omega-Carboxy Aryl Substituted Diphenyl Ureas As p38 Kinase Inhibitors

• US 20080027061A1
• Filed: 08/27/2007
• Published: 01/31/2008
• Est. Priority Date: 01/13/1999
• Status: Active Grant

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Lowinger, Timothy, Monahan, Mary-Katherine, Dumas, Jacques, Natero, Reina, Smith, Roger, Renick, Joel, Riedl, Bernd, Khire, Uday, Scott, William, Wood, Jill, Sibley, Robert
• Granted Patent: US 7,897,623 B2
• Time in Patent Office: Days
• US Class Current: 514/237.8
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/24 having an amino or nitro group
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4453 only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/535 having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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 35/00 Antineoplastic agents
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to the use of a group of aryl ureas in treating p38 mediated diseases, and pharmaceutical compositions for use in such therapy.

Claims

1-38. -38. (canceled)

39. A method of treating a condition mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a 5 or 6 membered cyclic structure bound directly to D, L¹ comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and

each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur other than phenyl,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R_x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷, —

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷, with R⁷ as defined above.

40. A method as in claim 39 for the treatment of a disease other than cancer.

41. A method as in claim 39 wherein the condition within a host treated by administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system.

44. A method of claim 39 wherein L¹ is substituted by —

C(O)R_x or —

SO₂R_x, wherein R_x is NR_aR_b.

45. A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L¹ comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and

each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur other than phenyl,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R_x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷—

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷; and

wherein M is one or more bridging groups selected from the group consisting of —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O—

(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, X^a is halogen and R⁷ is as defined above.

46. A method of claim 45 for treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a substituted or unsubstituted phenyl or pyridine moiety bound directly to D, L¹ comprises a substituted phenyl or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and

B is a substituted or unsubstituted pyridine group bound directly to D,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R^x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷, —

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷;

with R⁷ is as defined above; and

wherein M is one or more bridging groups selected from the group consisting of —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O—

(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, X^a is halogen and R⁷ is as defined above.

47. A method of treating a condition mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a 5 or 6 membered cyclic structure bound directly to D, L¹ comprises a substituted cyclic moiety having at least 5 members other than pyridyl, M is a bridging group having at least one atom, q is an integer of from 1-3; and

each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur other than phenyl,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R_x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen; and

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷, —

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷, with R⁷ as defined above.

48. A method as in claim 47 for the treatment of a disease other than cancer.

49. A method as in claim 47 wherein the condition within a host treated by administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system.

52. A method of claim 47 wherein L¹ is substituted by —

C(O)R_x or —

SO₂R_x, wherein R_x is NR_aR_b.

55. A method as in claim 47 wherein the compound of formula I is N-(5-tert-butyl-2-methoxyphenyl)-N′

-(4-(4-methoxy-3-(N-methylcarbamoyl)phenoxy)phenyl) urea and its pharmaceutically acceptable salts.

53. A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L¹ comprises a substituted cyclic moiety having at least 5 members other than pyridyl, M is a bridging group having at least one atom, q is an integer of from 1-3; and

each cyclic structure of L and L¹ contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and

B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur other than phenyl,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R_x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷, —

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷; and

wherein M is one or more bridging groups selected from the group consisting of —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O—

(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, X^a is halogen and R⁷ is as defined above.

54. A method of claim 53 for treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I:

A-D-B 

 

(I)

or a pharmaceutically acceptable salt thereof, wherein

D is —

NH—

C(O)—

NH—

,

A is a substituted moiety of up to 40 carbon atoms of the formula;

-L-(M-L¹)_q, where L is a substituted or unsubstituted phenyl or pyridine moiety bound directly to D, L¹ comprises a substituted phenyl or pyrimidinyl moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and

B is a substituted or unsubstituted pyridine group bound directly to D,

wherein L¹ is substituted by at least one substituent selected from the group consisting of —

SO₂R_x, —

C(O)R^x and —

C(NR_y)R_z,

R_y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo;

R_z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

R_x is R_z or NR_aR_b where R_a and R_b are

a) independently hydrogen,

a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen, or

—

OSi(R_f)₃ where R_f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

b) R_a and R_b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

or

c) one of R_a or R_b is —

C(O)—

, a C₁-C₅ divalent alkylene group or a substituted C₁-C₅ divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted C₁-C₅ divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen;

where B is substituted, L is substituted or L¹ is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3;

wherein each W is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)NR⁷R⁷, —

C(O)—

R⁷, —

NO₂, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents independently selected from the group consisting of —

CN, —

CO₂R⁷—

C(O)R⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NR⁷R⁷, —

NO₂, —

NR⁷C(O)R⁷, —

NR⁷C(O)OR⁷ and halogen up to per-halo;

with each R⁷ independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen,

wherein Q is —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m—

, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, and X^a is halogen;

Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Z_n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of —

CN, —

CO₂R⁷, —

C(O)R⁷, —

C(O)NR⁷R⁷, —

NO₂, —

OR⁷, —

SR⁷—

NR⁷R⁷, —

NR⁷C(O)OR⁷, —

NR⁷C(O)R⁷, and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and O and optionally substituted by one or more substituents selected from the group consisting of —

CN, —

CO₂R⁷, —

COR⁷, —

C(O)NR⁷R⁷, —

OR⁷, —

SR⁷, —

NO₂, —

NR⁷R⁷, —

NR⁷C(O)R⁷, and —

NR⁷C(O)OR⁷;

with R⁷ is as defined above; and

wherein M is one or more bridging groups selected from the group consisting of —

O—

, —

S—

, —

N(R⁷)—

, —

(CH₂)_m, —

C(O)—

, —

CH(OH)—

, —

(CH₂)_mO—

, —

(CH₂)_mS—

, —

(CH₂)_mN(R⁷)—

, —

O—

(CH₂)_m—

CHX^a—

, —

CX^a₂—

, —

S—

(CH₂)_m— and

—

N(R⁷)(CH₂)_m—

, where m=1-3, X^a is halogen and R⁷ is as defined above.