ is —

N(R′

)C(O)—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)C(O)O—

; and

Y₄ is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₄ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

,

each R′

is independently hydrogen or optionally substituted C_1-6aliphatic;

R¹ is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is substituted at one or more carbon atoms with m independent occurrences of R²;

m is 0-6;

each occurrence of R² is independently halogen, ═

O, ═

S, —

CN, —

R^2b, —

N(R^2a)₂, —

OR^2a, —

SR^2b, —

S(O)₂R^2b, —

C(O)R^2a, —

C(O)OR^2a, —

C(O)N(R^2a)₂, —

S(O)₂N(R^2a)₂, —

OC(O)N(R^2a)₂, —

N(R′

)C(O)R^2a, —

N(R′

)SO₂R^2b, —

N(R′

)C(O)OR^2a, —

N(R′

)C(O)N(R^2a)₂, or —

N(R′

)SO₂N(R^2a)₂, or two occurences of R^2a or R^2b are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^2a, taken together with the nitrogen atom to which they are bound, from an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^2a is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^2b is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring B is substituted with r independent occurrences of —

R³;

r is 0-6;

each occurrence of R³ is independently —

R^3a, -T₁-R^3d, or —

V₁-T₁-R^3d, wherein;

each occurrence of —

R^3a is independently halogen, —

CN, —

NO₂, —

R^3c, —

N(R^3b)₂, —

OR^3b, —

SR^3c, —

S(O)₂R^3c, —

C(O)R^3b, —

C(O)OR^3b, —

C(O)N(R^3b)₂, —

S(O)₂N(R^3b)₂, —

OC(O)N(R^3b)₂, —

N(R′

)C(O)R^3b, —

N(R′

)SO₂R^3c, —

N(R′

)C(O)OR^3b, —

N(R′

)C(O)N(R^3b)₂, or —

N(R′

)SO₂N(R^3b)₂, or two occurences of R^3b or R^3c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^3b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3d is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

;

each occurrence of T₁ is independently C_1-6 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

X is —

O—

, —

S—

, —

SO₂—

, or —

N(W—

R⁴)—

;

W is absent or is a group selected from —

W₁-L₂-W₂—

, wherein W₁ and W₂ are each independently absent or are an optionally substituted C_1-3alkylene chain, and L₂ is absent or is a group selected from —

N(R)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R)—

, —

S(O)₂N(R)—

, —

OC(O)N(R)—

, —

N(R)C(O)—

, —

N(R)SO₂—

, —

N(R)C(O)O—

, —

N(R)C(O)N(R)—

, —

N(R)SO₂N(R)—

, —

OC(O)—

, or —

C(O)N(R)O—

, wherein R is hydrogen or C₁-C₄alkyl, provided that if W₁ is absent then L₂ is selected from —

C(O)—

, —

C(O)O—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R), or (O)₂N(R)—

R⁴ is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

provided that the compound is other than;

a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

b) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-;

d) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo;

e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride;

f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

g) Benzeneacetamide, 3,4-difluoro-α

-(1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl)-, ((α

S)—

;

i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl)-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl), (α

R)-;

j) 11,4′

-Bipiperidine]-3-carboxamide, 1′

-[(2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl)-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)-;

k) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and

l) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-.

46. A method for treating an inflammatory disorder comprising administering to a subject an effective amount of a compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:

n is 1 or 2;

Y is —

Y₁-Y₂—

, or —

Y₃-Y₄—

wherein;

Y₁ is —

SO₂N(R′

)—

, —

C(O)N(R′

)—

;

—

C(O)N(R′

)C(O)—

, —

N(R′

)SO₂—

, or —

N(R′

)SO₂N(R′

)—

,

Y₂ is absent or is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₂ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

, or wherein Y₂, or a portion thereof, is an optionally substituted ring selected from 3-6-membered cycloaliphatic, 3-6-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-membered aryl, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

Y₃ is —

N(R′

)C(O)—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)C(O)O—

; and

Y₄ is an optionally substituted C_1-6 alkylene chain, wherein one or two methylene units of Y₄ are optionally and independently interrupted by —

O—

, —

S—

, —

N(R′

)—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

N(R′

)S(O)₂—

, or —

S(O)₂N(R′

)—

,

each R′

is independently hydrogen or optionally substituted C_1-6aliphatic;

R′

is an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring A is substituted at one or more carbon atoms with m independent occurrences of R²;

m is 0-6;

each occurrence of R² is independently halogen, ═

O, ═

S, —

CN, —

R^2b, —

N(R^2a)₂, —

OR^2a, —

SR^2b, —

(O)₂R^2b—

C(O)R^2a, —

C(O)OR^2a, —

C(O)N(R^2a)₂, —

S(O)₂N(R^2a)₂, —

OC(O)N(R^2a)₂, —

N(R′

)C(O)R^2a, —

N(R′

)SO₂R^2b, —

N(R′

)C(O)OR^2a, —

N(R′

)C(O)N(R^2a)₂, or —

N(R′

)SO₂N(R^2a)₂, or two occurences of R^2a or R^2b are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^2a, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^2a is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

each occurrence of R^2b is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

ring B is substituted with r independent occurrences of —

R³;

r is 0-6;

each occurrence of R³ is independently —

R^3a, -T₁-R^3d, or —

V₁-T₁-R^3d, wherein;

each occurrence of —

R^3a is independently halogen, —

CN, —

NO₂, —

R^3c, —

N(R^3b)₂, —

OR^3b, —

SR^3c, —

S(O)₂R^3c, —

C(O)R^3b, —

C(O)OR^3b, —

C(O)N(R^3b)₂, —

S(O)₂N(R^3b)₂, —

OC(O)N(R^3b)₂, —

N(R′

)C(O)R^3b, —

N(R′

)SO₂R^3c, —

N(R′

)C(O)OR^3b, —

N(R′

)C(O)N(R^3b)₂, or —

N(R′

)SO₂N(R^3b)₂, or two occurences of R^3b or R^3c are optionally taken together with their intervening atom(s) to form an optionally substituted spiro, fused, or bridged ring selected from 6-membered aryl, 3-6-membered cycloaliphatic, 3-7-membered heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6-membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two occurrences of R^3b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring having 1-3 additional heteroatoms selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3b is independently hydrogen or an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3c is independently an optionally substituted group selected from C_1-6aliphatic, 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of R^3d is independently an optionally substituted group selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each occurrence of V₁ is independently —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

;

each occurrence of T₁ is independently C_1-6 alkylene chain optionally substituted with R^3a, wherein the alkylene chain optionally is interrupted by —

C(R′

)═

C(R′

)—

, —

C≡

C—

, —

N(R′

)—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R′

)—

, —

S(O)₂N(R′

)—

, —

OC(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)SO₂—

, —

N(R′

)C(O)O—

, —

NR′

C(O)N(R′

)—

, —

N(R′

)SO₂N(R′

)—

, —

OC(O)—

, or —

C(O)N(R′

)—

O—

or wherein T¹ or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;

X is —

O—

, —

S—

, —

SO₂—

, or —

N(W—

R⁴)—

;

W is absent or is a group selected from —

W₁-L₂-W₂—

, wherein W₁ and W₂ are each independently absent or are an optionally substituted C_1-3alkylene chain, and L₂ is absent or is a group selected from —

N(R)—

, —

O—

, —

S—

, —

S(O)₂—

, —

S(O)₂—

, —

C(O)—

, —

C(O)O—

, —

C(O)N(R)—

, —

S(O)₂N(R)—

, —

OC(O)N(R)—

, —

N(R)C(O)—

, —

N(R)SO₂—

, —

N(R)C(O)O—

, —

N(R)C(O)N(R)—

, —

N(R)SO₂N(R)—

, —

OC(O)—

, or —

C(O)N(R)O—

, wherein R is hydrogen or C₁-C₄alkyl, provided that if W₁ is absent then L₂ is selected from —

C(O)—

, —

C(O)O—

, —

C(O)O—

, —

S(O)—

, —

S(O)₂—

, —

C(O)N(R)—

, or —

S(O)₂N(R)—

R⁴ is an optionally substituted monocyclic or bicyclic ring selected from 3-10-membered cycloaliphatic, 3-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

provided that the compound is other than;

a) 4-Morpholinebutanamide, N-[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

b) 4-Morpholinebutaniamide, N-[3-cyano-1-(tetrahydro-2H-thiopyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo-;

c) 4-Morpholinecarboxamide, N-[(1S)-2-[[3-cyano-1-(1-methyl-4-piperidinyl)-3-pyrrolidinyl]amino]-1-(cyclohexylmethyl)-2-oxoethyl]-;

d) 4-Morpholinebutanamide, N[3-cyano-1-(tetrahydro-2H-pyran-4-yl)-3-pyrrolidinyl]-α

-(cyclohexylmethyl)-γ

-oxo;

e) Benzeneacetamide, N-[(3S)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-, monohydrochloride;

f) Benzeneacetamide, 3,4-difluoro-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

g) Benzeneacetamide, 3,4-difluoro-α

-(1-methylethyl)-N-[(3R)-1-[1-(2-nitrophenyl)-4-piperidinyl]-3-pyrrolidinyl]-, hydrochloride;

h) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl)-, (α

S)—

;

i) Benzeneacetamide, N-[(3R)-1-[1-(2-cyanophenyl)-4-piperidinyl]-3-pyrrolidinyl]-3,4-difluoro-α

-(1-methylethyl)-, ((α

R)-;

j) [1,4′

-Bipiperidine]-3-carboxamide, 1′

-[[2,6-bis(4-chlorophenyl)-4-pyridinyl]carbonyl]-N-methyl-N-(1-methyl-4-piperidinyl)-, (3R)-;

k) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-, monohydrochloride; and

l) Benzeneacetamide, N-[1′

-(2-cyanophenyl)[1,4′

-bipiperidin]-3-yl]-3,4-difluoro-.

47. The method of claim 46, wherein the disorder is rheumatoid arthritis, multiple sclerosis, scleroderma, atherosclerosis, neuropathic pain, and type II diabetes.

48. The method of claim 47, wherein the disorder is rheumatoid arthritis or multiple sclerosis.