Deazapurines useful as inhibitors of Janus kinases
First Claim
Patent Images
1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein:
- Ring A is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur linked via a carbon atom to the deazapurine, provided that there is no more than one oxygen or sulfur heteroatom in Ring A, and if there is an oxygen or sulfur heteroatom, then there are no more than two nitrogen heteroatoms in Ring A, wherein Ring A is optionally substituted with up to 1-3 occurrences of R8;
R1 is —
(C1-2aliphatic)p-R4, wherein R1 is optionally substituted with 1-3 occurrences of JR1;
R2 is —
(C1-2aliphatic)d-R2, wherein R2 is optionally substituted with 1-3 occurrences of JR2;
p and d are each independently 0 or 1;
R4 is H, halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NCH3, OCH3, —
C(═
O)NH2, —
C(═
O)CH3, —
NC(═
O)CH3, or OH;
R5 is H, halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NCH3, OCH3, —
C(═
O)NH2, —
C(═
O)CH3, —
NC(═
O)CH3, or OH;
each JR1 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2aliphatic;
or two JR1, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;
each JR2 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2aliphatic;
or two JR2, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;
R3 is —
(U)m—
X;
U is a C1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by GU and wherein U is optionally substituted with 1-4 JU;
GU is —
NH—
, —
NR6—
, —
O—
, —
S—
, —
CO2—
, —
OC(O)—
, —
C(O)CO—
, —
C(O)—
, —
C(O)NH—
, —
C(O)NR6—
, —
NC(═
N—
CN)N—
, —
NHCO—
, —
NR6CO—
, —
NHC(O)O—
, —
NR6C(O)O—
, —
SO2NH—
, —
SO2NR6—
, —
NHSO2—
, —
NR6SO2—
, —
NHC(O)NH—
, —
NR6C(O)NH—
, —
NHC(O)NR6—
, —
NR6C(O)NR6, —
OC(O)NH—
, —
OC(O)NR6—
, —
NHSO2NH—
, —
NR6SO2NH—
, —
NHSO2NR6—
, —
NR6SO2NR6—
, —
SO—
, or —
SO2—
;
R6 is C1-6 aliphatic or a C3-10cycloaliphatic;
or two R6 groups, together with the atom to which they are attached, optionally form a 3-7 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R″
, —
OR″
, —
SR″
, —
NO2, —
CF3, —
CN, —
CO2R″
, —
COR″
, OCOR″
, CONHR″
, or NHCOR″
, wherein R″
is H or an unsubstituted C1-6 aliphatic;
m is 0 or 1;
X is H, halogen, CN, NO2, S(O)R, SO2R, or a group selected from a C1-6 aliphatic, a C3-10 cycloaliphatic, a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein said group is optionally substituted with 1-4 JX;
R is an optionally substituted group selected from a C1-6 aliphatic, a C3-10cycloaliphatic, a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein R is independently and optionally substituted with 1-6 occurrences of JR;
each JR is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
, or NR′
C(O)R′
;
or two JR groups, on the same substituent or different substituents, together with the atom(s) to which each JR group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;
each JU is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
, or NR′
C(O)R′
;
or two JU groups, on the same substituent or different substituents, together with the atom(s) to which each JU group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;
each JX is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4 haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
;
each L is independently a C1-6 aliphatic wherein up to three methylene units are replaced by —
NH—
, —
NR7—
, —
O—
, —
S—
, —
CO2—
, —
OC(O)—
, —
C(O)CO—
, —
C(O)—
, —
C(O)NH—
, —
C(O)NR7—
, —
NC(═
N—
CN)N, —
NHCO—
, —
NR7CO—
, —
NHC(O)O—
, —
NR7C(O)O—
, —
SO2NH—
, —
SO2NR7—
, —
NHSO2—
, —
NR7SO2—
, —
NHC(O)NH—
, —
NR7C(O)NH—
, —
NHC(O)NR7—
, —
NR7C(O)NR7, —
OC(O)NH—
, —
OC(O)NR7—
, —
NHSO2NH—
, —
NR7SO2NH—
, —
NHSO2NR7—
, —
NR7SO2NR7—
, —
SO—
, or —
SO2—
;
each n is independently 0 or 1;
each R′
is independently H or C1-6 aliphatic;
or two R′
groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —
OR*, —
SR*, —
NO2, —
CF3, —
CN, —
CO2R*, —
COR*, OCOR*, NHCOR*, wherein R* is H or C1-6 aliphatic;
R7 is selected from C1-6 aliphatic, C3-10 cycloaliphatic, C6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
or two R7 groups, on the same substituent or different substituents, together with the atom(s) to which each R6 group is bound, form a 3-8 membered heterocyclyl;
each R8 is independently —
(C1-3 aliphatic)y-R9, wherein R8 is optionally substituted with 1-5 occurrences of JR8;
each y is independently 0 or 1;
R9 is halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NHR10, N(R10)2, OR10, C(O)OR10, —
C(O)NH2, —
C(O)R10, —
NC(O)R10, or OH;
R10 is C1-4 aliphatic;
each JR8 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2 aliphatic;
or two JR8, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;
provided that said compound is not
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Abstract
The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
-
Citations
60 Claims
-
1. A compound of formula I
or a pharmaceutically acceptable salt thereof, wherein: -
Ring A is a 5-membered monocyclic heteroaryl having 1-4 heteroatoms selected from nitrogen, oxygen, or sulfur linked via a carbon atom to the deazapurine, provided that there is no more than one oxygen or sulfur heteroatom in Ring A, and if there is an oxygen or sulfur heteroatom, then there are no more than two nitrogen heteroatoms in Ring A, wherein Ring A is optionally substituted with up to 1-3 occurrences of R8; R1 is —
(C1-2aliphatic)p-R4, wherein R1 is optionally substituted with 1-3 occurrences of JR1;R2 is —
(C1-2aliphatic)d-R2, wherein R2 is optionally substituted with 1-3 occurrences of JR2;p and d are each independently 0 or 1; R4 is H, halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NCH3, OCH3, —
C(═
O)NH2, —
C(═
O)CH3, —
NC(═
O)CH3, or OH;R5 is H, halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NCH3, OCH3, —
C(═
O)NH2, —
C(═
O)CH3, —
NC(═
O)CH3, or OH;each JR1 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2aliphatic;
or two JR1, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;each JR2 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2aliphatic;
or two JR2, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;R3 is —
(U)m—
X;U is a C1-6 aliphatic, wherein up to two methylene units are optionally and independently replaced by GU and wherein U is optionally substituted with 1-4 JU; GU is —
NH—
, —
NR6—
, —
O—
, —
S—
, —
CO2—
, —
OC(O)—
, —
C(O)CO—
, —
C(O)—
, —
C(O)NH—
, —
C(O)NR6—
, —
NC(═
N—
CN)N—
, —
NHCO—
, —
NR6CO—
, —
NHC(O)O—
, —
NR6C(O)O—
, —
SO2NH—
, —
SO2NR6—
, —
NHSO2—
, —
NR6SO2—
, —
NHC(O)NH—
, —
NR6C(O)NH—
, —
NHC(O)NR6—
, —
NR6C(O)NR6, —
OC(O)NH—
, —
OC(O)NR6—
, —
NHSO2NH—
, —
NR6SO2NH—
, —
NHSO2NR6—
, —
NR6SO2NR6—
, —
SO—
, or —
SO2—
;R6 is C1-6 aliphatic or a C3-10cycloaliphatic;
or two R6 groups, together with the atom to which they are attached, optionally form a 3-7 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R″
, —
OR″
, —
SR″
, —
NO2, —
CF3, —
CN, —
CO2R″
, —
COR″
, OCOR″
, CONHR″
, or NHCOR″
, wherein R″
is H or an unsubstituted C1-6 aliphatic;m is 0 or 1; X is H, halogen, CN, NO2, S(O)R, SO2R, or a group selected from a C1-6 aliphatic, a C3-10 cycloaliphatic, a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein said group is optionally substituted with 1-4 JX; R is an optionally substituted group selected from a C1-6 aliphatic, a C3-10cycloaliphatic, a C6-10 aryl, a 5-10 membered heteroaryl, or a 5-10 membered heterocyclyl, wherein R is independently and optionally substituted with 1-6 occurrences of JR; each JR is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
, or NR′
C(O)R′
;
or two JR groups, on the same substituent or different substituents, together with the atom(s) to which each JR group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;each JU is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
, or NR′
C(O)R′
;
or two JU groups, on the same substituent or different substituents, together with the atom(s) to which each JU group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring;each JX is independently selected from halogen, L, -(Ln)-R′
, -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-10 cycloaliphatic), -(Ln)-(C6-10 aryl), -(Ln)-(5-10 membered heteroaryl), -(Ln)-(5-10 membered heterocyclyl), oxo, C1-4haloalkoxy, C1-4 haloalkyl, -(Ln)-NO2, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, C(O)N(R′
)2, —
NHC(O)R′
;each L is independently a C1-6 aliphatic wherein up to three methylene units are replaced by —
NH—
, —
NR7—
, —
O—
, —
S—
, —
CO2—
, —
OC(O)—
, —
C(O)CO—
, —
C(O)—
, —
C(O)NH—
, —
C(O)NR7—
, —
NC(═
N—
CN)N, —
NHCO—
, —
NR7CO—
, —
NHC(O)O—
, —
NR7C(O)O—
, —
SO2NH—
, —
SO2NR7—
, —
NHSO2—
, —
NR7SO2—
, —
NHC(O)NH—
, —
NR7C(O)NH—
, —
NHC(O)NR7—
, —
NR7C(O)NR7, —
OC(O)NH—
, —
OC(O)NR7—
, —
NHSO2NH—
, —
NR7SO2NH—
, —
NHSO2NR7—
, —
NR7SO2NR7—
, —
SO—
, or —
SO2—
;each n is independently 0 or 1; each R′
is independently H or C1-6 aliphatic;
or two R′
groups, together with the atom to which they are attached, optionally form a 3-6 membered cycloaliphatic or heterocyclyl, wherein said aliphatic, cycloaliphatic or heterocyclyl is optionally substituted with R*, —
OR*, —
SR*, —
NO2, —
CF3, —
CN, —
CO2R*, —
COR*, OCOR*, NHCOR*, wherein R* is H or C1-6 aliphatic;R7 is selected from C1-6 aliphatic, C3-10 cycloaliphatic, C6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl;
or two R7 groups, on the same substituent or different substituents, together with the atom(s) to which each R6 group is bound, form a 3-8 membered heterocyclyl;each R8 is independently —
(C1-3 aliphatic)y-R9, wherein R8 is optionally substituted with 1-5 occurrences of JR8;each y is independently 0 or 1; R9 is halogen, CN, NH2, NO2, CF3, C1-4 aliphatic, cyclopropyl, NHR10, N(R10)2, OR10, C(O)OR10, —
C(O)NH2, —
C(O)R10, —
NC(O)R10, or OH;R10 is C1-4 aliphatic; each JR8 is independently selected from halogen, OCH3, OH, NO2, NH2, SCH3, NCH3, CN, or unsubstituted C1-2 aliphatic;
or two JR8, together with the carbon to which they are attached, form a cyclopropyl ring or C═
O;provided that said compound is not - View Dependent Claims (8, 9, 12, 17, 18, 23, 24, 27, 30, 31, 34, 38, 39, 44, 45, 48, 51, 52, 53, 54, 55, 56, 57, 58, 59)
wherein Ring A is optionally substituted with 1-3 occurrences of R8.
-
-
9. The compound according to claim 8, wherein Ring A is selected from the following:
-
wherein Ring A is optionally substituted with 1-3 occurrences of R8.
-
-
12. The compound according to claim 8, wherein Ring A is selected from
wherein Ring A is optionally substituted with 1-3 occurrences of R8. -
17. The compound according to claim 1, wherein R3 is not H.
-
18. The compound according to claim 17, wherein m is 1 and U is selected from C(O)NH, C(O)NR6, NHC(O), NR6C(O), C(O), C(O)O, C(O)NH(CH2)1-3, C(O)NR6 (CH2)1-3, NHC(O)(CH2)1-3, NR6C(O)(CH2)1-3, C(O)(CH2)1-3, C(O)O(CH2)1-3, (CH2)1-3C(O)NH, (CH2)1-3C(O)NR6, (CH2)1-3NHC(O), (CH2)1-3NR6C(O), (CH2)1-3C(O) or (CH2)1-3C(O)O.
-
23. The compound according to claim 17, wherein m is 0.
-
24. The compound according to claim 1, wherein X is a group selected from a C1-6 aliphatic, a C3-7 cycloaliphatic, a C6-10 aryl, a 5-8 membered heteroaryl, or a 5-8 membered heterocyclyl, wherein said group is optionally substituted with 1-4 JX.
-
27. The compound according to claim 1, wherein each JX is independently selected from halogen, R′
- , -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-6 cycloaliphatic), oxo, C1-4haloalkyl, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, or —
NC(O)R′
.
- , -(Ln)-N(R′
-
30. The compound according to claim 1, having formula II
or a pharmaceutically acceptable salt thereof. -
31. The compound according to claim 30, wherein Ring A is selected from the following:
-
wherein Ring A is optionally substituted with 1-3 occurrences of R8.
-
-
34. The compound according to claim 30, wherein Ring A is selected from
wherein Ring A is optionally substituted with 1-3 occurrences of R8. -
38. The compound according to claim 30, wherein R3 is not H.
-
39. The compound according to claim 38, wherein m is 1 and U is selected from C(O)NH, C(O)NR6, NHC(O), NR6C(O), C(O), C(O)O, C(O)NH(CH2)1-3, C(O)NR6(CH2)1-3, NHC(O)(CH2)1-3, NR6C(O)(CH2)1-3, C(O)(CH2)1-3, C(O)O(CH2)1-3, (CH2)1-3C(O)NH, (CH2)1-3C(O) NR6, (CH2)1-3NHC(O), (CH2)1-3NR6C(O), (CH2)1-3C(O) or (CH2)1-3C(O)O.
-
44. The compound according to claim 38, wherein m is 0.
-
45. The compound according to claim 30, wherein X is a group selected from a C1-6 aliphatic, a C3-7 cycloaliphatic, a C6-10 aryl, a 5-8 membered heteroaryl, or a 5-8 membered heterocyclyl, wherein said group is optionally substituted with 1-4 JX.
-
48. The compound according to claim 30, wherein each JX is independently selected from halogen, R′
- , -(Ln)-N(R′
)2, -(Ln)-SR′
, -(Ln)-OR′
, -(Ln)-(C3-6 cycloaliphatic), oxo, C1-4haloalkyl, -(Ln)-CN, -(Ln)-OH, -(Ln)-CF3, —
CO2R′
, —
CO2H, —
COR′
, —
COH, —
OC(O)R′
, —
C(O)NHR′
, or —
NC(O)R′
;
or two JX groups, on the same substituent or different substituents, together with the atom(s) to which each JX group is bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring.
- , -(Ln)-N(R′
-
51. A compound according to claim 1, selected from Table 1.
-
52. A compound according to claim 1, selected from Table 2.
-
53. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
-
54. The composition according to claim 53, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, 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 anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders.
-
55. A method of inhibiting JAK kinase activity in a biological sample, comprising contacting said biological sample with a compound according to claim 1 or with a composition comprising said compound.
-
56. A method of inhibiting JAK kinase activity in a patient, comprising administering to said patient a compound according to claim 1 or with a composition comprising said compound.
-
57. A method of treating or lessening the severity of a disease of condition selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to said patient a compound according to claim 1 or with a composition comprising said compound.
-
58. The method of claim 57, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein said additional therapeutic agent is appropriate for the disease being treated.
-
59. The method according to claim 58, wherein the disease or disorder is allergic or type I hypersensitivity reactions, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia, stroke, baldness, transplant rejection, graft versus host disease, rheumatoid arthritis, a solid malignancy, a hematologic malignancy, a leukemia, a lymphoma and a myeloproliferative disorder.
-
2-7. -7. (canceled)
-
10-11. -11. (canceled)
-
13-16. -16. (canceled)
-
19-22. -22. (canceled)
-
25-26. -26. (canceled)
-
28-29. -29. (canceled)
-
32-33. -33. (canceled)
-
35-37. -37. (canceled)
-
40-43. -43. (canceled)
-
46-47. -47. (canceled)
-
49-50. -50. (canceled)
-
60-64. -64. (canceled)
Specification